Guzy wilmsa – Patofizjologia i mechanizm

Guzy wilmsa
Patofizjologia i mechanizm

Guz Wilmsa (nephroblastoma) jest najczęstszym nowotworem nerki u dzieci, wywodzącym się z zaburzeń embriologicznego rozwoju układu moczowo-płciowego. Patogeneza obejmuje mutacje genów supresorowych i onkogenów, takich jak WT1 (mutacje w 10-20% przypadków), CTNNB1, AMER1 (15-30%), TP53 (głównie w guzach anaplastycznych), TRIM28 (5%) oraz NYNRIN (6,6% w guzach obustronnych). Kluczową rolę odgrywają także mutacje genów przetwarzających mikroRNA (DROSHA, DGCR8, DICER1, XPO5), które zaburzają ekspresję supresorowych mikroRNA, np. rodziny LET7. Zmiany epigenetyczne, zwłaszcza utrata imprintingu (LOI) na locus 11p15, występują w około 69% przypadków, prowadząc do nadekspresji IGF2 i deregulacji genów H19. Hipermetylacja H19/ICR1 jest mechanizmem predysponującym do obustronnych guzów Wilmsa. Guzy często rozwijają się z reszt nefrogennych, które występują u 1% niemowląt i są obecne w 40% guzów, a w 90-100% przypadków obustronnych nowotworów. Patogeneza obejmuje aktywację szlaków sygnałowych Wnt/β-katenina, IGF, mTOR/ERK, kalcyneuryny, ERBB, Notch oraz PI3K/AKT, co prowadzi do proliferacji i zahamowania różnicowania komórek nowotworowych.

Patogeneza Guzów Wilmsa

Guz Wilmsa (nephroblastoma) jest najczęstszym nowotworem nerki występującym u dzieci. To embrionalny nowotwór wywodzący się z pierwotnego pączka nerkowego, który rozwija się w wyniku zaburzeń w normalnym rozwoju embriologicznym układu moczowo-płciowego. Pomimo znaczących postępów w leczeniu i zrozumieniu biologii tego nowotworu, jego dokładna patogeneza wciąż pozostaje nie w pełni wyjaśniona¹².

Podłoże genetyczne guzów Wilmsa

Guzy Wilmsa można podzielić na dwie główne kategorie: sporadyczne (około 95% przypadków) i dziedziczne (około 5% przypadków). Patogeneza guza Wilmsa jest złożona i obejmuje liczne zmiany genetyczne i epigenetyczne¹².

Główne geny związane z patogenezą guzów Wilmsa to:

WT1 – gen supresorowy zlokalizowany na chromosomie 11p13, kodujący czynnik transkrypcyjny zaangażowany we wczesne etapy rozwoju embriologicznego nerki. Mutacje WT1 występują w około 10-20% sporadycznych guzów Wilmsa¹².
CTNNB1 – gen kodujący β-kateninę, onkogen zaangażowany w szlak sygnałowy Wnt. Mutacje tego genu często współwystępują z mutacjami WT1¹².
AMER1 (WTX) – gen supresorowy występujący na chromosomie X, inaktywowany w około 15-30% guzów Wilmsa¹.
TP53 – mutacje tego genu obserwuje się głównie w guzach anaplastycznych i są one związane z gorszym rokowaniem¹².
TRIM28 – gen związany z predyspozycją do guza Wilmsa, występuje w około 5% przypadków, zwłaszcza w obustronnych guzach¹.
NYNRIN – gen predysponujący do guza Wilmsa, występuje w około 6,6% przypadków obustronnych guzów¹.

Istotną rolę odgrywają również geny zaangażowane w przetwarzanie mikroRNA, takie jak DROSHA, DGCR8, DICER1 i XPO5, których mutacje mogą prowadzić do powstania guza Wilmsa poprzez zaburzenie ekspresji mikroRNA o właściwościach supresorowych, w tym rodziny LET7¹².

Zmiany epigenetyczne w patogenezie guzów Wilmsa

Zmiany epigenetyczne odgrywają kluczową rolę w patogenezie guzów Wilmsa, szczególnie w obrębie chromosomu 11p15¹. Wśród najważniejszych zaburzeń epigenetycznych wymienia się:

Utrata imprintingu (LOI) na locus 11p15, wpływająca na ekspresję genów IGF2 i H19. Występuje w około 69% guzów Wilmsa, czy to przez zyskanie metylacji w regionie kontrolującym imprinting H19 (H19-ICR, 37% przypadków), czy przez jednorodzicielską disomię paternas (32% przypadków)¹.
Hipometylacja regionów międzygenowych – jedna z najwcześniejszych zmian epigenetycznych w kancerogenezie, związana z lepszym rokowaniem u pacjentów¹.
Hipermetylacja locus H19 – występuje w około 58% klonalnych ekspansji poprzedzających rozwój guza¹.

Wykazano, że hipermetylacja H19/ICR1 w locus 11p15.5 to częsty mechanizm predyspozycji do obustronnych guzów Wilmsa. Jest to zdarzenie postyzgotyczne, które może powodować ekspansję klonalną histologicznie normalnych komórek nerkowych podczas rozwoju nerki, a następnie prowadzić do rozwoju obustronnych i wieloogniskowych guzów¹².

Reszty nefrogenne jako prekursory guzów Wilmsa

Guzy Wilmsa często rozwijają się z tzw. reszt nefrogennych (nephrogenic rests), które są pozostałościami tkanki embrionalnej nerki utrzymującymi się po urodzeniu¹². Reszty nefrogenne mogą występować u około 1% niemowląt, ale zwykle zanikają w dzieciństwie¹.

Reszty nefrogenne można podzielić na dwa główne typy:

Reszty okołopłatowe (PLNR, perilobar nephrogenic rests) – znajdują się na obwodzie płata nerkowego i są związane z utratą imprintingu na locus 11p15 oraz z nadekspresją IGF2¹.
Reszty śródpłatowe (ILNR, intralobar nephrogenic rests) – związane z tzw. guzami Wilmsa typu 1, charakteryzującymi się młodszym wiekiem zachorowania, dominacją podścieliska, inaktywacją genu WT1 i aktywacją β-kateniny¹.

Obecność reszt nefrogennych jest szczególnie istotna w przypadku obustronnych guzów Wilmsa, gdzie stwierdza się je w 90-100% przypadków, w porównaniu do 28-40% przypadków jednostronnych guzów¹. W co najmniej 40% przypadków guzów Wilmsa u pacjentów można zidentyfikować reszty nefrogenne¹.

Szlaki sygnałowe w patogenezie guzów Wilmsa

W patogenezie guzów Wilmsa uczestniczy kilka kluczowych szlaków sygnałowych, których zaburzenia przyczyniają się do rozwoju nowotworu¹²:

Szlak Wnt/β-katenina

Szlak Wnt/β-katenina odgrywa kluczową rolę w patogenezie guzów Wilmsa. Jest on często aktywowany w tych nowotworach, co prowadzi do nadmiernej proliferacji komórek¹. Guzy Wilmsa z mutacją WT1 charakteryzują się aktywacją szlaku Wnt poprzez aktywujące mutacje w genie CTNNB1 kodującym β-kateninę¹.

W guzach Wilmsa związanych z zespołem Beckwitha-Wiedemanna (BWS) obserwuje się nadekspresję dzikiego typu CTNNB1, z szerokim zakresem interakcji CTNNB1 z genami innych szlaków sygnałowych, co sugeruje unikalną sygnaturę sygnalizacji Wnt napędzaną przez nadekspresję CTNNB1¹.

Szlak sygnałowy IGF

Szlak sygnałowy insulinopodobnego czynnika wzrostu (IGF) odgrywa istotną rolę w patogenezie guzów Wilmsa, szczególnie tych związanych z zaburzeniami epigenetycznymi w locus 11p15¹. Zwiększona ekspresja IGF2 w wyniku utraty imprintingu prowadzi do aktywacji szlaku sygnałowego insuliny w komórce¹.

Badania wykazały, że:

Nadekspresja IGF2 jest najbardziej powszechną aberracją somatyczną w guzach Wilmsa (około 70% przypadków)¹.
Zwiększona ekspresja transkryptu INS-IGF2 w tkankach nowotworowych pacjentów z nawrotem choroby jest 20-krotnie wyższa w porównaniu do pacjentów z całkowitą remisją¹.
Niska metylacja w regionach DMR0 i DMR2 jest prawdopodobną przyczyną zwiększonej ekspresji transkryptu fuzyjnego INS-IGF2¹.

Inne szlaki sygnałowe

W patogenezie guzów Wilmsa zaangażowane są również inne szlaki sygnałowe, takie jak¹²:

mTOR/ERK – szlak zaangażowany w regulację wzrostu, proliferacji i przeżycia komórek¹.
Szlak kalcyneuryny – bierze udział w regulacji ekspresji genów i aktywacji komórek¹.
Szlak ERBB – wzmożona aktywacja tego szlaku jest ściśle związana z rozwojem i progresją guzów Wilmsa. CCT4 może hamować szlak sygnałowy ERBB, zwiększać apoptozę i zmniejszać zdolność komórek nowotworowych do inwazji i przerzutów¹.
Szlak Notch – miR-539 hamuje progresję guzów Wilmsa poprzez obniżenie regulacji JAG1 i Notch1/3¹.
Szlak PI3K/AKT – miRNA-140-5p uczestniczy w progresji guzów Wilmsa poprzez celowanie w szlaki sygnałowe TGFBRI/SMAD2/3 i IGF-1R/AKT¹.

Modelowanie molekularne guzów Wilmsa

Na podstawie profili ekspresji genów i cech molekularnych, guzy Wilmsa można podzielić na kilka podtypów¹²:

Klasyfikacja histologiczna

Guzy Wilmsa można podzielić na dwie główne kategorie histopatologiczne¹²:

Guzy o korzystnej histologii (favorable histology) – zawierające dobrze rozwinięte składniki nowotworowe, stanowiące około 90% wszystkich przypadków, z 5-letnim przeżyciem powyżej 90%¹.
Guzy anaplastyczne (anaplastic histology) – charakteryzujące się obecnością atypowych, wielobiegunowych figur mitotycznych, znacznym powiększeniem jąder (co najmniej 3-krotnie) i hiperchromatycznością. Anaplazja jest związana ze słabą odpowiedzią na leczenie i gorszym rokowaniem¹.

