Schwannomatosis – Patofizjologia i mechanizm

Schwannomatosis
Patofizjologia i mechanizm

Schwannomatoza to rzadka choroba genetyczna charakteryzująca się rozwojem mnogich schwannoma oraz rzadziej oponiaków, odrębna od neurofibromatozy typu 2 (NF2) ze względu na brak obustronnych nerwiaków osłonkowych nerwu przedsionkowego. Kluczowymi genami predysponującymi są SMARCB1 i LZTR1, z mutacjami germinalnymi wykrywanymi u 86% pacjentów z rodzinnymi i 40% ze sporadycznymi przypadkami. Patogeneza opiera się na modelu „4 uderzeń/3 kroków”, obejmującym mutacje germinalne SMARCB1 lub LZTR1, utratę heterozygotyczności chromosomu 22q oraz somatyczne mutacje NF2, co wskazuje na złożony mechanizm onkogenezy z udziałem co najmniej dwóch genów supresorowych nowotworów. Białko merlin kodowane przez NF2 reguluje liczne szlaki sygnałowe (m.in. Wnt/β-katenina, Ras/Raf/MEK/ERK, PI3K/AKT), a jego inaktywacja wpływa na proliferację komórek Schwanna i mielinizację. Klinicznie schwannomatoza charakteryzuje się przewlekłym bólem, którego mechanizm wiąże się z wydzielaniem przez guzy czynników uwrażliwiających neurony, co potwierdzają badania na neuronach z zwojów rdzeniowych (DRG).

<a href="#pathogeneza-schwannomatozy”>Patogeneza schwannomatozy

Mutacje genetyczne w schwannomatozie
Model patogenezy schwannomatozy

Rola genów w patogenezie schwannomatozy

Gen SMARCB1
Gen LZTR1
Gen NF2

Mechanizmy molekularne w patogenezie schwannomatozy

Współdziałanie genów supresorowych nowotworów
Utrata heterozygotyczności i somatyczne mutacje
Szlaki sygnałowe w patogenezie schwannomatozy

Mechanizmy bólu w schwannomatozie

Sekrecja czynników prozapalnych
Rola genów w powstawaniu bólu

Implikacje kliniczne i diagnostyczne

Diagnoza schwannomatozy
Badania genetyczne w schwannomatozie

Przyszłe kierunki badań

Kolejne rozdziały

schwannomatozy”>Patogeneza schwannomatozy

Schwannomatoza to rzadka choroba charakteryzująca się predyspozycją do rozwoju mnogich schwannoma (nerwiaków osłonkowych) oraz, rzadziej, oponiaków. Jest to zaburzenie genetyczne, które zostało po raz pierwszy wyodrębnione jako odrębna jednostka chorobowa od neurofibromatozy typu 2 (NF2) pod koniec lat 90. XX wieku. W przeciwieństwie do NF2, schwannomatoza nie wiąże się z występowaniem obustronnych nerwiaków osłonkowych nerwu przedsionkowego, a jej mechanizm rozwoju jest odmienny¹².

Mutacje genetyczne w schwannomatozie

Dotychczas zidentyfikowano co najmniej dwa główne geny predysponujące do rozwoju schwannomatozy: SMARCB1 i LZTR1. Mutacje germinalne tych genów supresorowych nowotworów wykryto u 86% pacjentów z rodzinnymi przypadkami schwannomatozy i u 40% pacjentów ze sporadycznymi przypadkami tej choroby³⁴. Gen SMARCB1 (znany również jako INI1, hSNF5 lub BAF47) zlokalizowany jest na chromosomie 22q11 i działa jako supresor nowotworów, regulując cykl komórkowy, wzrost i różnicowanie komórek⁵⁶.

W 2022 roku zaktualizowano nomenklaturę schwannomatozy, uznając ją za część spektrum zespołów predysponujących do rozwoju schwannoma, definiowanych często przez patogenne warianty w jednym z kilku genów na chromosomie 22, wyróżniając:⁷:

Schwannomatozę związaną z SMARCB1
Schwannomatozę związaną z LZTR1

Model patogenezy schwannomatozy

Chociaż u pacjentów ze schwannomatozą wykryto bialleliczne mutacje genów SMARCB1 lub LZTR1, klasyczny dwuetapowy model onkogenezy (two-hit model) jest niewystarczający do wyjaśnienia rozwoju schwannoma, ponieważ w tych guzach często inaktywowany jest również gen NF2⁸. W związku z tym onkogeneza w schwannomatozie musi obejmować mutacje co najmniej dwóch różnych genów supresorowych nowotworów, co często jest związane z utratą heterozygotyczności dużych fragmentów chromosomu 22q, zawierającego zarówno SMARCB1 i LZTR1, jak i NF2⁹.

Badania wykazały, że rozwój schwannoma w schwannomatozie opiera się na modelu „4 uderzeń/3 kroków” (4-hit/3-step model), który obejmuje¹⁰¹¹:

Pierwsza mutacja germinalna genu SMARCB1 lub LZTR1 (pierwsze uderzenie)
Utrata heterozygotyczności na chromosomie 22, powodująca utratę drugiego allelu SMARCB1 lub LZTR1 i utratę jednego z alleli NF2 (drugie i trzecie uderzenie)
Somatyczna mutacja pozostałego dzikiego allelu NF2 (czwarte uderzenie)

Ten wzorzec zdarzeń mutacyjnych wskazuje na złożony mechanizm onkogenezy u pacjentów z schwannomatozą, znacznie bardziej skomplikowany niż w klasycznych zespołach predysponujących do nowotworów¹². Schwannomatoza jest więc paradygmatycznym przykładem zespołu predysponującego do nowotworów, spowodowanego jednoczesną inaktywacją mutacyjną dwóch lub więcej genów supresorowych nowotworów¹³.

Rola genów w patogenezie schwannomatozy

Gen SMARCB1

SMARCB1 jest jednym z głównych genów związanych z rozwojem schwannomatozy. Inaktywująca mutacja germinalna w eksonie 1 tego genu została stwierdzona u pacjentów z schwannomatozą¹⁴. Badania wykazały, że nieprawidłowa ekspresja białka spowodowana mutacjami germinalnymi w genie SMARCB1 może być główną przyczyną rozwoju schwannomatozy¹⁵.

Białko kodowane przez gen SMARCB1 pełni funkcję supresora nowotworów poprzez regulację proliferacji komórkowej i różnicowania. Jego inaktywacja prowadzi do zaburzenia kontroli nad cyklem komórkowym i wzrostem komórek¹⁶. Badania przeprowadzone przez Dr. Shermana wykazały, że zakłócenie funkcji SMARCB1 w komórkach Schwanna powoduje wydzielanie czynników, które zwiększają ekspresję receptorów bólu, co sugeruje mechanizm powstawania przewlekłego bólu występującego w schwannomatozie¹⁷.

Gen LZTR1

LZTR1 jest drugim głównym genem predysponującym do rozwoju schwannomatozy. Mutacje w tym genie zostały zidentyfikowane u znacznej części pacjentów ze schwannomatozą, zwłaszcza w przypadkach, gdy nie wykryto mutacji SMARCB1¹⁸. Model 3-etapowej onkogenezy wydaje się dotyczyć większości schwannoma z mutacjami LZTR1¹⁹.

Badania wykazały, że analiza molekularna genu LZTR1 może przyczynić się do charakterystyki molekularnej pacjentów ze schwannomatozą, oprócz analizy mutacji NF2 i wykrywania utraty chromosomu 22 w tkance guza. Jest to szczególnie przydatne w różnicowaniu schwannomatozy od mozaikowej neurofibromatozy typu 2²⁰.

Gen NF2

Rola genu NF2 w patogenezie schwannomatozy jest złożona. Zamiast konstytucyjnych (germinalnych) mutacji NF2, w schwannoma pacjentów ze schwannomatozą często występują niezależne somatyczne mutacje dotyczące obu alleli NF2²¹. Gen NF2 koduje białko merlin (schwannomin), które działa jako supresor nowotworów²².

Zarówno kopie genu NF2 są inaktywowane w guzach pobranych od osób ze schwannomatozą, co sugeruje, że ten sam mechanizm obserwowany w NF1 i NF2 – utrata genu supresora nowotworów – może być również aktywny w schwannomatozie²³. Jednak obie kopie genu NF2 pozostają funkcjonalne w zdrowych tkankach osób ze schwannomatozą, co wyklucza tę teorię²⁴.