Anaplazję można podzielić na ogniskową (focal anaplasia) – ograniczoną do pierwotnego wewnątrznerkowego guza, oraz rozlaną (diffuse anaplasia) – rozszerzającą się poza torebkę guza, przy czym ta druga wiąże się z gorszym rokowaniem¹².

Klasyfikacja molekularna

Na podstawie cech molekularnych, guzy Wilmsa można podzielić na dwa główne typy¹:

Typ 1 – charakteryzuje się młodszym wiekiem zachorowania, dominacją podścieliska w obrazie histologicznym, obecnością śródpłatowych reszt nefrogennych, inaktywacją genu WT1 i aktywacją β-kateniny.
Typ 2 – charakteryzuje się starszym wiekiem zachorowania, obecnością okołopłatowych reszt nefrogennych i deregulacją IGF2.

Podział ten jest jednak znacznym uproszczeniem złożoności molekularnej guzów Wilmsa¹.

Badania pokazują również, że guzy Wilmsa z rozlaną anaplazją wykazują znacznie bardziej złożone filogenety w porównaniu z guzami bez rozlanej anaplazji, w tym cechy ewolucji skokowej i równoległej¹².

Mechanizmy molekularne w patogenezie guzów Wilmsa

Nieprawidłowości chromosomowe

W guzach Wilmsa często obserwuje się utratę heterozygotyczności (LOH) w kilku regionach chromosomowych, co wiąże się z gorszym rokowaniem¹:

LOH na chromosomach 1p i 16q – związane z wyższym ryzykiem nawrotu choroby i gorszym rokowaniem¹².
LOH na chromosomie 11p15 – często obserwowane jako mechanizm utraty pozostałego normalnego allelu WT1¹.
Zysk 1q – występuje w około 30% guzów i jest markerem nawrotu guza¹.

Ponadto w guzach Wilmsa często obserwuje się zyski całych i częściowych chromosomów 1q, 2, 7q, 8, 12, 13 oraz utraty chromosomów 1p, 7p, 16q i 22q¹.

Zaburzenia mikroRNA

MikroRNA (miRNA) odgrywają istotną rolę w patogenezie guzów Wilmsa poprzez regulację ekspresji genów i progresji nowotworu¹. Są one modulowane podczas wczesnego rozwoju nerki i zaangażowane w regulację szlaków biologicznych, takich jak PI3K, Wnt, TGF-β i Hippo¹.

Badania wykazały, że:

miRNA-140-5p uczestniczy w progresji guzów Wilmsa poprzez celowanie w szlaki sygnałowe TGFBRI/SMAD2/3 i IGF-1R/AKT¹.
miR-483-5p hamuje proliferację komórek guzów Wilmsa poprzez indukcję apoptozy przez cel MKNK1¹.
miR-539 hamuje progresję guzów Wilmsa poprzez obniżenie regulacji JAG1 i Notch1/3¹.

Mutacje w genach przetwarzających miRNA, takich jak DROSHA i DICER1, wpływają na przetwarzanie miRNA poprzez odmienne mechanizmy: mutacje RNazy IIIB DICER1 preferują upośledzenie przetwarzania miRNA pochodzących z ramienia 5-prime pre-miRNA, podczas gdy mutacje RNazy IIIB DROSHA globalnie hamują biogenezę miRNA poprzez mechanizm dominująco-negatywny¹.

Zmiany w czynnikach transkrypcyjnych

Białko WT1 pełni podwójną rolę w nowotworach – może działać zarówno jako gen supresorowy, jak i onkogen, w zależności od kontekstu¹². Ostatnie badania wykazały nową rolę WT1 w regulacji programów epigenetycznych w komórkach białaczkowych poprzez interakcję z białkami TET¹.

Innym ważnym czynnikiem jest STAT3, który wykazuje wielowymiarowe efekty w guzach Wilmsa. Na przykład, IL-6-aktywowany STAT3 może hamować ekspresję WTX¹.

Ostatnie badania odkryły również nowy mechanizm w patogenezie guzów Wilmsa związany z białkiem ENL. Zmutowane białko ENL grupuje się w miejscach wiązania DNA, powodując ciągłą transkrypcję genów do RNA, co prowadzi do zaburzenia różnicowania komórek nerki i ich zatrzymania w niedojrzałym stadium, co sprzyja rozwojowi guza¹².

Znaczenie kliniczne mechanizmów patogenetycznych

Zrozumienie mechanizmów patogenetycznych guzów Wilmsa ma istotne znaczenie kliniczne, szczególnie w kontekście stratyfikacji ryzyka, identyfikacji nowych biomarkerów i opracowania celowanych terapii¹.

Stratyfikacja ryzyka

Na podstawie cech molekularnych można wyodrębnić czynniki prognostyczne związane z gorszym rokowaniem¹²:

Histologia anaplastyczna w guzach w stadium II-IV, przy czym rozlana anaplazja jest gorsza niż ogniskowa¹.
Utrata heterozygotyczności na chromosomach 1p, 1q, 11p15 i 16q¹.
Obecność mutacji TP53¹.
Starszy wiek w momencie diagnozy¹.
Niepełna odpowiedź na początkowe leczenie¹.

Biomarkery

Badania identyfikują potencjalne biomarkery prognostyczne i diagnostyczne w guzach Wilmsa:

Zwiększona ekspresja INS-IGF2 jest związana z nawrotem choroby¹.
Trzy sondy CpG (cg15822093, cg07086381 i cg21987076) korelują z czasem do nawrotu choroby¹.
EMCN i CCNA1 zidentyfikowano jako kluczowe markery prognostyczne w guzach Wilmsa, sugerujące ich potencjał jako celów terapeutycznych¹.
CCT4 może być obiecującym biomarkerem guzów Wilmsa¹.

Potencjalne cele terapeutyczne

Zrozumienie patogenezy guzów Wilmsa pozwala na identyfikację potencjalnych celów terapeutycznych¹²:

IGF1R – ze względu na nadekspresję IGF2 w guzach Wilmsa, celowanie w IGF1R wydaje się uzasadnione, choć należy wziąć pod uwagę, że nowotwory mogą przezwyciężyć zależność od szlaku IGF¹.
EMCN – którego obniżona regulacja w guzach Wilmsa jest związana z gorszym rokowaniem¹.
CCNA1 – którego nadekspresja może ułatwiać progresję cyklu komórkowego i proliferację, a jego rola w oporności na apoptozę może zwiększać przeżycie i wzrost guza¹.
ENL – interwencje zakłócające zdolność ENL do wiązania się z genomem lub do tworzenia skupisk mogą stabilizować poziomy ekspresji genów i umożliwiać normalne różnicowanie komórek¹.

Badania na inhibitorach deacetylazy histonów, takich jak LBH589 (Panobinostat), wykazały aktywność przeciwnowotworową w liniach komórkowych guzów Wilmsa poprzez indukcję apoptozy i hamowanie proliferacji komórek¹².

Związek z zespołami predysponującymi

Guzy Wilmsa mogą występować w skojarzeniu z różnymi wrodzonymi zespołami i anomaliami, które zwiększają ryzyko rozwoju tego nowotworu¹².

Zespół WAGR

Zespół WAGR (Wilms tumor, Aniridia, anomalie układu moczowo-płciowego, niepełnosprawność intelektualna) jest związany z delecją w regionie chromosomu 11p13, obejmującą gen WT1¹².

Zespół Denysa-Drasha

Zespół Denysa-Drasha charakteryzuje się mutacjami zarodkowymi w genie WT1, prowadzącymi do rozwoju guzów Wilmsa, dysgenezji gonad i nefropatii. Ryzyko rozwoju guza Wilmsa u dzieci z tym zespołem wynosi około 90%, a obustronna choroba rozwija się u 20% pacjentów¹.

Zespół Beckwitha-Wiedemanna

Zespół Beckwitha-Wiedemanna (BWS) jest związany z defektami w locus WT2 (11p15) i charakteryzuje się przerostem języka, wątroby, nerek i innych narządów¹². Dzieci z BWS mają zwiększone ryzyko rozwoju guzów Wilmsa¹.

Badania molekularne wykazały, że guzy Wilmsa związane z BWS wykazują pojedyncze warianty nukleotydowe w genach BCORL1, ASXL1, ATM i AXL, ale brak powtarzających się mutacji genowych związanych ze sporadycznymi guzami Wilmsa¹.

Inne anomalie

Guz Wilmsa występuje również w skojarzeniu z¹:

Hemihypertrofią (asymetryczny przerost ciała)
Aniridzią (brak tęczówki oka)
Anomaliami urologicznymi, takimi jak wnętrostwo, nerka podkowiasta i spodziectwo

Obecność jakiejkolwiek izolowanej cechy przerostu była związana z ryzykiem rozwoju raka¹.

Najnowsze kierunki badań

Obecne badania nad patogenezą guzów Wilmsa koncentrują się na kilku obiecujących kierunkach¹:

Analiza wielowymiarowych mechanizmów dysfunkcji, obejmujących geny związane z chorobą, czynniki transkrypcyjne i niekodujące RNA¹.
Badanie roli polimorfizmów genetycznych w podatności na guzy Wilmsa, w tym polimorfizmów FOXP3 i CXCL12¹².
Zrozumienie mechanizmów epigenetycznych, zwłaszcza zmian metylacji DNA, które mogą służyć jako biomarkery prognostyczne¹.
Badanie różnic międzyetnicznych w charakterystyce klinicznej, patologicznej i molekularnej guzów Wilmsa¹.
Rozwój ukierunkowanych terapii opartych na zrozumieniu szlaków sygnałowych zaangażowanych w patogenezę guzów Wilmsa¹.

Wyniki tych badań mogą przyczynić się do opracowania nowych strategii diagnostycznych, prognostycznych i terapeutycznych w leczeniu guzów Wilmsa¹.

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Materiały źródłowe

#1 Wilms Tumor: Updates about Pathogenesis and New Possible Clinical Treatments of the Most Frequent Pediatric Urogenital Cancer: A Narrative Review
https://www.mdpi.com/2673-4095/4/4/64
Wilms tumor (or nephroblastoma) is a malignant and solid neoplasm that derives from the primitive renal bud. […] Most scientific literature agrees that Wilms tumor develops as a result of a genetic mutation. The implicated gene is called WT1 (from âWilms Tumorâ) and is a tumor suppressor. The WT1 gene has been located on the short arm of chromosome 11 at position 11p13 and encodes a protein involved in the early stages of embryological development of the kidney (nephroblast differentiation). […] Other mutations are implicated in Wilmsâ tumor, such as the inactivation of the WTX gene located on the short arm of chromosome 11 at position 11p15, deletion of WT2 and loss of the heterozygosity of 16q and 1p, as well as the TP53 mutation being associated with a worse prognosis. […] Gene expression profiling revealed that WT cell lines are highly human mesenchymal stem cells (MSCs), and FACS analysis demonstrated the expression of MSC-specific surface proteins CD105, CD90 and CD73.
#1 Wilms Tumour | Cancer Genetics Web
http://www.cancerindex.org/geneweb/X210202.htm
The vast majority (~95%) of Wilms tumors are sporadic; – not due to inherited genetic alterations, but rather developing as a result of genetic alterations that occur in just a few cells in the body. […] The WT1 gene located at 11p13 was identified in 1989, however, only about a third of patients carry detectable mutations. Thus the development of Wilms’ tumour is complex and is likely to involve several other genetic loci. A number of other genes on chromosome 11p have also been implicated in Wilms’ tumour, including the putative WT2 gene (11p15). Loci at 1p, 7p, 16q, 17p, and 19q (the putative FWT2 gene) are also implicated. […] Several genetic and epigenetic factors have been found to account for the development of Wilms’ tumor. […] We demonstrated that miRNA-140-5p participates in the progression of Wilms’ tumor by targeting the TGFBRI/SMAD2/3 and the IGF-1R/AKT signaling pathways.
#1 Wilms’ tumor – Wikipedia
https://en.wikipedia.org/wiki/Wilms%27_tumor
The mesenchymal component may include cells showing rhabdomyoid differentiation or malignancy (rhabdomyosarcomatous Wilms). […] Wilms’ tumors may be separated into two prognostic groups based on pathologic characteristics: Favorable contains well developed components mentioned above; Anaplastic contains diffuse anaplasia (poorly developed cells). […] Mutations of the WT1 gene which is located on the short arm of chromosome 11 (11p13) are observed in approximately 20% of Wilms’ tumors, the majority of them being inherited from the germline, while a minority are acquired somatic mutations. In addition at least half of the Wilms’ tumors with mutations in WT1 also carry acquired somatic mutations in CTNNB1, the gene encoding the proto-oncogene beta-catenin.
#1 Wilmsâ tumour: biology, diagnosis and treatment – Szychot – Translational Pediatrics
https://tp.amegroups.org/article/view/3228/html
The WT1 gene is inactivated, usually by inactivating deletion or point mutation in 10-20% of sporadic Wilms tumors. The IGF2 locus is deregulated in 30-69% of tumors through loss of imprinting resulting in IGF2 expression or somatic loss of the maternal allele and duplication of the paternal allele. Other genes implicated in Wilms pathogenesis include the WTX gene which is inactivated in 15-30% of sporadic tumors, FBXW7 and MYCN. […] Attempts have been made to sub-classify Wilms tumors based on their molecular pathogenesis; so called type 1 tumors are characterised by a younger age of diagnosis, stromal predominant histology, the presence of intra-lobar nephrogenic rests, inactivation of the WT1 gene and activation of beta catenin. In contrast so called type 2 are characterised by an older age at diagnosis, the presence of perilobar nephrogenic rests and deregulation of IGF2, though in reality such a dichotomy is likely a simplification.
#1 Wilms Tumor – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK442004/
Even with „Favorable” histology, the loss of heterozygosity at 1p and 16q loci tend to have a worse prognosis. […] Anaplasia is histologically defined as hyperchromatic, pleomorphic nuclei that are three times larger than adjacent cells and have abnormal mitotic figures. Anaplasia is associated with a poor response to treatment. […] A poorer prognosis is associated with the following characteristics: Anaplastic histology in stage II to IV tumors, Diffuse anaplasia is worse than focal, Loss of heterozygosity at chromosomes 1p, 1q, 11p15, and 16q or presence of TP53.
#1 Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Childrenâs Oncology Group AREN18B5-Q | Nature Communications
https://www.nature.com/articles/s41467-023-43730-0
Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. […] We determine the predominant events for bilateral Wilms tumor predisposition: 1) pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2) post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. […] Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition. […] BWT development is highly suggestive of an underlying genetic or epigenetic predisposition. […] Known genetic variants associated with unilateral WT, including germline pathogenic variants in WT1 and somatic pathogenic variants in CTNNB1, are thought to occur with increased frequency in BWT.
#1
https://omim.org/entry/194070
Miyagawa et al. (1998) focused on the ectopic formation of skeletal muscle in Wilms tumors. They presented evidence supporting a negative regulatory role for WT1 in myogenesis. Their findings suggested that the metanephric-mesenchymal stem cells of the kidney may have the capacity to differentiate into skeletal muscle cells as well as epithelial cells. Normally, the expression of WT1 appears to prevent this ectopic differentiation program from being activated. In vitro studies suggested that WT1 may play a direct role in suppressing the formation of skeletal muscle. […] Rakheja et al. (2014) reported the whole-exome sequencing of 44 Wilms tumors, which identified missense mutations in the microRNA (miRNA)-processing enzymes DROSHA (608828) and DICER1 (606241), and novel mutations in MYCN (164840), SMARCA4 (603254), and ARID1A (603024). Examination of tumor miRNA expression, in vitro processing assays, and genomic editing in human cells demonstrated that DICER1 and DROSHA mutations influence miRNA processing through distinct mechanisms. DICER1 RNase IIIB mutations preferentially impair processing of miRNAs deriving from the 5-prime arm of pre-miRNA hairpins, while DROSHA RNase IIIB mutations globally inhibit miRNA biogenesis through a dominant-negative mechanism. Both DROSHA and DICER1 mutations impair expression of tumor-suppressing miRNAs, including the LET7 family (see 605386), which are important regulators of MYCN, LIN28 (see 611043), and other Wilms tumor oncogenes. Rakheja et al. (2014) concluded that these results provided insights into the mechanisms through which mutations in miRNA biogenesis components reprogram miRNA expression in human cancer and suggested that these defects define a distinct subclass of Wilms tumors.
#1 Methylation changes and INS-IGF2 expression predict progression in early-stage Wilms tumor | Clinical Epigenetics | Full Text
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-024-01775-y
Wilms tumor, the most common pediatric kidney cancer, accounts for 5% of childhood cancers and is classified by stage and histological subtype. […] Epigenetic changes, particularly DNA methylation, play a critical role in Wilms tumor pathogenesis. […] The analysis revealed hypomethylation in intergenic regions in remission patients, identifying 14 differentially methylated positions as potential biomarkers. Increased INS-IGF2 expression was associated with relapse, suggesting its role in disease progression. […] Similar to other cancers, requiring multiple hits, several genetic and epigenetic changes were identified to be involved in WT etiology. […] One of the earliest identified epigenetic hallmarks of cancer is the hypomethylation of repetitive regions across the entire genome. […] Aberrant DNA methylation is an early event in tumorigenesis, occurring not only in cancerous tissues but also in abnormal non-neoplastic tissues.
#1 The IGF signalling pathway in Wilms tumours – A report from the ENCCA Renal Tumours Biology-driven drug development workshop | Oncotarget
https://www.oncotarget.com/article/2485/text/
Of the known epimutations in WT, epigenetic aberration at 11p15 has received the most attention due to its association with Beckwith-Wiedemann Syndrome (BWS), a paediatric overgrowth disorder with germline gain of methylation at 11p15 and functional relationship with expression of imprinted genes IGF2 and H19. […] Specifically, LOI of IGF2 and H19 is seen in ~69% WT either by gain of methylation at the H19-ICR (37%) or by paternal UPD (32%). […] The H19-ICR (which regulates expression of paternally imprinted IGF2 and maternally imprinted H19) contains differentially methylated domains (DMD) and is located between IGF2 and H19. […] Clinically, WT with LOI at 11p15 are associated with perilobar nephrogenic rests (PLNRs), lesions of retained embryonic renal tissue found towards the periphery of the renal lobe, and with blastemal or epithelial-predominant WTs and show increased expression of IGF2.
#1
https://omim.org/entry/194070
To investigate whether Wilms tumor develops from a premalignant background, Coorens et al. (2019) examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), they found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. Coorens et al. (2019) also found hypermethylation of the H19 locus (103280), a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. Coorens et al. (2019) concluded that their findings revealed embryonal precursors from which unilateral and multifocal cancers develop.
#1 Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Childrenâs Oncology Group AREN18B5-Q | Nature Communications
https://www.nature.com/articles/s41467-023-43730-0
Recent studies have suggested that BWT predisposition in some patients is due to post-zygotic somatic mosaic hypermethylation at H19/ICR1, which results in clonal expansion of histologically normal renal cells during kidney development (clonal nephrogenesis) and subsequent bilateral and multifocal WT development. […] We hypothesize that paired synchronous BWT specimens will exhibit shared genetic or epigenetic predisposing molecular events, while also harboring secondary somatic variants unique to each tumor. […] This study provides a comprehensive assessment of the genetic and epigenetic features of predisposition for BWT, the most common of which is somatic mosaic 11p15.5 H19/ICR1 hypermethylation (LOI), which is shared among synchronous BWT samples and often detectable in adjacent non-diseased kidney.