Badania wskazują, że utrata funkcji merlin wpływa na ścieżki sygnałowe mitogenne i cykl komórkowy. Merlin hamuje szlaki takie jak Wnt/β-katenina, p21, Ras/Raf/MEK/ERK, Rac/PAK/JNK, PI3K/AKT, FAK/Src oraz mTORC1²⁵. Nieprawidłowości w szlaku Hippo są powiązane z wieloma nowotworami, a także z zaburzeniami proliferacji komórek Schwanna i mielinizacji²⁶.

Mechanizmy molekularne w patogenezie schwannomatozy

Współdziałanie genów supresorowych nowotworów

Unikalną cechą schwannomatozy jest konieczność współdziałania mutacji w co najmniej dwóch różnych genach supresorowych nowotworów²⁷. Niektórzy badacze sugerują, że utrata jakiegoś innego genu supresora nowotworów, być może w połączeniu z utratą genu NF2, może w jakiś sposób powodować schwannomatozę²⁸.

Badania przeprowadzone przez Sestini i współpracowników (2008) sugerują, że mechanizm 4-uderzeniowy obejmujący 2 odrębne, ale powiązane geny supresorowe nowotworów, SMARCB1 i NF2, może leżeć u podstaw rozwoju guzów u części pacjentów ze schwannomatozą²⁹. Jednak biorąc pod uwagę niską częstość występowania mutacji germinalnych SMARCB1, możliwe jest również zaangażowanie dodatkowych loci³⁰.

Utrata heterozygotyczności i somatyczne mutacje

Mechanizm związany z utratą heterozygotyczności (LOH) na chromosomie 22q odgrywa kluczową rolę w patogenezie schwannomatozy. Analiza guzów od pacjentów ze schwannomatozą wykazała, że wiele rodzajów zmian genetycznych występuje na chromosomie 22, zwykle, ale nie zawsze, w tym samym obszarze co gen NF2³¹.

Wydaje się, że same mutacje w genie SMARCB1 lub LZTR1 nie wystarczą do wywołania rozwoju schwannoma. Dodatkowe zmiany genetyczne (mutacje somatyczne), które są nabywane w ciągu życia człowieka i występują tylko w niektórych komórkach, mogą być również wymagane do tworzenia się schwannoma. Najczęstszymi mutacjami somatycznymi w schwannoma są mutacje w genie NF2 i utrata chromosomu 22 (na którym znajdują się geny SMARCB1, LZTR1 i NF2)³².

Ważne jest rozróżnienie między mutacjami konstytucyjnymi a somatycznymi w odniesieniu do genów SMARCB1 i NF2. Schwannoma od jednego pacjenta mają te same mutacje konstytucyjne, ale różne mutacje somatyczne³³.

Szlaki sygnałowe w patogenezie schwannomatozy

Badania na modelach mysich schwannomatozy wykazały, że dysregulacja szlaku Hippo może pośredniczyć w tworzeniu schwannoma, a sygnalizacja RAS/MAPK może modyfikować rozwój schwannoma³⁴. Badania przeprowadzone przez Dr. Le wykazały, że rozwój nowotworu jest podatny na modyfikację poprzez modulację szlaku Hippo, ścieżki sygnałowej, która kontroluje wzrost komórek i została zaangażowana w liczne typy nowotworów³⁵.

Spostrzeżenia z badań nad HIV i pediatrycznymi guzami rhabdoidowymi rzuciły światło na potencjalne szlaki molekularne, które są dysregulowane w schwannoma związanych ze schwannomatozą³⁶. Modele mysie schwannomatozy zostały opracowane i obiecują dalsze rozszerzenie naszego zrozumienia onkogenezy i mikrośrodowiska guza³⁷.

Mechanizmy bólu w schwannomatozie

Jedną z głównych cech klinicznych schwannomatozy jest przewlekły ból, który często stanowi wyzwanie terapeutyczne. Międzynarodowe Warsztaty Schwannomatozy z 2011 roku zidentyfikowały odkrycie mechanizmu bólu w schwannomatozie jako priorytet badawczy³⁸.

Sekrecja czynników prozapalnych

Badania sugerują, że niektóre guzy, ale nie wszystkie, wydzielają czynniki, które działają na pobliskie nerwy, aby zwiększyć nocycepcję poprzez wywołanie sensytyzacji neuronalnej lub spontanicznego wyładowania neuronalnego³⁹. Medium kondycjonowane (CM) zbierane z bolesnych guzów SWN, ale nie z niebolesnych guzów SWN, uwrażliwiało neurony DRG, powodując zwiększoną wrażliwość na depolaryzację przez KCl, zwiększoną odpowiedź na szkodliwe agonisty TRPV1 i TRPA1, a także zwiększało ekspresję genów związanych z bólem w hodowlach DRG⁴⁰.

Obserwowano, że neurony traktowane medium kondycjonowanym przez bolesne schwannoma były bardziej responsywne na KCl niż te traktowane medium kondycjonowanym przez niebolesne schwannoma lub normalne komórki Schwanna⁴¹. Kilka genów związanych z bólem zapalnym było silnie regulowanych w górę w DRG traktowanych CM z bolesnych guzów⁴².

Wykazano, że CM z bolesnych schwannoma wykazuje różną zdolność do uwrażliwiania neuronów DRG w porównaniu z CM z niebolesnych guzów, a ten efekt funkcjonalny jest związany ze zmianami w ekspresji kilku genów związanych z bólem w DRG⁴³. Wiele cytokin i chemokin jest wydzielanych przez bolesne schwannoma⁴⁴.

Rola genów w powstawaniu bólu

Dr. Giovannini bada, jaką rolę geny SMARCB1, LZTR1 i NF2 odgrywają w rozwoju schwannoma i dlaczego mutacje w SMARCB1 i LZTR1 prawdopodobnie prowadzą do bolesnych schwannoma w schwannomatozie w porównaniu do schwannoma wywołanych mutacją NF2, które częściej powodują deficyty neurologiczne⁴⁵.

Ból jest prawdopodobnie spowodowany rozwijającymi się guzami w obrębie obwodowego i centralnego układu nerwowego, ale związek ten nie zawsze jest jednoznaczny, a obecność i intensywność bólu nie zawsze korelują z liczbą, lokalizacją i wielkością guzów⁴⁶.

Implikacje kliniczne i diagnostyczne

Diagnoza schwannomatozy

Diagnoza schwannomatozy opiera się na kryteriach diagnostyki molekularnej i/lub klinicznej według Plotkin i wsp. (2013) oraz Ostrow i wsp. (2016)⁴⁷. Połączona diagnoza molekularna i kliniczna może być postawiona na podstawie:

2 guzów z utratą heterozygotyczności 22q i różnymi somatycznymi mutacjami NF2 ORAZ 2 potwierdzonymi patologicznie schwannoma lub oponiakami⁴⁸
LUB
Germinalnej patogennej mutacji SMARCB1 lub LZTR1 ORAZ jednego potwierdzonego patologicznie schwannoma lub oponiaka⁴⁹

Schwannomatoza powinna być brana pod uwagę w diagnostyce różnicowej pacjentów z wieloma schwannoma lub rozległym zajęciem pojedynczego nerwu, szczególnie tych, którzy nie spełniają kryteriów neurofibromatozy typu 2⁵⁰.

Badania genetyczne w schwannomatozie

Kehrer-Sawatzki i wsp. (2017) zalecają: „Kompleksową analizę mutacji wszystkich trzech genów, LZTR1, SMARCB1 i NF2, u pacjentów ze schwannomatozą, aby zidentyfikować pełne spektra mutacji i liczbę uderzeń mutacyjnych, które wpływają na te geny⁵¹. Te kompleksowe testy mogą pomóc sklasyfikować guzy zgodnie z ich profilem mutacji.

Ze względu na nakładanie się objawów klinicznych między schwannomatozą a NF2, diagnostyka różnicowa jest dość trudna, szczególnie w przypadkach sporadycznych i mozaikowych z wieloma schwannoma, ale bez obustronnych nerwiaków osłonkowych nerwu przedsionkowego i wykrywalnych mutacji germinalnych genu NF2⁵².