#1 Wilms Tumor – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK442004/
The cause of Wilms tumor is not precisely known, but it is believed to be due to genetic alterations that deal with the normal embryological development of the genitourinary tract. Some of the genetic markers that have been associated with Wilms tumor include WT1, CTNNB1, and WTX gene alterations that have been found in about 1/3 of all Wilms tumors. […] A poorer prognosis has been linked to TP53 and with the loss of heterozygosity at chromosomes 1p, 1q, 11p15, and 16q. […] Wilms is thought to develop from persistent metanephric tissue or nephrogenic rests. These may occur in 1% of infantile kidneys but typically regress during childhood. […] Hemihypertrophy and aniridia as well as a variety of urological disorders like cryptorchidism, horseshoe kidney, and hypospadias, are associated with the malignancy although it is unlikely they play any role in actual carcinogenesis.
#1 Inter-Ethnic Variations in the Clinical, Pathological, and Molecular Characteristics of Wilms Tumor
https://www.mdpi.com/2072-6694/16/17/3051
The presence of nephrogenic rests (NRs) is also known to be associated with bilateral Wilms tumors, which have a poorer prognosisâapproximately 28 to 40% of unilateral Wilms tumors are associated with NR, compared to 90 to 100% of bilateral Wilms tumors. […] The low frequency of NRs in Asian patients with sporadic Wilms tumors appears to be congruent with the similarly low frequency of bilateral Wilms tumors.
#1 Wilmsâ tumour: biology, diagnosis and treatment – Szychot – Translational Pediatrics
https://tp.amegroups.org/article/view/3228/html
Wilms tumors can be observed to develop within a proportion of nephrogenic rests and in 40% of Wilms tumor patients nephrogenic rest can be identified. […] Nephrogenic rests are thought to be the precursor lesions of Wilms tumors. Rests may have a variety of fates, many will become obsolescent and disappear, however, a proportion will become proliferative and may undergo neoplastic transformation into a Wilms tumor. Each stage of progression is thought to result from the acquisition of stable somatic changes, either in the form of genetic mutation or epimutation. […] In 1972 Knudson proposed a two hit model of Wilms tumorigenesis similar to his earlier model of retinoblastoma. This has subsequently been found not to be the case with a diverse range of genes and mechanisms implicated in Wilms pathogenesis.
#1 Investigating the dysfunctional pathogenesis of Wilms’ tumor through a multidimensional integration strategy
https://atm.amegroups.org/article/view/24808/html
Wilms tumor (WT) is a common kidney tumor in early childhood which is characterized by multiple congenital anomalies and syndromes. However, its molecular mechanism is still elusive. […] By integrating the potential pathogenic genes of kidney cancer and performing co-expression analysis on the disease-related genes, 23 functional modules were obtained. All the genes were differentially expressed in WT, and were mainly involved in many biological processes and signaling pathways, such as Wnt/-catenin, mTOR/ERK and calcineurin. […] A multidimensional dysfunction mechanism, involving disease-related genes, TFs and ncRNAs was revealed in the pathogenesis of WT. […] Studies have shown that WT is caused by genetic abnormalities, epigenetics, genetic mutations and environmental factors. Multiple studies have identified and confirmed that mutations in the Wilms tumor suppressor gene (WT1) are associated with the pathogenesis of WT.
#1 Investigating the dysfunctional pathogenesis of Wilms’ tumor through a multidimensional integration strategy
https://atm.amegroups.org/article/view/24808/html
Furthermore, in the case of WT, the Wnt/beta-catenin pathway is highly activated which is influenced by AXIN2. […] By combining RNA-seq data, gene co-expression networks and differential expression analysis, dysfunctional co-expression modules were identified. […] In the pathogenesis of genes involved in a disease, their function and pathway are important. […] The KEGG pathway mainly includes Wnt/beta-catenin, JNK cascade and mTOR/ERK signaling pathways, which are involved in the development, progression and prognosis of WT. […] WT is a complex cancer, and the dysfunctional modules of WT are regulated by many factors. […] This study reveals the multidimensional effects of STAT3 in WT, and for instance, IL-6-activated STAT3 can inhibit expression of WTX. […] In summary, this work reveals the multifactor-mediated dysfunctional network and characterizes the potential molecular mechanisms of WT.
#1 Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQÂ®) – NCI
https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq
Approximately one-third of Wilms tumor cases involve variants in WT1, CTNNB1, or AMER1 (WTX). Another subset of Wilms tumor cases results from variants in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5. Other genes critical for early renal development that are recurrently altered in Wilms tumor include SIX1 and SIX2 (transcription factors that play key roles in early renal development). […] Anaplastic Wilms tumor is characterized by the presence of TP53 variants. […] The molecular subtypes of the syndrome predispose patients to the development of different tumor histotypes. […] The presence of any isolated overgrowth feature was associated with the risk of developing cancer. […] Wilms tumor with a WT1 variant is characterized by evidence of WNT pathway activation by activating variants in the CTNNB1 gene. Loss of heterozygosity (LOH) at 11p15 is commonly observed, as paternal uniparental disomy for chromosome 11 represents a common mechanism for losing the remaining normal WT1 allele.
#1 Cancer predisposition signaling in Beckwith-Wiedemann Syndrome drives Wilms tumor development | British Journal of Cancer
https://www.nature.com/articles/s41416-023-02538-x
Given the propensity of BWS patients to develop WT and the fact that at least two-thirds of WT have alterations at 11p15 (either LOH or IC1 GOM), we stratified patients by 11p15 status to study downstream signaling using a multi-omics approach. […] The gene ontology study of DMRs showed that the Wnt signaling pathway played a significant role in BWS-WT and altered-11p15 nonBWS-WT oncogenesis. […] This suggests that BWS-WT may have a dysregulated progenitor cells as a causal agent in disease development and/or progression. […] Overall, we observed upregulation of wildtype CTNNB1 in BWS-WT, with broadest range of CTNNB1 interactions with genes across other signaling pathways. This observation suggests that BWS-WT has a unique signature of Wnt signaling driven by CTNNB1 overexpression which also has a major role in nephron patterning.
#1 The IGF signalling pathway in Wilms tumours – A report from the ENCCA Renal Tumours Biology-driven drug development workshop | Oncotarget
https://www.oncotarget.com/article/2485/text/
It is hypothesised that Wilms tumour (WT) results from aberrant renal development due to its embryonic morphology, associated undifferentiated precursor lesions (termed nephrogenic rests) and embryonic kidney-like chromatin and gene expression profiles. […] From the study of overgrowth syndrome-associated WT, germline dysregulation was identified in the imprinted region at 11p15 affecting imprinted genes IGF2 and H19. This is also detected in ~70% sporadic cases, making this the most common somatic molecular aberration in WT. […] Here, we discuss the subset of WTs with epigenetic aberrations at 11p15 resulting in activation of the IGF signaling pathway and the therapeutic opportunities provided by targeting either the IGF pathway or the epigenome. […] The IGF pathway is comprised of a complex network of molecules stimulated by insulin-like growth factors (IGFs), which are synthesized by almost any tissue in the body and are important mediators of growth, development, and survival including the embryonic kidney.
#1 The IGF signalling pathway in Wilms tumours – A report from the ENCCA Renal Tumours Biology-driven drug development workshop | Oncotarget
https://www.oncotarget.com/article/2485/text/
Increased expression of IGF2 results in activation of the insulin signalling pathway. […] Therefore, in WT, LOI is driving IGF2 overexpression and oncogenic pathway activation in the cell. […] Further supporting IGF pathway disruption in WT, low level copy number increase of IGF1R resulting in aberrant mRNA and protein levels was found in WT, particularly in those with blastemal predominance. […] This showed that although 11p15 defects are one of the most common aberrations in WT, additional events are necessary for WT development. […] Given IGF2 overexpression in WT, targeting IGF1R seems plausible. However, it must be considered that tumours can overcome IGF pathway dependence and therefore combination therapy might be a more effective option, though the effective pathways to be co-inhibited have not yet been defined.
#1 Methylation changes and INS-IGF2 expression predict progression in early-stage Wilms tumor | Clinical Epigenetics | Full Text
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-024-01775-y
We observed a 20-fold higher expression level of INS-IGF2 transcript in tumor tissues of relapse patients when compared to complete remission patients, in contrast with a modest twofold higher expression level of IGF2. […] The loss of methylation at DMR0 and DMR2 is a likely reason for the increased expression of the INS-IGF2 fusion transcript. […] The identification of methylation changes at the chromosome 11 DMR2 and the association with increased INS-IGF2 expression provides mechanistic insights into the molecular mechanisms underlying disease progression.
#1
https://journals.lww.com/md-journal/fulltext/2023/04140/role_of_cct4_erbb_signaling_in_nephroblastoma_.22.aspx
Wilms tumor is a common abdominal malignant tumor in children. However, the molecular mechanism of Wilms tumor is unclear. A total of 925 DEGs were identified. The differently expressed genes were mainly enriched in the metabolic pathway, AMPK signaling pathway, ErbB signaling pathway, mRNA detection pathway, and folded protein binding. CCT4 might play an essential role in the occurrence and development of Wilms tumor, and they may participate in the occurrence and development of Wilms tumor through the ERBB signal pathway. CCT4 may be a promising biomarker of Wilms tumor. The main result of this study is that the expression of CCT4 is low in nephroblastoma. When CCT4 is activated, the ERBB signal pathway is inhibited, the apoptosis is enhanced, the expression of MMP3/9 is downregulated, and cancer cells invasion and metastasis ability is decreased. CCT4 may be involved in the cell cycle, promote apoptosis, and may be involved in the occurrence and development of nephroblastoma through the ERBB signal pathway. The enhanced activation of the ERBB signaling pathway is closely related to the occurrence and development of nephroblastoma. CCT4 interacts with several subunits of pre-folded protein (PFDN). Therefore, it is speculated that the low expression of CCT4 promotes the development of nephroblastoma by regulating cell proliferation. CCT4 might be a promising nephroblastoma biomarker.
#1 Wilms Tumour | Cancer Genetics Web
http://www.cancerindex.org/geneweb/X210202.htm
Our findings suggest that inactivation of TRIM28 early in renal development contributes to the formation of this unique subset of FHWTs, although the precise manner in which TRIM28 impacts both normal renal development and oncogenesis remains elusive. […] MiR-539 inhibited the progression of WT through downregulation of JAG1 and Notch1/3. […] The smallest consensus region of deletion in our analysis of Wilms’ tumor 16q LOH measures 2.4 megabases at 16q23.2-q24.2. […] These observations have led to speculation that DIS3L2-mediated tumor suppression is attributable to let-7 regulation.
#1 Wilms’ tumor pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Wilms%27_tumor_pathophysiology
Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. The changes may be somatic or germline. […] Wilms tumor metastases to the lung are common. […] Based on a study, Wilms tumor is divided into 2 pathologic categories: favorable and anaplastic.
#1 Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQÂ®) – NCI
https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq
The presence of any isolated overgrowth feature was associated with the risk of developing cancer. […] The presence of tumor thrombus in the renal vein and/or inferior vena cava was associated with worse EFS. […] The prognosis for patients with Wilms tumor depends on the following: Histopathological features of the tumor (FH vs. anaplastic histology), stage of disease at diagnosis, molecular features of the tumor such as 1q gain and loss of heterozygosity of 1p and 16q. […] The 5-year survival rate for Wilms tumor with favorable histology (FH) has been consistently greater than 90%.
#1 Our Six-year Wilms Tumor Results: A Single-center Experience – Bagcilar Medical Bulletin
https://www.behmedicalbulletin.org/articles/our-six-year-wilms-tumor-results-a-single-center-experience/doi/BMB.galenos.2025.49469
Wilms tumor (WT) is the most common renal tumor, accounting for approximately 6% of malignancies in infants and children. It is estimated that a germ cell mutation is responsible for about 10-15% of WTs. […] WT is similar to the histology of the developing kidney, and originates from the nephrogenic blastema. Histopathologically, it comprises blastemal, epithelial, and stromal components. The blastema component consists of undifferentiated cells with small and regular nuclei. The epithelial component contains differentiated elements, such as tubules and papillary structures. The stromal component may contain heterologous elements, such as adipose tissue and cartilage. Anaplasia, seen in 7-10% of WTs, is characterized by atypical multipolar mitotic figures, marked nuclear enlargement (at least 3-fold), and hyperchromasia. Anaplasia is divided into focal anaplasia, which is confined to the primary intrarenal tumor, and diffuse anaplasia, which extends beyond the tumor capsule. […] Nephrogenic rest is a precursor lesion of WT originating from various sites, such as blastemal, stromal, and embryonal nephroblastic tissue, and may be confused with other malignant tumors.
#1 Resolving the Pathogenesis of Anaplastic Wilms Tumors through Spatial Mapping of Cancer Cell Evolution | Lund University Publications
https://lup.lub.lu.se/search/publication/10d066e6-4673-4275-abc4-bdcc882e3129
PURPOSE: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors. […] RESULTS: Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments.
#1 Wilms Tumor – Pediatrics – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/pediatrics/pediatric-cancers/wilms-tumor
Wilms tumor is an embryonal cancer of the kidney composed of blastemal, stromal, and epithelial elements. Genetic abnormalities have been implicated in the pathogenesis, but familial inheritance accounts for only 1 to 2% of cases. […] A chromosomal deletion of WT1 (a Wilms tumor suppressor gene) has been identified in some cases. Other associated genetic abnormalities include deletion of WT2 (a second Wilms tumor suppressor gene), loss of heterozygosity (LOH) of 16q and 1p, and inactivation of the WTX gene. Wilms tumor is primarily nonfamilial; only approximately 2% of patients have a family member with the disease. […] Prognosis for Wilms tumor depends on molecular findings (loss of heterozygosity at 1p, 11p15, and 16q, and 1q gain are associated with increased relapse).
#1 Wilms Tumor | Pediatric Surgery NaT
https://www.pedsurglibrary.com/apsa/view/Pediatric-Surgery-NaT/829119/all/Wilms_Tumor
Genetic analysis of tumors from NWTSG have identified specific genetic mutations that have been incorporated into a risk based stratagem which directly impacts patient care. Loss of heterozygosity (LOH) at 1p/16q is a specific marker for increased risk of relapse in favorable histology WT. This finding was studied in the prospective, nonrandomized NWTS-5 trial which established that combined LOH at both chromosomes 1p and 16q was an adverse prognostic indicator for all stages of WT. Although only occurring in five percent of patients, identification of LOH 1p/16q selectively targets these patients for intensification of treatment. […] Subsequent analysis of subsets of very low risk tumors from NWTS-5 have demonstrated that WT1 mutation and 11p15 LOH are associated with relapse and this finding may be incorporated in future clinical trials. Recent COG data indicates that 1q gain occurs in approximately thirty percent of tumors and is a marker for tumor recurrence.
#1 Wilmsâ tumour: biology, diagnosis and treatment – Szychot – Translational Pediatrics
https://tp.amegroups.org/article/view/3228/html
Inactivation of the TP53 gene is found particularly in anaplastic tumors, and in tumors with focal anaplasia may only be inactivated in anaplastic areas. Genetic changes resulting in loss of TP53 function are also the commonest change observed between primary and relapse tumor samples. […] In addition to specific genes implicated in Wilms tumorigenesis, whole and partial chromosomal gains and losses, as well as LOH are commonly seen in Wilms tumors, particularly gains of chromosomes 1q, 2, 7q, 8, 12 13 and losses of chromosomes 1p, 7p, 16q and 22q. […] Further understanding of the molecular pathology and genetic changes in Wilms tumors is hoped to support the development of novel biomarkers to aid diagnosis, risk stratification and monitoring of therapy and relapse.
#1
https://link.springer.com/article/10.1007/s00109-021-02075-1
Non-coding RNAs are involved with maintenance and regulation of physiological mechanisms and are involved in pathological processes, such as cancer. […] Among the small ncRNAs, miRNAs are the most explored in tumorigenesis, metastasis development, and resistance to chemotherapy. These small molecules of ~ 22 nucleotides are modulated during early renal development, involved in the regulation of gene expression and Wilms tumor progression. Wilms tumors are embryonic tumors with few mutations and complex epigenetic dysregulation. […] Besides, genes regulated by miRNAs are related to biological pathways as PI3K, Wnt, TGF-, and Hippo signaling pathways, among others, which may be involved with the underlying mechanisms of resistance to chemotherapy, and in this way, it has emerged as potential targets for cancer therapies, including for Wilms tumors.
#1 Wilms’ Tumour | Children’s Cancer Web
http://www.cancerindex.org/ccw/guide2w.htm
Wilms tumor (WT) is the most common childhood kidney cancer globally. […] A1CF is a positive regulator of Axin2, a Wnt/-catenin pathway inhibitor, and A1CF-Axin2 signal axis regulates Wilms tumor-derived cells’ apoptosis and migration through Axin2. […] Salidroside inhibits Wilms’ tumor cells growth, migration and invasion via down-regulating miR-891b, which leads to the deactivation of PI3K/AKT/mTOR and NF-B signaling pathways. […] miR-483-5p suppressed WT cell proliferation via inducing apoptosis through targeting MKNK1. […] MiR-539 inhibited the progression of WT through downregulation of JAG1 and Notch1/3. […] The botryoid growth itself is not a criterion for stage II. […] This study explores the genomic alterations that contribute to the formation of a unique subset of low-risk, epithelial differentiated, favorable histology Wilms tumors (WT). […] Wilms tumor is the most common renal malignancy that occurs in children.
#1
https://haematologica.org/article/view/7732
Wilms tumor 1 (WT1) has long been implicated in acute myeloid leukemia. […] However, the precise mechanism through which WT1 may play a role in leukemogenesis has remained elusive. In recent years, new evidence has emerged that points towards a novel role of WT1 mutations in the deregulation of epigenetic programs in leukemic cells through its interaction with TET proteins. […] The fact that WT1 may be either overexpressed or mutated has given rise to the concept that it may act as both a tumor suppressor and oncogene, depending on the context. […] Indeed, work by several groups has demonstrated that WT1 appears to play a role along with TET proteins in mediating 5-hydroxymethylation of cytosines. […] These novel observations have given rise to an enhanced understanding of the complexity of this protein and its pathogenic role in leukemogenesis.
#1 The Rockefeller University » Researchers discover a new mechanism in childhood kidney cancer
https://www.rockefeller.edu/news/27051-wilms-tumor-new-mechanism/
The mutant proteins, however, clumped at these sites, causing the genes to be constantly transcribed into RNA, the first steps before turning into proteins. […] This abnormal gene expression confuses the cells as to what they want to become, Wan says. Instead of differentiating into mature kidney cells, they start to proliferate more and get stuck in the immature stage, which leads to the formation of a tumor. […] Having discovered this previously unknown mechanism in cancer, Wan and her colleagues are now asking if it might be possible to revert cancer cells back to normal, for instance with drugs that disrupt ENLs ability to bind to the genome or to form clumps. […] So far we have proof of concept that intervening in any stage of this process can stabilize the gene expression levels and allow the cells to develop normally, Wan says.
#1 Wilms Tumor – Diagnosis & Disease Information
https://www.cancertherapyadvisor.com/ddi/wilms-tumor/
Wilms tumor prognosis varies by stage at diagnosis, and histology of the tumor. Children diagnosed with early-stage Wilms tumor with a favorable histology have a 4-year survival rate of 95% to 100%. In contrast, patients with advanced disease and/or unfavorable Wilms tumor histology (anaplastic, with poorly differentiated cells) have slightly lower survival rates, but generally favorable outcomes compared with many other childhood cancers. […] In addition to advanced-stage disease and anaplastic histology, older age at diagnosis and incomplete response to initial treatment also are associated with a worse prognosis. Patients with these factors may require more intensive therapies and close monitoring to improve outcomes. […] Combining surgery, chemotherapy, and radiation therapy has improved survival rates for patients with Wilms tumor. Treatment plans are adjusted based on the tumor stage, histological findings, and response to initial therapy, ensuring a comprehensive approach to managing the disease.