Przyszłe kierunki badań

Patogeneza schwannomatozy nadal nie jest w pełni zrozumiana i wymaga dalszych badań. Niektóre kluczowe obszary badań obejmują:

Identyfikację dodatkowych genów predysponujących lub modyfikujących, które mogą przyczyniać się do rozwoju schwannomatozy⁵³
Określenie szlaków komórkowych zaangażowanych w patogenezę choroby⁵⁴
Ustalenie korelacji genotyp/fenotyp⁵⁵
Projektowanie nowych terapii opartych na zaburzonych szlakach⁵⁶

Terapia genowa może stanowić skuteczną i obiecującą strategię terapeutyczną dla schwannomatozy związanej z NF2 w przyszłości⁵⁷. Terapia wymiany genu dla schwannomatozy związanej z NF2 bezpośrednio dostarcza funkcjonalną kopię zmutowanego lub inaktywowanego genu NF2, aby zwiększyć re-ekspresję funkcjonalnego białka merlin w komórkach guza z deficytem NF2 w celu leczenia fenotypu choroby spowodowanego wadliwym genem NF2⁵⁸.

W ciągu najbliższych 5 lat oczekuje się, że postępy w badaniach podstawowych nad patogenezą schwannomatozy doprowadzą do badań klinicznych potencjalnych terapii lekowych⁵⁹. Patogeneza tej choroby wymaga wyjaśnienia, konieczne jest znalezienie nowych leków immunologicznych i nowych celów genetycznych, a to będzie ważnym kierunkiem poprawy leczenia tego rzadkiego guza⁶⁰.