#1 Methylation changes and INS-IGF2 expression predict progression in early-stage Wilms tumor | Clinical Epigenetics | Full Text
https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-024-01775-y
The early onset of DNA methylation changes make detection of these an attractive diagnostic and prognostic biomarker. […] Focal methylation changes, such as reduced P73 promoter methylation, was found to be associated with poor prognosis. […] In this study, we aimed to identify biomarkers for relapse in patients with stages I and II FHWT. […] We report several differentially methylated regions (DMRs) that show potential as prognostic biomarkers for disease relapse and overall patient survival. […] To explain the mechanistic role of DNA methylation changes in WT relapse, we explore the genes controlled by the differentially methylated IGF2 region and show elevated expression of INS-IGF2 transcript in tumor tissue of patients who have relapsed after treatment. […] We identified three probes that correlate with time to disease relapse, cg15822093, cg07086381 and cg21987076.
#1 Screening of potential hub genes involved in Kidney Wilms tumor via bioinformatics analysis and experimental validation | BMC Cancer | Full Text
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-024-12541-x
Wilms tumor (WT) is the most common pediatric embryonal tumor. Improving patient outcomes requires advances in understanding and targeting the multiple genes and cellular control pathways, but its pathogenesis is currently not well-researched. […] We aimed to identify the potential molecular biological mechanism of WT and develop new prognostic markers and molecular targets by comparing gene expression profiles of Wilms tumors and fetal normal kidneys. […] The enrichment analysis revealed that DEGs were significantly involved in the regulation of angiogenesis and regulation of cell differentiation. […] Functionally, over-expression of EMCN and CCNA1 knockdown inhibited cell viability, proliferation, migration, and invasion of Wilms tumor cells. […] EMCN and CCNA1 were identified as key prognostic markers in Wilms tumor, suggesting their potential as therapeutic targets.
#1 Screening of potential hub genes involved in Kidney Wilms tumor via bioinformatics analysis and experimental validation | BMC Cancer | Full Text
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-024-12541-x
Differential gene expression and enrichment analyses indicate significant roles in angiogenesis and cell differentiation. […] Our observations in Wilms tumor suggested that regulation of angiogenesis and regulation of cell differentiation play a key role in WT. […] The central role of EMCN and CCNA1 within this network highlights their potential as biomarkers for prognosis and targets for therapeutic intervention. […] The involvement of these genes in critical biological processes such as cell proliferation, apoptosis, and angiogenesis underscores their importance in WT pathogenesis. […] Our findings suggest that EMCN downregulation in WT is associated with poor prognosis, which aligns with its known role in promoting endothelial cell stability and inhibiting metastasis. […] In WT, CCNA1 overexpression may facilitate cell cycle progression and proliferation, while its role in apoptosis resistance could enhance tumor survival and growth. […] The identification of EMCN and CCNA1 as key regulators in WT provides a rationale for exploring targeted therapies that modulate their expression. […] These insights pave the way for developing targeted therapies aimed at improving prognosis and treatment efficacy for WT patients.
#1 Molecular Mechanism of the Cell Death Induced by the Histone Deacetylase Pan Inhibitor LBH589 (Panobinostat) in Wilms Tumor Cells | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126566
Wilms tumor (WT) is an embryonic kidney cancer, for which histone acetylation might be a therapeutic target. […] LBH589, a novel targeted agent, suppresses histone deacetylases in many tumors. This study investigated the antitumor activity of LBH589 in SK-NEP-1 and G401 cells. […] LBH589 inhibited cell proliferation of SK-NEP-1 and G401 cells in a dose-dependent manner. […] LBH589 treatment caused apoptosis and inhibition of cell proliferation of SK-NEP-1 and G401 cells. […] Expression profiling, and GO, KEGG and IPA analyses identified new targets and a new network of genes responding to LBH589 treatment in SK-NEP-1 cells. RPRM, HSP70 and MYC may be important regulators during LBH589 treatment. […] Our results provide new clues to the proapoptotic mechanism of LBH589. […] The present study indicated that HDACs are also important targets for human wilms tumor cells.
#1 Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQÂ®) – NCI
https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq
Wilms tumor is the most frequent tumor of the kidney in infants and children. The incidence of Wilms tumor is 9.7 cases for every 1 million children younger than 15 years and 13.5 cases per 1 million infants. Approximately 650 cases of Wilms tumor are diagnosed in the United States each year. The incidence is substantially lower in Asian people. […] Wilms tumor typically develops in otherwise healthy children without any predisposition to developing cancer. However, approximately 10% of children with Wilms tumor have been reported to have a congenital anomaly. In patients with congenital anomalies and Wilms tumor, nephrogenic rests have been reported in 60% of cases. […] The WT1 gene is located on the short arm of chromosome 11 (11p13). WT1 is a transcription factor that is required for normal genitourinary development and is important for differentiation of the renal blastema. WT1 variants are observed in 10% to 20% of cases of sporadic Wilms tumor.
#1 Wilms Tumor: Practice Essentials, Background, Etiology
https://emedicine.medscape.com/article/989398-overview
Wilms tumor is thought to be caused by alterations of genes responsible for normal genitourinary development. […] In the early 1970s, Knudson and Strong proposed a genetic model for the development of Wilms tumor. […] WT1, the first Wilms tumor suppressor gene at chromosomal band 11p13, was identified as a direct result of the study of children with Wilms tumor who also had aniridia, genitourinary anomalies, and intellectual disability (WAGR syndrome). […] Characterization of this novel tumor suppressor gene has provided insight into the mechanisms underlying normal kidney development and Wilms tumorigenesis. […] The WT1 gene is the specific target of mutations and deletions in a subset of patients with sporadic Wilms tumors, as well as in the germline of some children (eg, those with Denys-Drash syndrome) with a genetic predisposition to develop this cancer.
#1 Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQÂ®) – NCI
https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq
The genomic and genetic characteristics of Wilms tumor are summarized below. […] Wilms tumors show differences in gene expression and methylation patterns with different genetic aberrations. Wilms tumors have a large number of candidate driver genes, most of which are altered in less than 5% of Wilms tumors. […] Wilms tumors have recurrent variants in genes with common functions, with most involved in either early renal development or epigenetic regulation (e.g., chromatin modifications, transcription elongation, and miRNA). […] The male-to-female ratio in unilateral cases of Wilms tumor is 0.92 to 1.00, but in bilateral cases, there is a female excess (0.60). […] The risk of Wilms tumor is about 90% for children with Denys-Drash syndrome, and bilateral disease develops in 20% of patients.
#1 Wilmsâ Tumor of the Kidney: Insights into Risk Factors, Pathogenesis, Diagnosis and Management
https://pubs.sciepub.com/jcrt/4/3/4/
Wilms tumor occurs in association with either hemihypertrophy of the extremities or Beckwith-Weidemann syndrome, which includes enlargement of the tongue, liver, kidney, and other organs. […] About 10% of sporadic cases of Wilms tumor are associated with defects of WT1, the Wilms tumor gene located on chromosome 11 (11p13). WT1 is a tumor suppressor gene that regulates the transcription of other genes including IGF-2 and PDGF. […] The presence of a germline mutation and loss of heterozygosity at the WT1 locus are associated with tumor formation in a manner similar to the pathogenesis of hereditary retinoblastoma. […] Two uncommon congenital syndromes that are associated with Wilms tumor and other developmental defects include WAGR (Wilms, Aniridia, Genitourinary anomalies, and mental Retardation) and Denys-Drash syndrome.
#1 Cancer predisposition signaling in Beckwith-Wiedemann Syndrome drives Wilms tumor development | British Journal of Cancer
https://www.nature.com/articles/s41416-023-02538-x
Wilms tumor (WT) exhibits structural and epigenetic changes at chromosome 11p15, which also cause Beckwith-Wiedemann Syndrome (BWS). Children diagnosed with BWS have increased risk for WT. […] BWS-WT samples showed single nucleotide variants in BCORL1, ASXL1, ATM and AXL but absence of recurrent gene mutations associated with sporadic WT. […] While WT predisposition in BWS is well-established, as are 11p15 alterations in nonBWS-WT, this study focused on stratifying tumor genomics by 11p15 status. Further investigation of our findings may identify novel therapeutic targets in WT oncogenesis. […] Loss-of-heterozygosity (LOH) is both a common somatic oncogenic driver within tumors and can be present in the somatic tissues of patients with a mosaic cancer predisposition syndrome like BWS. LOH is reflected in parallel alterations on 11p15 in both BWS and present somatically in at least two thirds of WT.
#1
https://apcz.umk.pl/QS/article/view/41434
Wilms tumor appears more often among people with certain genetic syndromes. […] Despite already advanced treatment techniques for the tumor, and extensive knowledge about it, its pathogenesis still remains somewhat unknown. Increased understanding of the aberrant molecular pathways active in Wilms tumorigenesis has identified many potential targeted therapeutic approaches that could be applied in a clinical setting.
#1 Wilmsâ tumor susceptibility: possible involvement of FOXP3 and CXCL12 genes | Molecular and Cellular Pediatrics | Full Text
https://molcellped.springeropen.com/articles/10.1186/s40348-016-0064-4
Wilms tumor is an embryonal neoplasm of the kidney that accounts for approximately 6 % of all childhood tumors. […] The aim of the present study was to analyze rs3761548 and rs2232365 FOXP3 polymorphisms, as well as evaluate rs1801157 CXCL12 polymorphism in Wilms tumor samples. […] The case-control study indicated a significant association for allele A carriers of rs1801157 polymorphism in relation to Wilms tumor susceptibility (OR=5.261; 95 % CI 2.156 to 12.84; p=0.0002). […] All in all, these markers may contribute to this neoplasia susceptibility and progression; however, further studies are needed to real clarify their role in Wilms tumor pathogenesis. […] The present study aimed to analyze two polymorphisms in FOXP3 and one polymorphism in CXCL12 in WT samples, in a search for new possible molecular markers to this childhood neoplasia.
#1 Inter-Ethnic Variations in the Clinical, Pathological, and Molecular Characteristics of Wilms Tumor
https://www.mdpi.com/2072-6694/16/17/3051
Wilms tumor, also known as nephroblastoma, is the most common pediatric primary renal malignancy, despite only comprising 5% of childhood malignancies, affecting 1 in 10,000 children. […] Wilms tumor arises from abnormalities of embryonic development with disrupted nephrogenic differentiation thought to be the key pathogenic process giving rise to rapid cellular proliferation. […] Studies have implicated population differences in the incidence of WT1 mutations, loss of imprinting of the IGF2 locus, and loss of heterozygosity of 1p/16q, or 1q gain as possible bases for epidemiological differences in the disease profile of Wilms tumors in various ethnic groups. […] Anaplasia has been commonly associated with TP53 loss, while mutations in WT1 and epigenetic changesâparticularly loss of imprinting (LOI)âat the Insulin-like Growth Factor II (IGF2)/H19 locus have been associated with favorable histology.
#2 Investigating the dysfunctional pathogenesis of Wilms’ tumor through a multidimensional integration strategy
https://atm.amegroups.org/article/view/24808/html
Wilms tumor (WT) is a common kidney tumor in early childhood which is characterized by multiple congenital anomalies and syndromes. However, its molecular mechanism is still elusive. […] By integrating the potential pathogenic genes of kidney cancer and performing co-expression analysis on the disease-related genes, 23 functional modules were obtained. All the genes were differentially expressed in WT, and were mainly involved in many biological processes and signaling pathways, such as Wnt/-catenin, mTOR/ERK and calcineurin. […] A multidimensional dysfunction mechanism, involving disease-related genes, TFs and ncRNAs was revealed in the pathogenesis of WT. […] Studies have shown that WT is caused by genetic abnormalities, epigenetics, genetic mutations and environmental factors. Multiple studies have identified and confirmed that mutations in the Wilms tumor suppressor gene (WT1) are associated with the pathogenesis of WT.
#2 Wilms Tumor: Practice Essentials, Background, Etiology
https://emedicine.medscape.com/article/989398-overview
Wilms tumor is thought to be caused by alterations of genes responsible for normal genitourinary development. […] In the early 1970s, Knudson and Strong proposed a genetic model for the development of Wilms tumor. […] WT1, the first Wilms tumor suppressor gene at chromosomal band 11p13, was identified as a direct result of the study of children with Wilms tumor who also had aniridia, genitourinary anomalies, and intellectual disability (WAGR syndrome). […] Characterization of this novel tumor suppressor gene has provided insight into the mechanisms underlying normal kidney development and Wilms tumorigenesis. […] The WT1 gene is the specific target of mutations and deletions in a subset of patients with sporadic Wilms tumors, as well as in the germline of some children (eg, those with Denys-Drash syndrome) with a genetic predisposition to develop this cancer.
#2 Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQÂ®) – NCI
https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq
Wilms tumor is the most frequent tumor of the kidney in infants and children. The incidence of Wilms tumor is 9.7 cases for every 1 million children younger than 15 years and 13.5 cases per 1 million infants. Approximately 650 cases of Wilms tumor are diagnosed in the United States each year. The incidence is substantially lower in Asian people. […] Wilms tumor typically develops in otherwise healthy children without any predisposition to developing cancer. However, approximately 10% of children with Wilms tumor have been reported to have a congenital anomaly. In patients with congenital anomalies and Wilms tumor, nephrogenic rests have been reported in 60% of cases. […] The WT1 gene is located on the short arm of chromosome 11 (11p13). WT1 is a transcription factor that is required for normal genitourinary development and is important for differentiation of the renal blastema. WT1 variants are observed in 10% to 20% of cases of sporadic Wilms tumor.
#2 Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQÂ®) – NCI
https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq
Approximately one-third of Wilms tumor cases involve variants in WT1, CTNNB1, or AMER1 (WTX). Another subset of Wilms tumor cases results from variants in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5. Other genes critical for early renal development that are recurrently altered in Wilms tumor include SIX1 and SIX2 (transcription factors that play key roles in early renal development). […] Anaplastic Wilms tumor is characterized by the presence of TP53 variants. […] The molecular subtypes of the syndrome predispose patients to the development of different tumor histotypes. […] The presence of any isolated overgrowth feature was associated with the risk of developing cancer. […] Wilms tumor with a WT1 variant is characterized by evidence of WNT pathway activation by activating variants in the CTNNB1 gene. Loss of heterozygosity (LOH) at 11p15 is commonly observed, as paternal uniparental disomy for chromosome 11 represents a common mechanism for losing the remaining normal WT1 allele.
#2 Wilmsâ tumour: biology, diagnosis and treatment – Szychot – Translational Pediatrics
https://tp.amegroups.org/article/view/3228/html
Inactivation of the TP53 gene is found particularly in anaplastic tumors, and in tumors with focal anaplasia may only be inactivated in anaplastic areas. Genetic changes resulting in loss of TP53 function are also the commonest change observed between primary and relapse tumor samples. […] In addition to specific genes implicated in Wilms tumorigenesis, whole and partial chromosomal gains and losses, as well as LOH are commonly seen in Wilms tumors, particularly gains of chromosomes 1q, 2, 7q, 8, 12 13 and losses of chromosomes 1p, 7p, 16q and 22q. […] Further understanding of the molecular pathology and genetic changes in Wilms tumors is hoped to support the development of novel biomarkers to aid diagnosis, risk stratification and monitoring of therapy and relapse.
#2 Genetic and epigenetic features of bilateral Wilms tumor predisposition in patients from the Childrenâs Oncology Group AREN18B5-Q | Nature Communications
https://www.nature.com/articles/s41467-023-43730-0
These data demonstrate two predominant modes of BWT susceptibility: (1) Pre-zygotic germline genetic variants readily detectable in DNA derived from peripheral blood (WT1, NYNRIN, TRIM28, BRCA complex genes) often followed by 11p15.5 LOH or (2) Post-zygotic epigenetic hypermethylation at the 11p15.5 H19/ICR1 locus (LOI) that may require analysis of multiple tissue types for definitive diagnosis. […] Multiple lines of evidence in this study discussed below support 11p15.5 H19/ICR1 hypermethylation being a post-zygotic, somatic mosaic mesodermal epigenetic event that is common among patients who develop BWT.
#2 Wilms tumor: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/wilms-tumor/
In most cases of Wilms tumors involving one kidney and nearly all cases involving both kidneys, the tumors are thought to arise from immature kidney tissue that never developed properly. These immature tissues are known as nephrogenic rests. It is likely that genetic changes are involved in the presence of nephrogenic rests and that additional genetic changes trigger nephrogenic rests to develop into a tumor. […] Many children with Wilms tumor do not have identified variants in any of the known genes. In these cases, the cause of the condition is unknown. It is likely that other, unknown genes are also associated with the development of Wilms tumor.
#2 Investigating the dysfunctional pathogenesis of Wilms’ tumor through a multidimensional integration strategy
https://atm.amegroups.org/article/view/24808/html
Furthermore, in the case of WT, the Wnt/beta-catenin pathway is highly activated which is influenced by AXIN2. […] By combining RNA-seq data, gene co-expression networks and differential expression analysis, dysfunctional co-expression modules were identified. […] In the pathogenesis of genes involved in a disease, their function and pathway are important. […] The KEGG pathway mainly includes Wnt/beta-catenin, JNK cascade and mTOR/ERK signaling pathways, which are involved in the development, progression and prognosis of WT. […] WT is a complex cancer, and the dysfunctional modules of WT are regulated by many factors. […] This study reveals the multidimensional effects of STAT3 in WT, and for instance, IL-6-activated STAT3 can inhibit expression of WTX. […] In summary, this work reveals the multifactor-mediated dysfunctional network and characterizes the potential molecular mechanisms of WT.
#2
https://journals.lww.com/md-journal/fulltext/2023/04140/role_of_cct4_erbb_signaling_in_nephroblastoma_.22.aspx
Wilms tumor is a common abdominal malignant tumor in children. However, the molecular mechanism of Wilms tumor is unclear. A total of 925 DEGs were identified. The differently expressed genes were mainly enriched in the metabolic pathway, AMPK signaling pathway, ErbB signaling pathway, mRNA detection pathway, and folded protein binding. CCT4 might play an essential role in the occurrence and development of Wilms tumor, and they may participate in the occurrence and development of Wilms tumor through the ERBB signal pathway. CCT4 may be a promising biomarker of Wilms tumor. The main result of this study is that the expression of CCT4 is low in nephroblastoma. When CCT4 is activated, the ERBB signal pathway is inhibited, the apoptosis is enhanced, the expression of MMP3/9 is downregulated, and cancer cells invasion and metastasis ability is decreased. CCT4 may be involved in the cell cycle, promote apoptosis, and may be involved in the occurrence and development of nephroblastoma through the ERBB signal pathway. The enhanced activation of the ERBB signaling pathway is closely related to the occurrence and development of nephroblastoma. CCT4 interacts with several subunits of pre-folded protein (PFDN). Therefore, it is speculated that the low expression of CCT4 promotes the development of nephroblastoma by regulating cell proliferation. CCT4 might be a promising nephroblastoma biomarker.
#2 Wilms’ tumor pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Wilms%27_tumor_pathophysiology