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Materiały źródłowe

#1 Schwannomatoses related to genetic variants other than NF2 – UpToDate
https://www.uptodate.com/contents/schwannomatoses-related-to-genetic-variants-other-than-nf2
Schwannomatosis is the name originally coined for a neurocutaneous syndrome that is genetically distinct from neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). It was first recognized as distinct from NF2 in the late 1990s. […] In 2022, the nomenclature for NF2 and schwannomatosis was further updated to recognize the disorders as part of a spectrum of schwannoma predisposition syndromes with extensive clinical overlap, defined in many cases by pathogenic variants in one of several genes on chromosome 22: […] SMARCB1-related schwannomatosis […] LZTR1-related schwannomatosis.
#2 :: JKMS :: Journal of Korean Medical Science
https://jkms.org/DOIx.php?id=10.3346/jkms.2006.21.6.1136
Schwannomatosis or neurilemmomatosis has been used to describe patients with multiple nonvestibular schwannomas with no other stigmata of neurofibromatosis type-2 (NF-2). […] Several recent reports have suggested that some patients may develop multiple schwannomas without any associated NF-1 or NF-2 stigma. Such a presentation has been termed schwannomatosis or neurilemmomatosis. […] Honda et al. indicated that germline mutations in the NF-2 gene were the molecular mechanism of schwannomatosis, which in this sense would represent an incomplete form of NF-2. […] Many of previous reports described patients with highly localized disease of the peripheral nerve. […] Some differences have become apparent between schwannomatosis and neurofibromatosis with respect to their clinical manifestations.
#3 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC5258795/
Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. […] Instead, germline mutations of either the SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients. […] Although biallelic mutations of SMARCB1 or LZTR1 have been detected in the tumours of patients with schwannomatosis, the classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, since NF2 is also frequently inactivated in these tumours. […] Consequently, tumorigenesis in schwannomatosis must involve the mutation of at least two different tumour suppressor genes, an occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harbouring not only SMARCB1 and LZTR1 but also NF2.
#4 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis -ORCA
https://orca.cardiff.ac.uk/id/eprint/97891/
Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. […] Instead, germline mutations of either the SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients. […] Although biallelic mutations of SMARCB1 or LZTR1 have been detected in the tumours of patients with schwannomatosis, the classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, since NF2 is also frequently inactivated in these tumours. […] Consequently, tumorigenesis in schwannomatosis must involve the mutation of at least two different tumour suppressor genes, an occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harbouring not only SMARCB1 and LZTR1 but also NF2. […] Thus, schwannomatosis is paradigmatic for a tumour predisposition syndrome caused by the concomitant mutational inactivation of two or more tumour suppressor genes.
#5 Schwannomatosis – Wikipedia
https://en.wikipedia.org/wiki/Schwannomatosis
Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF). […] The candidate schwannomatosis gene, named SMARCB1, is a tumor suppressor gene that regulates cell cycle, growth and differentiation. […] An inactivating germline mutation in exon 1 of the tumor suppressor gene SMARCB1 has been reported in patients with schwannomatosis. […] A mechanism involving both the SMARCB1 and NF2 genes may be responsible for the development of the disease because tumor analysis of schwannomas indicates the presence of inactivating mutations in both the SMARCB1 and NF2 genes. […] Ultimately, the tumorigenesis of schwannomas is not solely dependent on one gene locus alone. […] In regards to the SMARCB1 and NF2 genes, it is important to understand constitutional mutations and somatic mutations. […] Schwannomas from one patient share the same constitutional mutations but have distinct somatic mutations. […] SMARCB1 is also known as INI1, hSNF5, or BAF47. […] Schwannomatosis is known to be a genetic disorder. However, familial occurrence is inexplicably rare.
#6
https://www.omim.org/entry/162091
A number sign (#) is used with this entry because susceptibility to the development of schwannomatosis-1 (SWN1) is conferred by germline heterozygous mutation in the tumor suppressor gene SMARCB1 (601607) on chromosome 22q11. […] Individual schwannoma tumors from patients with schwannomatosis have been found to harbor somatic mutations in the SMARCB1. […] Since the NF2 locus had been excluded as the germline event underlying familial schwannomatosis, and the gene placed centromeric to NF2 on chromosome 22, Hulsebos et al. (2007) investigated the SMARCB1 gene in a father and daughter with the disorder. Both were found to be heterozygous for a inactivating germline mutation of this gene (601607.0005). In 2 of 4 investigated schwannomas from these patients, inactivation of the wildtype INI1 allele by a second mutation in exon 5 of the gene (601607.0006) or by loss of the gene was found, consistent with the Knudson 2-hit hypothesis.
#7 Schwannomatoses related to genetic variants other than NF2 – UpToDate
https://www.uptodate.com/contents/schwannomatoses-related-to-genetic-variants-other-than-nf2
Schwannomatosis is the name originally coined for a neurocutaneous syndrome that is genetically distinct from neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). It was first recognized as distinct from NF2 in the late 1990s. […] In 2022, the nomenclature for NF2 and schwannomatosis was further updated to recognize the disorders as part of a spectrum of schwannoma predisposition syndromes with extensive clinical overlap, defined in many cases by pathogenic variants in one of several genes on chromosome 22: […] SMARCB1-related schwannomatosis […] LZTR1-related schwannomatosis.
#8 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC5258795/
Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. […] Instead, germline mutations of either the SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients. […] Although biallelic mutations of SMARCB1 or LZTR1 have been detected in the tumours of patients with schwannomatosis, the classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, since NF2 is also frequently inactivated in these tumours. […] Consequently, tumorigenesis in schwannomatosis must involve the mutation of at least two different tumour suppressor genes, an occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harbouring not only SMARCB1 and LZTR1 but also NF2.
#9 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis -ORCA
https://orca.cardiff.ac.uk/id/eprint/97891/
Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. […] Instead, germline mutations of either the SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients. […] Although biallelic mutations of SMARCB1 or LZTR1 have been detected in the tumours of patients with schwannomatosis, the classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, since NF2 is also frequently inactivated in these tumours. […] Consequently, tumorigenesis in schwannomatosis must involve the mutation of at least two different tumour suppressor genes, an occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harbouring not only SMARCB1 and LZTR1 but also NF2. […] Thus, schwannomatosis is paradigmatic for a tumour predisposition syndrome caused by the concomitant mutational inactivation of two or more tumour suppressor genes.
#10
https://www.omim.org/entry/162091
A number sign (#) is used with this entry because susceptibility to the development of schwannomatosis-1 (SWN1) is conferred by germline heterozygous mutation in the tumor suppressor gene SMARCB1 (601607) on chromosome 22q11. […] Individual schwannoma tumors from patients with schwannomatosis have been found to harbor somatic mutations in the SMARCB1. […] Since the NF2 locus had been excluded as the germline event underlying familial schwannomatosis, and the gene placed centromeric to NF2 on chromosome 22, Hulsebos et al. (2007) investigated the SMARCB1 gene in a father and daughter with the disorder. Both were found to be heterozygous for a inactivating germline mutation of this gene (601607.0005). In 2 of 4 investigated schwannomas from these patients, inactivation of the wildtype INI1 allele by a second mutation in exon 5 of the gene (601607.0006) or by loss of the gene was found, consistent with the Knudson 2-hit hypothesis.
#11 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC5258795/
The diagnosis of schwannomatosis is predicated upon the molecular and/or clinical diagnostic criteria according to Plotkin et al. (2013) and Ostrow et al. (2016). […] The classical two-hit model of tumorigenesis does not seem to pertain in the tumours of patients with SMARCB1 germline mutations, at least in the sense that this model would require biallelic SMARCB1 inactivation to be sufficient for tumour initiation or growth. […] This pattern of mutational events points to a 4-hit/3-step model of tumorigenesis in patients with SMARCB1-positive schwannomatosis. […] The 3-step model of tumorigenesis appears to apply to the majority of LZTR1 mutation-positive schwannomas. […] However, not all schwannomas from patients with LZTR1 germline mutations exhibit this pattern of mutational events similar to that observed in some schwannomas of patients with germline SMARCB1 mutations.
#12 Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria
https://lirias.kuleuven.be/343390
Schwannomatosis is the third major form of neurofibromatosis and is characterized by the development of multiple schwannomas in the absence of bilateral vestibular schwannomas. […] Genetic studies indicate that constitutional mutations in the SMARCB1 tumor suppressor gene occur in 40-50% of familial cases and in 8-10% of sporadic cases of schwannomatosis. Tumorigenesis is thought to occur through a four-hit, three-step model, beginning with a germline mutation in SMARCB1 (hit 1), followed by loss of a portion of chromosome 22 that contains the second SMARCB1 allele and one NF2 allele (hits 2 and 3), followed by mutation of the remaining wild-type NF2 allele (hit 4). […] Insights from research on HIV and pediatric rhabdoid tumors have shed light on potential molecular pathways that are dysregulated in schwannomatosis-related schwannomas.
#13 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC5258795/
Thus, schwannomatosis is paradigmatic for a tumour predisposition syndrome caused by the concomitant mutational inactivation of two or more tumour suppressor genes. […] The majority of patients with schwannomatosis are sporadic, whereas 13-25% are familial cases. […] However, instead of constitutional (germline) NF2 mutations, independent somatic mutations affecting both NF2 alleles are frequently found in schwannomas of patients with schwannomatosis. […] So far, two schwannomatosis predisposition genes have been identified, SMARCB1 and LZTR1. […] The clinical overlap between schwannomatosis and NF2 renders differential diagnosis somewhat difficult, particularly in sporadic and mosaic cases with multiple schwannomas but without bilateral vestibular schwannomas and detectable germline NF2 gene mutations.