Wilms tumor has a triphasic appearance. It is comprised of 3 types of cells which are stromal, epithelial and blastemal. All the 3 types are not required for the diagnosis of Wilms tumor. Primitive tubules and glomeruli are often seen comprised of neoplastic cells. Lesions comprising of nephrogenic rests can lead to Wilms tumor. Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. Based on a study Wilms tumor is divided into 2 pathologic categories: favorable and anaplastic. […] Aberrations in germline or clonal WT1, WT2, and Wnt activation when combined with stage of development of the nephron, characterize different subsets of Wilms tumor that can be differentiated by using gene expression profiling. This genetic/ontogenic categorization describes some of the heterogeneity among Wilms tumors.
#2 Wilms’ tumor – Wikipedia
https://en.wikipedia.org/wiki/Wilms%27_tumor
The mesenchymal component may include cells showing rhabdomyoid differentiation or malignancy (rhabdomyosarcomatous Wilms). […] Wilms’ tumors may be separated into two prognostic groups based on pathologic characteristics: Favorable contains well developed components mentioned above; Anaplastic contains diffuse anaplasia (poorly developed cells). […] Mutations of the WT1 gene which is located on the short arm of chromosome 11 (11p13) are observed in approximately 20% of Wilms’ tumors, the majority of them being inherited from the germline, while a minority are acquired somatic mutations. In addition at least half of the Wilms’ tumors with mutations in WT1 also carry acquired somatic mutations in CTNNB1, the gene encoding the proto-oncogene beta-catenin.
#2 Wilms tumour in children | CCLG – The Children & Young People’s Cancer Association
https://www.cclg.org.uk/about-cancer/cancer-children-and-young-people/types-cancer-children-and-young-people/wilms-tumour-children
There are two types of high-risk Wilms tumour – anaplastic and blastemal which require more intensive (stronger) chemotherapy: […] About 5-10% of Wilms tumours have an appearance called anaplasia, which means the cells look very disorganised under a microscope. […] This group of high-risk tumours cannot be identified by looking at the biopsy because they occur when a particular type of early kidney cell survives the pre-surgery chemotherapy. These cells are known as blastemal cells. Tumours where most of these cells survive chemotherapy are called 'blastemal-type’ tumours.
#2 Resolving the Pathogenesis of Anaplastic Wilms Tumors through Spatial Mapping of Cancer Cell Evolution | Lund University Publications
https://lup.lub.lu.se/search/publication/10d066e6-4673-4275-abc4-bdcc882e3129
CONCLUSIONS: Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.
#2 Wilms Tumor | Pediatric Surgery NaT
https://www.pedsurglibrary.com/apsa/view/Pediatric-Surgery-NaT/829119/all/Wilms_Tumor
Genetic analysis of tumors from NWTSG have identified specific genetic mutations that have been incorporated into a risk based stratagem which directly impacts patient care. Loss of heterozygosity (LOH) at 1p/16q is a specific marker for increased risk of relapse in favorable histology WT. This finding was studied in the prospective, nonrandomized NWTS-5 trial which established that combined LOH at both chromosomes 1p and 16q was an adverse prognostic indicator for all stages of WT. Although only occurring in five percent of patients, identification of LOH 1p/16q selectively targets these patients for intensification of treatment. […] Subsequent analysis of subsets of very low risk tumors from NWTS-5 have demonstrated that WT1 mutation and 11p15 LOH are associated with relapse and this finding may be incorporated in future clinical trials. Recent COG data indicates that 1q gain occurs in approximately thirty percent of tumors and is a marker for tumor recurrence.
#2 The mechanism of action of the Wilms’ tumour 1 protein WT1 | Bristol Cancer Research Network | University of Bristol
https://www.bristol.ac.uk/cancer/research/projects/wt1.html
The Wilms tumour 1 protein, WT1, was first identified as a tumour suppressor in paediatric nephroblastoma. […] In recent years, however, it has become clear that WT1 can also act as an oncogene in several paediatric and adult cancers. […] WT1 is a gene regulator that can activate or repress transcription, but the mechanisms by which WT1 regulates differentiation, and how it manifests tumor suppressor and oncogenic activities are not known. […] Our studies involve the analysis of WT1 target genes and how the interaction partners of WT1 regulate its activity. […] BASP1 (acting as part of a complex) interacts directly with WT1 at a gene promoter and converts WT1 from a transcriptional activator to a repressor. […] HtrA2 is an apoptotic protease that degrades WT1 upon treatment of cells with cytotoxic drugs. BASP1 can enhance this process, which is consistent with a tumour suppressor role for BASP1.
#2 Azthena logo with the word Azthena
https://www.news-medical.net/news/20191218/Study-opens-up-new-treatment-possibilities-for-Wilms-tumor.aspx
To execute their respective manuals, the cells employ so-called chromatin reader proteins that identify which gene is up for expression. Now a new study has found that a problem in this gene-regulatory process may cause normal cells to turn malignant and produce Wilms’ tumor, the most common kidney cancer in children. […] The researchers found that the implicated reader protein causes problems by acquiring a new property and being too active. […] The team then took a closer look to understand how mutations in ENL turn these cells into tumor cells. […] The mutant proteins, however, clumped at these sites, causing the genes to be constantly transcribed into RNA, the first steps before turning into proteins. […] „This abnormal gene expression confuses the cells as to what they want to become,” Wan says. „Instead of differentiating into mature kidney cells, they start to proliferate more and get stuck in the immature stage, which leads to the formation of a tumor.” […] Having discovered this previously unknown mechanism in cancer, Wan and her colleagues are now asking if it might be possible to revert cancer cells back to normal, for instance with drugs that disrupt ENL’s ability to bind to the genome or to form clumps.
#2 Wilms Tumor – Diagnosis & Disease Information
https://www.cancertherapyadvisor.com/ddi/wilms-tumor/
Wilms tumor prognosis varies by stage at diagnosis, and histology of the tumor. Children diagnosed with early-stage Wilms tumor with a favorable histology have a 4-year survival rate of 95% to 100%. In contrast, patients with advanced disease and/or unfavorable Wilms tumor histology (anaplastic, with poorly differentiated cells) have slightly lower survival rates, but generally favorable outcomes compared with many other childhood cancers. […] In addition to advanced-stage disease and anaplastic histology, older age at diagnosis and incomplete response to initial treatment also are associated with a worse prognosis. Patients with these factors may require more intensive therapies and close monitoring to improve outcomes. […] Combining surgery, chemotherapy, and radiation therapy has improved survival rates for patients with Wilms tumor. Treatment plans are adjusted based on the tumor stage, histological findings, and response to initial therapy, ensuring a comprehensive approach to managing the disease.
#2 Screening of potential hub genes involved in Kidney Wilms tumor via bioinformatics analysis and experimental validation | BMC Cancer | Full Text
https://bmccancer.biomedcentral.com/articles/10.1186/s12885-024-12541-x
Differential gene expression and enrichment analyses indicate significant roles in angiogenesis and cell differentiation. […] Our observations in Wilms tumor suggested that regulation of angiogenesis and regulation of cell differentiation play a key role in WT. […] The central role of EMCN and CCNA1 within this network highlights their potential as biomarkers for prognosis and targets for therapeutic intervention. […] The involvement of these genes in critical biological processes such as cell proliferation, apoptosis, and angiogenesis underscores their importance in WT pathogenesis. […] Our findings suggest that EMCN downregulation in WT is associated with poor prognosis, which aligns with its known role in promoting endothelial cell stability and inhibiting metastasis. […] In WT, CCNA1 overexpression may facilitate cell cycle progression and proliferation, while its role in apoptosis resistance could enhance tumor survival and growth. […] The identification of EMCN and CCNA1 as key regulators in WT provides a rationale for exploring targeted therapies that modulate their expression. […] These insights pave the way for developing targeted therapies aimed at improving prognosis and treatment efficacy for WT patients.
#2 Molecular Mechanism of the Cell Death Induced by the Histone Deacetylase Pan Inhibitor LBH589 (Panobinostat) in Wilms Tumor Cells | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126566
Our results indicated that LBH589 treatment caused inhibition of cell proliferation of SK-NEP-1 and G401 cells in a dose-dependent manner. […] These results demonstrated for the first time that LBH589 induced apoptosis in SK-NEP-1 and G401 cells. […] Our research also indicated that LBH589 treatment inhibits the growth of SK-NEP-1 xenograft tumors in nude mice. […] The results may provide new clues to the molecular mechanism of apoptosis induced by LBH589.
#2 Wilmsâ Tumor of the Kidney: Insights into Risk Factors, Pathogenesis, Diagnosis and Management
https://pubs.sciepub.com/jcrt/4/3/4/
Wilms tumor occurs in association with either hemihypertrophy of the extremities or Beckwith-Weidemann syndrome, which includes enlargement of the tongue, liver, kidney, and other organs. […] About 10% of sporadic cases of Wilms tumor are associated with defects of WT1, the Wilms tumor gene located on chromosome 11 (11p13). WT1 is a tumor suppressor gene that regulates the transcription of other genes including IGF-2 and PDGF. […] The presence of a germline mutation and loss of heterozygosity at the WT1 locus are associated with tumor formation in a manner similar to the pathogenesis of hereditary retinoblastoma. […] Two uncommon congenital syndromes that are associated with Wilms tumor and other developmental defects include WAGR (Wilms, Aniridia, Genitourinary anomalies, and mental Retardation) and Denys-Drash syndrome.
#2 Wilmsâ Tumor of the Kidney: Insights into Risk Factors, Pathogenesis, Diagnosis and Management
https://pubs.sciepub.com/jcrt/4/3/4/
Less than 10% of sporadic Wilms tumors exhibit abnormalities at the WT1 locus suggesting that other genes may play a role in their formation. […] Another uncommon congenital disease, Beckwith-wiedemann syndrome, also features Wilms tumor and other abnormalities and is also associated with defects at the WT2 locus. […] The genetic defects at the locus are complex and are likely to involve genomic imprinting.
#2 Wilmsâ tumor susceptibility: possible involvement of FOXP3 and CXCL12 genes | Molecular and Cellular Pediatrics | Full Text
https://molcellped.springeropen.com/articles/10.1186/s40348-016-0064-4
In conclusion, the present study demonstrated that FOXP3 rs2232365 is negatively and CXCL12 rs1801157 is positively associated with WT susceptibility. […] Thus, this study demonstrated, for the first time, an association between FOXP3 and CXCL12 genetic polymorphisms with this cancer, demonstrating that these markers are, somehow, involved in WT pathogenesis.