#14 Schwannomatosis – Wikipedia
https://en.wikipedia.org/wiki/Schwannomatosis
Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF). […] The candidate schwannomatosis gene, named SMARCB1, is a tumor suppressor gene that regulates cell cycle, growth and differentiation. […] An inactivating germline mutation in exon 1 of the tumor suppressor gene SMARCB1 has been reported in patients with schwannomatosis. […] A mechanism involving both the SMARCB1 and NF2 genes may be responsible for the development of the disease because tumor analysis of schwannomas indicates the presence of inactivating mutations in both the SMARCB1 and NF2 genes. […] Ultimately, the tumorigenesis of schwannomas is not solely dependent on one gene locus alone. […] In regards to the SMARCB1 and NF2 genes, it is important to understand constitutional mutations and somatic mutations. […] Schwannomas from one patient share the same constitutional mutations but have distinct somatic mutations. […] SMARCB1 is also known as INI1, hSNF5, or BAF47. […] Schwannomatosis is known to be a genetic disorder. However, familial occurrence is inexplicably rare.
#15 Frontiers | 18F-FDG PET/CT revealed sporadic schwannomatosis involving the lumbar spinal canal and both lower limbs: a case report
https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1346647/full
Schwannomatosis is a rare autosomal dominant hereditary syndrome disease characterized by multiple schwannomas throughout the body, without bilateral vestibular schwannoma or dermal schwannoma. […] The mechanism of this disease has not been thoroughly studied yet and may be related to abnormal expression of gene mutations. According to literature records, the abnormal expression of genes such as SMARCB1 (INI1), the LZTR1 gene, and the NF2 gene has been reported more frequently as possible causes of neurofibromatosis patientsâ onset, among which the SMARCB1 gene is considered the susceptibility gene for neurofibromatosis. […] Moreover, many scholars believe that germline mutations in the SMARCB1 gene leading to abnormalities in the structure and functional expression of the protein may be the main cause of the development of schwannomatosis.
#16 Neurofibromatosis – Wikipedia
https://en.wikipedia.org/wiki/Neurofibromatosis
The third type is called schwannomatosis and often presents in early adulthood with widespread pain, numbness, or tingling due to nerve compression. […] Schwannomatosis is caused by a mutation on the SMARCB1 gene. […] The mutation of the SMARCB1 gene causes a loss of function in the complex leading to the formation of tumors indicative of schwannomatosis.
#17 2020 Neurofibromatosis Highlight – The Pain of Neurofibromatosis, Neurofibromatosis Research Program, Congressionally Directed Medical Research Programs
https://cdmrp.health.mil/nfrp/research_highlights/20NFPain_highlight
Neurofibromatosis (NF) is a group of hereditary cancer syndromes where different gene mutations result in tumors developing in the central and peripheral nervous systems. […] One important neurofibromatosis clinical manifestation is pain. […] Clinical presentation of pain is mainly associated with schwannomatosis. […] The predominant characteristic of both NF2 and schwannomatosis is the development of schwannomas, tumors in the Schwann cells wrapped around peripheral nerves. […] One retrospective study found that schwannomatosis patients’ most common symptom was chronic pain. […] In addition, the 2011 International Schwannomatosis Workshop identified uncovering the mechanism of pain in schwannomatosis as a top research priority. […] Dr. Sherman’s research found that disrupting SMARCB1 in Schwann cells caused secretion of factors that increased expression of pain receptors, suggesting a mechanism for the prevalent pain found in schwannomatosis.
#18 Expanding the mutational spectrum of LZTR1 in schwannomatosis | European Journal of Human Genetics
https://www.nature.com/articles/ejhg2014220
Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. […] In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation. […] To further assess the involvement of LZTR1 in schwannomatosis, we screened all coding sequence and exon/intron boundaries of LZTR1 in 60 additional SMARCB1-unrelated schwannomatosis cases. […] Our work confirms that LZTR1 is the most prevalent gene causing schwannomatosis. However, a fraction of schwannomatosis cases, mainly the sporadic ones, remain genetically unsolved.
#19 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC5258795/
The diagnosis of schwannomatosis is predicated upon the molecular and/or clinical diagnostic criteria according to Plotkin et al. (2013) and Ostrow et al. (2016). […] The classical two-hit model of tumorigenesis does not seem to pertain in the tumours of patients with SMARCB1 germline mutations, at least in the sense that this model would require biallelic SMARCB1 inactivation to be sufficient for tumour initiation or growth. […] This pattern of mutational events points to a 4-hit/3-step model of tumorigenesis in patients with SMARCB1-positive schwannomatosis. […] The 3-step model of tumorigenesis appears to apply to the majority of LZTR1 mutation-positive schwannomas. […] However, not all schwannomas from patients with LZTR1 germline mutations exhibit this pattern of mutational events similar to that observed in some schwannomas of patients with germline SMARCB1 mutations.
#20 Expanding the mutational spectrum of LZTR1 in schwannomatosis
https://escholarship.org/uc/item/6xb2f811
Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. […] In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation.
#21 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC5258795/
Thus, schwannomatosis is paradigmatic for a tumour predisposition syndrome caused by the concomitant mutational inactivation of two or more tumour suppressor genes. […] The majority of patients with schwannomatosis are sporadic, whereas 13-25% are familial cases. […] However, instead of constitutional (germline) NF2 mutations, independent somatic mutations affecting both NF2 alleles are frequently found in schwannomas of patients with schwannomatosis. […] So far, two schwannomatosis predisposition genes have been identified, SMARCB1 and LZTR1. […] The clinical overlap between schwannomatosis and NF2 renders differential diagnosis somewhat difficult, particularly in sporadic and mosaic cases with multiple schwannomas but without bilateral vestibular schwannomas and detectable germline NF2 gene mutations.
#22 NF2-related schwannomatosis (NF2-SWN; formerly neurofibromatosis type 2) – UpToDate
https://www.uptodate.com/contents/nf2-related-schwannomatosis-nf2-swn-formerly-neurofibromatosis-type-2
NF2-related schwannomatosis (NF2-SWN; formerly neurofibromatosis type 2) is caused by pathogenic variants in the NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor (NF2) gene, which produces merlin, a tumor suppressor. […] The molecular pathogenesis, clinical features, diagnosis, and management of NF2-SWN are reviewed here.
#23 Schwannomatosis | Neupsy Key
https://neupsykey.com/schwannomatosis/
Both copies of the NF2 gene are inactivated in tumors taken from people with schwannomatosis, suggesting that the same mechanism seen in NF1 and NF2âa loss of a tumor suppressor geneâmight be at work. […] Based on analysis of tumor samples, some speculated that schwannomatosis might be caused by such a two-hit loss of the NF2 gene. […] Researchers have discovered, however, that both copies of the NF2 gene remain functional in healthy tissue from people with schwannomatosis, which rules out this theory. […] Analysis of tumors from people with schwannomatosis has revealed that multiple types of genetic alterations occur on chromosome 22, usually, but not always, in the same vicinity as the NF2 gene. […] This has led researchers to speculate that loss of some other tumor suppressor gene, perhaps combined with loss of the NF2 gene, may somehow cause schwannomatosis. […] In light of the conflicting data, some researchers theorize that any one of several different pathological mechanisms may result in schwannomatosis. […] The mechanism responsible for the familial version of the disorder may be different from the defect involved in sporadic cases.
#24 Schwannomatosis | Neupsy Key
https://neupsykey.com/schwannomatosis/
Both copies of the NF2 gene are inactivated in tumors taken from people with schwannomatosis, suggesting that the same mechanism seen in NF1 and NF2âa loss of a tumor suppressor geneâmight be at work. […] Based on analysis of tumor samples, some speculated that schwannomatosis might be caused by such a two-hit loss of the NF2 gene. […] Researchers have discovered, however, that both copies of the NF2 gene remain functional in healthy tissue from people with schwannomatosis, which rules out this theory. […] Analysis of tumors from people with schwannomatosis has revealed that multiple types of genetic alterations occur on chromosome 22, usually, but not always, in the same vicinity as the NF2 gene. […] This has led researchers to speculate that loss of some other tumor suppressor gene, perhaps combined with loss of the NF2 gene, may somehow cause schwannomatosis. […] In light of the conflicting data, some researchers theorize that any one of several different pathological mechanisms may result in schwannomatosis. […] The mechanism responsible for the familial version of the disorder may be different from the defect involved in sporadic cases.
#25 NF2-related schwannomatosis | MedLink Neurology
https://www.medlink.com/articles/nf2-related-schwannomatosis
NF2-related schwannomatosis is caused by mutations in the neurofibromatosis 2 (NF2) gene, a tumor suppressor gene that encodes for merlin/schwannomin and is located on chromosome 22. […] NF2-related schwannomatosis is due to inactivation of the neurofibromatosis 2 gene. […] The protein product is merlin, which is a member of the FERM gene family (ezrin, radixin, moesin) and regulates multiple proliferative signaling pathways. […] Merlin can be regarded as a scaffold protein indirectly linking F-actin, transmembrane receptors, and intracellular effectors to modulate receptor-mediated signaling pathways controlling cell growth, proliferation, and survival. […] Merlin inhibits downstream pathways, such as the Wnt/-catenin, p21, Ras/Raf/MEK/ERK, Rac/PAK/JNK, PI3K/AKT, FAK/Src, and mTORC1 pathways.
#26 NF2-related schwannomatosis | MedLink Neurology
https://www.medlink.com/articles/nf2-related-schwannomatosis
Abnormalities in the Hippo pathway are linked to a number of cancers as well as disorders of Schwann cell proliferation and myelination. […] Schwannoma growth requires the inactivation of both the two neurofibromatosis 2 alleles. […] Nonsense and frameshift mutations resulting in protein-truncating changes are the most commonly identified germline events and result in the most severe phenotype with a younger age at diagnosis and a higher tumor burden. […] On the other hand, missense and in-frame deletions are linked to milder disease courses.
#27 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC5258795/
Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. […] Instead, germline mutations of either the SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients. […] Although biallelic mutations of SMARCB1 or LZTR1 have been detected in the tumours of patients with schwannomatosis, the classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, since NF2 is also frequently inactivated in these tumours. […] Consequently, tumorigenesis in schwannomatosis must involve the mutation of at least two different tumour suppressor genes, an occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harbouring not only SMARCB1 and LZTR1 but also NF2.
#28 Schwannomatosis | Neupsy Key
https://neupsykey.com/schwannomatosis/
Both copies of the NF2 gene are inactivated in tumors taken from people with schwannomatosis, suggesting that the same mechanism seen in NF1 and NF2âa loss of a tumor suppressor geneâmight be at work. […] Based on analysis of tumor samples, some speculated that schwannomatosis might be caused by such a two-hit loss of the NF2 gene. […] Researchers have discovered, however, that both copies of the NF2 gene remain functional in healthy tissue from people with schwannomatosis, which rules out this theory. […] Analysis of tumors from people with schwannomatosis has revealed that multiple types of genetic alterations occur on chromosome 22, usually, but not always, in the same vicinity as the NF2 gene. […] This has led researchers to speculate that loss of some other tumor suppressor gene, perhaps combined with loss of the NF2 gene, may somehow cause schwannomatosis. […] In light of the conflicting data, some researchers theorize that any one of several different pathological mechanisms may result in schwannomatosis. […] The mechanism responsible for the familial version of the disorder may be different from the defect involved in sporadic cases.
#29
https://omim.org/entry/162091
Sestini et al. (2008) postulated that a 4-hit mechanism involving 2 distinct but linked tumor suppressor genes, SMARCB1 and NF2, may underlie the development of tumors in a subset of patients with schwannomatosis. However, given the low frequency of SMARCB1 germline mutations, there may also be additional loci involved.
#30
https://www.omim.org/entry/162091
Based on these results, Sestini et al. (2008) postulated that a 4-hit mechanism involving 2 distinct but linked tumor suppressor genes, SMARCB1 and NF2, may underlie the development of tumors in a subset of patients with schwannomatosis. However, given the low frequency of SMARCB1 germline mutations, there may also be additional loci involved.
#31 Schwannomatosis | Neupsy Key
https://neupsykey.com/schwannomatosis/
Both copies of the NF2 gene are inactivated in tumors taken from people with schwannomatosis, suggesting that the same mechanism seen in NF1 and NF2âa loss of a tumor suppressor geneâmight be at work. […] Based on analysis of tumor samples, some speculated that schwannomatosis might be caused by such a two-hit loss of the NF2 gene. […] Researchers have discovered, however, that both copies of the NF2 gene remain functional in healthy tissue from people with schwannomatosis, which rules out this theory. […] Analysis of tumors from people with schwannomatosis has revealed that multiple types of genetic alterations occur on chromosome 22, usually, but not always, in the same vicinity as the NF2 gene. […] This has led researchers to speculate that loss of some other tumor suppressor gene, perhaps combined with loss of the NF2 gene, may somehow cause schwannomatosis. […] In light of the conflicting data, some researchers theorize that any one of several different pathological mechanisms may result in schwannomatosis. […] The mechanism responsible for the familial version of the disorder may be different from the defect involved in sporadic cases.
#32 Schwannomatosis: MedlinePlus GeneticsLock
https://medlineplus.gov/genetics/condition/schwannomatosis/
Schwannomatosis is a disorder characterized by multiple noncancerous (benign) tumors called schwannomas, which are a type of tumor that grows on nerves. Schwannomas develop when Schwann cells, which are specialized cells that normally form an insulating layer around the nerve, grow uncontrollably to form a tumor. […] Mutations in at least two genes, SMARCB1 and LZTR1, can cause schwannomatosis. The proteins produced from both genes are thought to act as tumor suppressors, which normally keep cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in either of these genes may help cells grow and divide without control or order to form a tumor. […] It appears that mutations in the SMARCB1 or LZTR1 gene alone are not enough to trigger the development of schwannomas. Additional genetic changes (somatic mutations) that are acquired during a person’s lifetime and are present only in certain cells may also be required for schwannomas to form. The most common somatic mutations in schwannomas are mutations in the NF2 gene and a loss of chromosome 22 (which is the chromosome on which the SMARCB1, LZTR1, and NF2 genes are found). […] Some people with schwannomatosis do not have an identified mutation in the SMARCB1 or LZTR1 gene. In these cases, the cause of the disorder is unknown. Researchers suspect that mutations in other as-yet-unidentified genes, most likely on chromosome 22, also contribute to this condition.
#33 Schwannomatosis – Wikipedia
https://en.wikipedia.org/wiki/Schwannomatosis
Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF). […] The candidate schwannomatosis gene, named SMARCB1, is a tumor suppressor gene that regulates cell cycle, growth and differentiation. […] An inactivating germline mutation in exon 1 of the tumor suppressor gene SMARCB1 has been reported in patients with schwannomatosis. […] A mechanism involving both the SMARCB1 and NF2 genes may be responsible for the development of the disease because tumor analysis of schwannomas indicates the presence of inactivating mutations in both the SMARCB1 and NF2 genes. […] Ultimately, the tumorigenesis of schwannomas is not solely dependent on one gene locus alone. […] In regards to the SMARCB1 and NF2 genes, it is important to understand constitutional mutations and somatic mutations. […] Schwannomas from one patient share the same constitutional mutations but have distinct somatic mutations. […] SMARCB1 is also known as INI1, hSNF5, or BAF47. […] Schwannomatosis is known to be a genetic disorder. However, familial occurrence is inexplicably rare.
#34 Schwannomatosis – Le Lab
https://med.virginia.edu/le-lab/research/schwannomatosis/
Schwannomatosis is a recently characterized third major form of Neurofibromatosis that lacks the hallmark bilateral acoustic (vestibular) schwannomas of NF2. […] Schwannomas are benign tumors of Schwann cell origin and patients with schwannomatosis develop schwannomas throughout the body. […] Even after surgical removal of the tumor, the pain can still remain, indicating there are factors inherent to the nerves as the pain can occur in areas that do not have schwannoma. […] In addition to NF2, several newly identified genes, including LZTR1 and SMARCB1, have been implicated in Schwannomatosis, however their molecular roles are poorly defined. […] Using genetically engineered mouse models, the Le Lab has found that dysregulation of the Hippo pathway can mediate schwannoma formation, and that RAS/MAPK signaling can modify schwannoma development. […] These studies provide important insights into the molecular mechanisms underlying schwannoma development and offer promising targets for therapeutic strategies.
#35
https://www.nfnetwork.org/pages-news/investigating-the-role-of-fibroblasts-in-the-pathogenesis-in-neurofibromas/?lang=en
Neurofibromatosis consists of a family of syndromes, including neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis. […] With support from a Fiscal Year (FY) 2015 Exploration-Hypothesis Development Award through the Neurofibromatosis Research Program (NFRP), Dr. Lu Le and his team are investigating the contributions of fibroblasts in the pathogenesis of neurofibromas by defining the cellular interactions in the tumor microenvironment, specifically between neoplastic Schwann cells and fibroblasts. […] Dr. Le was also awarded an FY16 Investigator-Initiated Research Award through the NFRP to define molecular and developmental pathogenesis of Schwann cell tumors and elucidate the mechanisms by which specific cancer pathways may affect tumor formation. […] Furthermore, this work demonstrated that neurofibroma tumorigenesis is susceptible to modification through modulation of the Hippo pathway, a signaling pathway that controls cell growth and has been implicated in numerous cancer types. […] If successful, Dr. Les work will pave the way toward understanding the developmental origin and biology of cNF.
#36 Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria
https://lirias.kuleuven.be/343390
Schwannomatosis is the third major form of neurofibromatosis and is characterized by the development of multiple schwannomas in the absence of bilateral vestibular schwannomas. […] Genetic studies indicate that constitutional mutations in the SMARCB1 tumor suppressor gene occur in 40-50% of familial cases and in 8-10% of sporadic cases of schwannomatosis. Tumorigenesis is thought to occur through a four-hit, three-step model, beginning with a germline mutation in SMARCB1 (hit 1), followed by loss of a portion of chromosome 22 that contains the second SMARCB1 allele and one NF2 allele (hits 2 and 3), followed by mutation of the remaining wild-type NF2 allele (hit 4). […] Insights from research on HIV and pediatric rhabdoid tumors have shed light on potential molecular pathways that are dysregulated in schwannomatosis-related schwannomas.
#37 Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria
https://lirias.kuleuven.be/343390
Mouse models of schwannomatosis have been developed and promise to further expand our understanding of tumorigenesis and the tumor microenvironment. […] In the next 5 years, the authors expect that advances in basic research in the pathogenesis of schwannomatosis will lead toward clinical investigations of potential drug therapies.
#38 2020 Neurofibromatosis Highlight – The Pain of Neurofibromatosis, Neurofibromatosis Research Program, Congressionally Directed Medical Research Programs
https://cdmrp.health.mil/nfrp/research_highlights/20NFPain_highlight
Neurofibromatosis (NF) is a group of hereditary cancer syndromes where different gene mutations result in tumors developing in the central and peripheral nervous systems. […] One important neurofibromatosis clinical manifestation is pain. […] Clinical presentation of pain is mainly associated with schwannomatosis. […] The predominant characteristic of both NF2 and schwannomatosis is the development of schwannomas, tumors in the Schwann cells wrapped around peripheral nerves. […] One retrospective study found that schwannomatosis patients’ most common symptom was chronic pain. […] In addition, the 2011 International Schwannomatosis Workshop identified uncovering the mechanism of pain in schwannomatosis as a top research priority. […] Dr. Sherman’s research found that disrupting SMARCB1 in Schwann cells caused secretion of factors that increased expression of pain receptors, suggesting a mechanism for the prevalent pain found in schwannomatosis.
#39 The Secretomes of Painful Versus Nonpainful Human Schwannomatosis Tumor Cells Differentially Influence Sensory Neuron Gene Expression and Sensitivity | Scientific Reports
https://www.nature.com/articles/s41598-019-49705-w
Schwannomatosis is a multiple tumor syndrome in which patients develop benign tumors along peripheral nerves throughout the body. […] We speculate that some individual tumors, but not others, secrete factors that act on nearby nerves to augment nociception by producing neuronal sensitization or spontaneous neuronal firing. […] We have found that conditioned medium (CM) collected from painful SWN tumors, but not that from nonpainful SWN tumors, sensitized DRG neurons, causing increased sensitivity to depolarization by KCl, increased response to noxious TRPV1 and TRPA1 agonists and also upregulated the expression of pain-associated genes in DRG cultures. […] Here, we examine the hypothesis that painful SWN cells secrete substances, such as cytokines, into the extracellular space that sensitize neurons and make them easier to excite.
#40 The Secretomes of Painful Versus Nonpainful Human Schwannomatosis Tumor Cells Differentially Influence Sensory Neuron Gene Expression and Sensitivity | Scientific Reports
https://www.nature.com/articles/s41598-019-49705-w
Schwannomatosis is a multiple tumor syndrome in which patients develop benign tumors along peripheral nerves throughout the body. […] We speculate that some individual tumors, but not others, secrete factors that act on nearby nerves to augment nociception by producing neuronal sensitization or spontaneous neuronal firing. […] We have found that conditioned medium (CM) collected from painful SWN tumors, but not that from nonpainful SWN tumors, sensitized DRG neurons, causing increased sensitivity to depolarization by KCl, increased response to noxious TRPV1 and TRPA1 agonists and also upregulated the expression of pain-associated genes in DRG cultures. […] Here, we examine the hypothesis that painful SWN cells secrete substances, such as cytokines, into the extracellular space that sensitize neurons and make them easier to excite.
#41 The Secretomes of Painful Versus Nonpainful Human Schwannomatosis Tumor Cells Differentially Influence Sensory Neuron Gene Expression and Sensitivity | Scientific Reports
https://www.nature.com/articles/s41598-019-49705-w
We observed that neurons treated with media conditioned by painful schwannomas were more responsive to KCl than those treated with medium conditioned by the non-painful schwannomas or normal Schwann cells. […] Together, these findings indicate that exposure to CM from painful SWN tumor cells results in greater sensory neuron responsiveness to depolarization than does exposure to CM from non-painful SWN tumor cells or control Schwann cells. […] Several genes related to inflammatory pain were highly upregulated in the DRGs treated with CM from painful tumors, and their encoded proteins thus constitute downstream candidates for further investigation in their role in schwannomatosis-related pain. […] The reasons why some SWN tumors cause significant pain and others dont remain a mystery.
#42 The Secretomes of Painful Versus Nonpainful Human Schwannomatosis Tumor Cells Differentially Influence Sensory Neuron Gene Expression and Sensitivity | Scientific Reports
https://www.nature.com/articles/s41598-019-49705-w
We observed that neurons treated with media conditioned by painful schwannomas were more responsive to KCl than those treated with medium conditioned by the non-painful schwannomas or normal Schwann cells. […] Together, these findings indicate that exposure to CM from painful SWN tumor cells results in greater sensory neuron responsiveness to depolarization than does exposure to CM from non-painful SWN tumor cells or control Schwann cells. […] Several genes related to inflammatory pain were highly upregulated in the DRGs treated with CM from painful tumors, and their encoded proteins thus constitute downstream candidates for further investigation in their role in schwannomatosis-related pain. […] The reasons why some SWN tumors cause significant pain and others dont remain a mystery.
#43 The Secretomes of Painful Versus Nonpainful Human Schwannomatosis Tumor Cells Differentially Influence Sensory Neuron Gene Expression and Sensitivity | Scientific Reports
https://www.nature.com/articles/s41598-019-49705-w
We have demonstrated that CM from painful schwannomas exhibit a differential capacity to sensitize DRG neurons, relative to CM from nonpainful tumors, and that this functional effect is associated with alterations in the expression of several pain-related target genes in the DRG. […] Multiple cytokines and chemokines are secreted by painful schwannomas.
#44 The Secretomes of Painful Versus Nonpainful Human Schwannomatosis Tumor Cells Differentially Influence Sensory Neuron Gene Expression and Sensitivity | Scientific Reports
https://www.nature.com/articles/s41598-019-49705-w
We have demonstrated that CM from painful schwannomas exhibit a differential capacity to sensitize DRG neurons, relative to CM from nonpainful tumors, and that this functional effect is associated with alterations in the expression of several pain-related target genes in the DRG. […] Multiple cytokines and chemokines are secreted by painful schwannomas.
#45 2020 Neurofibromatosis Highlight – The Pain of Neurofibromatosis, Neurofibromatosis Research Program, Congressionally Directed Medical Research Programs
https://cdmrp.health.mil/nfrp/research_highlights/20NFPain_highlight
Dr. Giovannini’s research is examining what roles SMARCB1, LZTR1, and NF2 genes play in the development of schwannomas and why mutations in SMARCB1 and LZTR1 possibly lead to painful schwannomas in schwannomatosis compared to NF2 mutation-driven schwannomas that are more likely to result in neurological deficits. […] Pain is believed to be caused by the developing tumors within the peripheral and central nervous system, but the relationship is not always clear-cut, and the presence and intensity of pain does not always correlate with number, location, and size of tumors. […] Therefore, information collected from studies like those conducted by Dr. Sherman and Dr. Giovannini to uncover the unique mechanisms of neurofibromatosis pain is critical for development of alternative pain management therapies.
#46 2020 Neurofibromatosis Highlight – The Pain of Neurofibromatosis, Neurofibromatosis Research Program, Congressionally Directed Medical Research Programs
https://cdmrp.health.mil/nfrp/research_highlights/20NFPain_highlight
Dr. Giovannini’s research is examining what roles SMARCB1, LZTR1, and NF2 genes play in the development of schwannomas and why mutations in SMARCB1 and LZTR1 possibly lead to painful schwannomas in schwannomatosis compared to NF2 mutation-driven schwannomas that are more likely to result in neurological deficits. […] Pain is believed to be caused by the developing tumors within the peripheral and central nervous system, but the relationship is not always clear-cut, and the presence and intensity of pain does not always correlate with number, location, and size of tumors. […] Therefore, information collected from studies like those conducted by Dr. Sherman and Dr. Giovannini to uncover the unique mechanisms of neurofibromatosis pain is critical for development of alternative pain management therapies.
#47 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC5258795/
The diagnosis of schwannomatosis is predicated upon the molecular and/or clinical diagnostic criteria according to Plotkin et al. (2013) and Ostrow et al. (2016). […] The classical two-hit model of tumorigenesis does not seem to pertain in the tumours of patients with SMARCB1 germline mutations, at least in the sense that this model would require biallelic SMARCB1 inactivation to be sufficient for tumour initiation or growth. […] This pattern of mutational events points to a 4-hit/3-step model of tumorigenesis in patients with SMARCB1-positive schwannomatosis. […] The 3-step model of tumorigenesis appears to apply to the majority of LZTR1 mutation-positive schwannomas. […] However, not all schwannomas from patients with LZTR1 germline mutations exhibit this pattern of mutational events similar to that observed in some schwannomas of patients with germline SMARCB1 mutations.
#48 Genetic Testing for Neurofibromatosis and Related Disorders
https://member.myhealthtoolkitla.com/web/public/brands/medicalpolicy/external-policies/genetic-testing-for-neurofibromatosis-and-related-disorders/
Schwannomatosis is caused by inactivating mutations in SMARCB1 and LZTR and is characterized by multiple schwannomas and pain arising in adulthood (Bergner Yohay, 2024). […] Germline mutations of either the SMARCB1 or LZTR1 tumor suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients (Kehrer-Sawatzki et al., 2017). […] Biallelic inactivation of these tumor suppressor genes leads to schwannomatosis (Radhika Dhamija, 2023). […] A combined molecular and clinical diagnosis may be made with 2 tumors with 22q LOH and different somatic NF2 mutations AND 2 pathologically confirmed schwannomas or meningiomas […] OR […] Germline SMARCB1 or LZTR1 pathogenic mutation AND one pathologically confirmed schwannoma or meningioma. […] Kehrer-Sawatzki et al. (2017) also recommended, Comprehensive mutation analysis of all three genes, LZTR1, SMARCB1, and NF2, in patients with schwannomatosis should be performed to identify the complete mutational spectra and the number of mutational hits that affect these genes. […] This comprehensive testing may help to classify the tumors according to their mutation-profile.
#49 Genetic Testing for Neurofibromatosis and Related Disorders
https://member.myhealthtoolkitla.com/web/public/brands/medicalpolicy/external-policies/genetic-testing-for-neurofibromatosis-and-related-disorders/
Schwannomatosis is caused by inactivating mutations in SMARCB1 and LZTR and is characterized by multiple schwannomas and pain arising in adulthood (Bergner Yohay, 2024). […] Germline mutations of either the SMARCB1 or LZTR1 tumor suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients (Kehrer-Sawatzki et al., 2017). […] Biallelic inactivation of these tumor suppressor genes leads to schwannomatosis (Radhika Dhamija, 2023). […] A combined molecular and clinical diagnosis may be made with 2 tumors with 22q LOH and different somatic NF2 mutations AND 2 pathologically confirmed schwannomas or meningiomas […] OR […] Germline SMARCB1 or LZTR1 pathogenic mutation AND one pathologically confirmed schwannoma or meningioma. […] Kehrer-Sawatzki et al. (2017) also recommended, Comprehensive mutation analysis of all three genes, LZTR1, SMARCB1, and NF2, in patients with schwannomatosis should be performed to identify the complete mutational spectra and the number of mutational hits that affect these genes. […] This comprehensive testing may help to classify the tumors according to their mutation-profile.
#50
https://scitemed.com/article/4250/scitemed-aohns-2024-00184
Schwannomatosis should be considered in the differential diagnosis for patients presenting with multiple schwannomas or extensive involvement of a single nerve, especially those not meeting the criteria for neurofibromatosis type 2. The implications for malignancy risk, surveillance, genetic testing, and counseling are significant and distinct from other forms of neurofibromatosis. As diagnostic criteria continue to evolve, it is crucial for clinicians to stay updated with the latest developments in the field.
#51 Genetic Testing for Neurofibromatosis and Related Disorders
https://member.myhealthtoolkitla.com/web/public/brands/medicalpolicy/external-policies/genetic-testing-for-neurofibromatosis-and-related-disorders/
Schwannomatosis is caused by inactivating mutations in SMARCB1 and LZTR and is characterized by multiple schwannomas and pain arising in adulthood (Bergner Yohay, 2024). […] Germline mutations of either the SMARCB1 or LZTR1 tumor suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients (Kehrer-Sawatzki et al., 2017). […] Biallelic inactivation of these tumor suppressor genes leads to schwannomatosis (Radhika Dhamija, 2023). […] A combined molecular and clinical diagnosis may be made with 2 tumors with 22q LOH and different somatic NF2 mutations AND 2 pathologically confirmed schwannomas or meningiomas […] OR […] Germline SMARCB1 or LZTR1 pathogenic mutation AND one pathologically confirmed schwannoma or meningioma. […] Kehrer-Sawatzki et al. (2017) also recommended, Comprehensive mutation analysis of all three genes, LZTR1, SMARCB1, and NF2, in patients with schwannomatosis should be performed to identify the complete mutational spectra and the number of mutational hits that affect these genes. […] This comprehensive testing may help to classify the tumors according to their mutation-profile.
#52 The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis
https://pmc.ncbi.nlm.nih.gov/articles/PMC5258795/
Thus, schwannomatosis is paradigmatic for a tumour predisposition syndrome caused by the concomitant mutational inactivation of two or more tumour suppressor genes. […] The majority of patients with schwannomatosis are sporadic, whereas 13-25% are familial cases. […] However, instead of constitutional (germline) NF2 mutations, independent somatic mutations affecting both NF2 alleles are frequently found in schwannomas of patients with schwannomatosis. […] So far, two schwannomatosis predisposition genes have been identified, SMARCB1 and LZTR1. […] The clinical overlap between schwannomatosis and NF2 renders differential diagnosis somewhat difficult, particularly in sporadic and mosaic cases with multiple schwannomas but without bilateral vestibular schwannomas and detectable germline NF2 gene mutations.
#53 Schwannomatosis â Knowledge and References â Taylor & Francis
https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Oncology/Schwannomatosis/
Schwannomatosis is largely sporadic, likely representing new mutations, but some cases of autosomal-dominant transmission have been observed. […] The genetics of schwannomatosis is complex and remains incompletely understood, but recent evidence suggests that the NF2 gene is not the culprit in germline transmission of schwannomatosis. […] Germline involvement of the SMARCB1 gene on chromosome 22 seems to be implicated in the genesis of schwannomatosis, with many schwannomatosis patients showing an interplay of multihit mutations involving both SMARCB1 and NF2 in affected somatic tissues. […] SMARCB1 has been shown to play a role in the tumorigenesis of schwannomatosis but not in isolated sporadic schwannomas. […] Given our limited understanding of schwannomatosis and NF2 in relation to their genetics, pathogenesis, clinical presentation, and outcome, further studies are necessary to improve the detection of additional predisposing, or modifying, genes, the determination of cellular pathways, genotype/phenotype correlations, and the design of novel therapies based on affected pathways. […] Schwannomatosis is clinically and genetically considered to be a third form of neurofibromatosis, along with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2).
#54 Schwannomatosis â Knowledge and References â Taylor & Francis
https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Oncology/Schwannomatosis/
Schwannomatosis is largely sporadic, likely representing new mutations, but some cases of autosomal-dominant transmission have been observed. […] The genetics of schwannomatosis is complex and remains incompletely understood, but recent evidence suggests that the NF2 gene is not the culprit in germline transmission of schwannomatosis. […] Germline involvement of the SMARCB1 gene on chromosome 22 seems to be implicated in the genesis of schwannomatosis, with many schwannomatosis patients showing an interplay of multihit mutations involving both SMARCB1 and NF2 in affected somatic tissues. […] SMARCB1 has been shown to play a role in the tumorigenesis of schwannomatosis but not in isolated sporadic schwannomas. […] Given our limited understanding of schwannomatosis and NF2 in relation to their genetics, pathogenesis, clinical presentation, and outcome, further studies are necessary to improve the detection of additional predisposing, or modifying, genes, the determination of cellular pathways, genotype/phenotype correlations, and the design of novel therapies based on affected pathways. […] Schwannomatosis is clinically and genetically considered to be a third form of neurofibromatosis, along with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2).
#55 Schwannomatosis â Knowledge and References â Taylor & Francis
https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Oncology/Schwannomatosis/
Schwannomatosis is largely sporadic, likely representing new mutations, but some cases of autosomal-dominant transmission have been observed. […] The genetics of schwannomatosis is complex and remains incompletely understood, but recent evidence suggests that the NF2 gene is not the culprit in germline transmission of schwannomatosis. […] Germline involvement of the SMARCB1 gene on chromosome 22 seems to be implicated in the genesis of schwannomatosis, with many schwannomatosis patients showing an interplay of multihit mutations involving both SMARCB1 and NF2 in affected somatic tissues. […] SMARCB1 has been shown to play a role in the tumorigenesis of schwannomatosis but not in isolated sporadic schwannomas. […] Given our limited understanding of schwannomatosis and NF2 in relation to their genetics, pathogenesis, clinical presentation, and outcome, further studies are necessary to improve the detection of additional predisposing, or modifying, genes, the determination of cellular pathways, genotype/phenotype correlations, and the design of novel therapies based on affected pathways. […] Schwannomatosis is clinically and genetically considered to be a third form of neurofibromatosis, along with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2).
#56 Schwannomatosis â Knowledge and References â Taylor & Francis
https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Oncology/Schwannomatosis/
Schwannomatosis is largely sporadic, likely representing new mutations, but some cases of autosomal-dominant transmission have been observed. […] The genetics of schwannomatosis is complex and remains incompletely understood, but recent evidence suggests that the NF2 gene is not the culprit in germline transmission of schwannomatosis. […] Germline involvement of the SMARCB1 gene on chromosome 22 seems to be implicated in the genesis of schwannomatosis, with many schwannomatosis patients showing an interplay of multihit mutations involving both SMARCB1 and NF2 in affected somatic tissues. […] SMARCB1 has been shown to play a role in the tumorigenesis of schwannomatosis but not in isolated sporadic schwannomas. […] Given our limited understanding of schwannomatosis and NF2 in relation to their genetics, pathogenesis, clinical presentation, and outcome, further studies are necessary to improve the detection of additional predisposing, or modifying, genes, the determination of cellular pathways, genotype/phenotype correlations, and the design of novel therapies based on affected pathways. […] Schwannomatosis is clinically and genetically considered to be a third form of neurofibromatosis, along with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2).
#57
https://link.springer.com/article/10.1007/s40487-024-00279-2
Gene therapy holds potential as an effective and promising therapeutic strategy for NF2-related schwannomatosis in the future. […] Gene replacement therapy for NF2-related schwannomatosis directly supplies a functional copy of the mutated or inactivated NF2 gene to augment functional merlin protein re-expression in NF2-deficient tumor cells to treat the disease phenotype caused by the defective NF2 gene. […] The advantage of gene replacement therapy is that it can directly target the driver mutated NF2 gene and restore its function by delivering a functional copy of the NF2 gene to re-expression merlin protein in tumor cells. […] Gene knockdown and gene replacement combination therapy addresses the problem of whether the existing mutated NF2 gene has a dominant negative effect on the cell. […] The history of gene therapy for NF2-related schwannomatosis goes back to the 2010s. […] These studies support that gene therapy has the potential to provide therapeutic efficacy for NF2-related schwannomatosis.
#58
https://link.springer.com/article/10.1007/s40487-024-00279-2
Gene therapy holds potential as an effective and promising therapeutic strategy for NF2-related schwannomatosis in the future. […] Gene replacement therapy for NF2-related schwannomatosis directly supplies a functional copy of the mutated or inactivated NF2 gene to augment functional merlin protein re-expression in NF2-deficient tumor cells to treat the disease phenotype caused by the defective NF2 gene. […] The advantage of gene replacement therapy is that it can directly target the driver mutated NF2 gene and restore its function by delivering a functional copy of the NF2 gene to re-expression merlin protein in tumor cells. […] Gene knockdown and gene replacement combination therapy addresses the problem of whether the existing mutated NF2 gene has a dominant negative effect on the cell. […] The history of gene therapy for NF2-related schwannomatosis goes back to the 2010s. […] These studies support that gene therapy has the potential to provide therapeutic efficacy for NF2-related schwannomatosis.
#59 Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria
https://lirias.kuleuven.be/343390
Mouse models of schwannomatosis have been developed and promise to further expand our understanding of tumorigenesis and the tumor microenvironment. […] In the next 5 years, the authors expect that advances in basic research in the pathogenesis of schwannomatosis will lead toward clinical investigations of potential drug therapies.
#60
https://www.omim.org/entry/162091
A number sign (#) is used with this entry because susceptibility to the development of schwannomatosis-1 (SWN1) is conferred by germline heterozygous mutation in the tumor suppressor gene SMARCB1 (601607) on chromosome 22q11. […] Individual schwannoma tumors from patients with schwannomatosis have been found to harbor somatic mutations in the SMARCB1. […] Since the NF2 locus had been excluded as the germline event underlying familial schwannomatosis, and the gene placed centromeric to NF2 on chromosome 22, Hulsebos et al. (2007) investigated the SMARCB1 gene in a father and daughter with the disorder. Both were found to be heterozygous for a inactivating germline mutation of this gene (601607.0005). In 2 of 4 investigated schwannomas from these patients, inactivation of the wildtype INI1 allele by a second mutation in exon 5 of the gene (601607.0006) or by loss of the gene was found, consistent with the Knudson 2-hit hypothesis.