Materiały źródłowe

• #1 The pathology of ocular cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3574240/

  Primary cancers of the eye are rare. These include uveal melanoma, a tumor that preferentially affects the choroid of light-eyed, fair-skinned Europeans, and the pediatric retinal neoplasm retinoblastoma, which is slightly more common worldwide. Uveal melanoma kills about half of affected patients. Most succumb to hepatic metastases, which are unresponsive to current therapy. Factors indicative of poor prognosis include tumor size, ciliary body involvement, epithelioid cells, extraocular extension, lymphocytic and melanophagic infiltration, mitotic activity, vascular mimicry patterns, and most importantly, the detection of monosomy 3 and class 2 gene expression profile in tumor cells using special tests. […] Uveal melanoma’s propensity for lightly pigmented patients and the posterior part of the uveal tract suggests that UV light may have a role in its pathogenesis, but several studies in this regard are inconclusive.

• #2 The pathology of ocular cancer – ProQuest

  https://www.proquest.com/scholarly-journals/pathology-ocular-cancer/docview/1287507804/se-2

  Primary cancers of the eye are rare. These include uveal melanoma, a tumor that preferentially affects the choroid of light-eyed, fair-skinned Europeans, and the pediatric retinal neoplasm retinoblastoma, which is slightly more common worldwide. Uveal melanoma kills about half of affected patients. Most succumb to hepatic metastases, which are unresponsive to current therapy. Factors indicative of poor prognosis include tumor size, ciliary body involvement, epithelioid cells, extraocular extension, lymphocytic and melanophagic infiltration, mitotic activity, vascular mimicry patterns, and most importantly, the detection of monosomy 3 and class 2 gene expression profile in tumor cells using special tests. […] Most retinoblastomas are caused by sporadic somatic mutations in the RB1 gene, but about one-third arise in infants with germline mutations. The latter tend to develop earlier, are often bilateral and are transmissible to offspring as an autosomal dominant trait. Retinoblastoma displays varying degrees of differentiation including Homer Wright and Flexner-Wintersteiner rosettes and photoreceptor differentiation (eurettes).

• #3 The pathology of ocular cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3574240/

  Cancer is a genetic disease characterized by genomic instability and the progressive accumulation of genetic abnormalities or mutations. Fifty percent of uveal melanomas harbor mutations in the GNAQ gene that encodes a G-protein-coupled receptor in the RAF/MEK/ERK pathway. Also found in benign precursor lesions, such as congenital ocular melanocytosis GNAQ mutations are thought to be an early or initiating event in the pathogenesis of uveal melanoma. […] The expression of genes in uveal melanomas changes as tumors undergo malignant transformation. Gene expression profile (GEP) analysis has identified two classes of tumors that differ markedly in their metastatic potential. The GEP of low-grade (Class I) melanomas resembles melanocytes. Class I tumor rarely metastasize (5%). In contrast, the GEP of class 2 tumors, which have more than a 90% risk for metastasis, resembles that of primitive neural or ectodermal stem cells.

• #4 The pathology of ocular cancer | Eye

  https://www.nature.com/articles/eye2012237

  Primary cancers of the eye are rare. These include uveal melanoma, a tumor that preferentially affects the choroid of light-eyed, fair-skinned Europeans, and the pediatric retinal neoplasm retinoblastoma, which is slightly more common worldwide. Uveal melanoma kills about half of affected patients. Most succumb to hepatic metastases, which are unresponsive to current therapy. Factors indicative of poor prognosis include tumor size, ciliary body involvement, epithelioid cells, extraocular extension, lymphocytic and melanophagic infiltration, mitotic activity, vascular mimicry patterns, and most importantly, the detection of monosomy 3 and class 2 gene expression profile in tumor cells using special tests. […] Cancer is a genetic disease characterized by genomic instability and the progressive accumulation of genetic abnormalities or mutations. Fifty percent of uveal melanomas harbor mutations in the GNAQ gene that encodes a G-protein-coupled receptor in the RAF/MEK/ERK pathway. Also found in benign precursor lesions, such as congenital ocular melanocytosis, GNAQ mutations are thought to be an early or initiating event in the pathogenesis of uveal melanoma.

• #5 Eye melanoma – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/eye-melanoma/symptoms-causes/syc-20372371

  Eye melanoma is a kind of eye cancer that starts in cells within the eye that make melanin. […] Eye melanoma happens when cells in the eye develop changes in their DNA. A cell’s DNA holds the instructions that tell the cell what to do. In healthy cells, the DNA tells the cells to grow and multiply at a set rate. The DNA also tells the cells to die at a set time. […] In cancer cells, the DNA changes give different instructions. The changes tell the cancer cells to grow and multiply quickly. Cancer cells can keep living when healthy cells would die. This causes too many cells. […] The cancer cells might form a mass called a tumor. The tumor can grow to invade and destroy healthy tissue. In time, cancer cells can break away and spread to other parts of the body. When cancer spreads, it’s called metastatic cancer.

• #6 Eye Cancer: Symptoms, Types & Treatment

  https://my.clevelandclinic.org/health/diseases/17292-eye-cancer

  Most eye cancers are melanomas that form in your choroid, ciliary body or iris. […] Eye cancer starts when cells multiply out of control and form a tumor. […] As with cancers in general, eye cancer occurs when cells begin to divide and multiply out of control, eventually forming a mass called a tumor. […] Scientists are still researching to understand what causes otherwise healthy cells to become cancer cells.

• #7 Uveal melanoma – Wikipedia

  https://en.wikipedia.org/wiki/Uveal_melanoma

  Uveal melanoma is a type of eye cancer in the uvea of the eye. It is traditionally classed as originating in the iris, choroid, and ciliary body, but can also be divided into class I (low metastatic risk) and class II (high metastatic risk). […] Tumors arise from the pigment cells that reside within the uvea and give color to the eye. These melanocytes are distinct from the retinal pigment epithelium cells underlying the retina that do not form melanomas. […] Uveal melanoma is distinct from most skin melanomas associated with ultraviolet exposure; however, it shares several similarities with non-sun-exposed melanomas, such as acral melanomas and mucosal melanomas. BRAF mutations are extremely rare in posterior uveal melanomas; instead, uveal melanomas frequently harbor GNAQ/GNA11 mutations, a trait shared with blue nevi, nevus of Ota, and ocular melanosis.

• #8 What Is Eye Cancer? | American Cancer Society

  https://www.cancer.org/cancer/types/eye-cancer/about/what-is-eye-cancer.html

  Eye cancer can refer to any cancer that starts in the eye. The most common type of eye cancer is melanoma (also known as ocular melanoma or intraocular melanoma). But there are other types of cancer that affect different kinds of cells in the eye. […] Different types of cancer can start in each of these areas. […] Cancers that are within the eye itself are called intraocular (or ocular) cancers: […] Intraocular melanoma, or ocular melanoma, is the most common eye cancer in adults, but it is still fairly rare. Melanomas that start in the skin are much more common than melanomas that start in the eye. […] Melanomas develop from pigment-making cells called melanocytes. In the eye, they usually start in the uvea (uveal melanoma) or much less often in the conjunctiva (conjunctival melanoma).

• #9 Molecular pathology of uveal melanoma | Eye

  https://www.nature.com/articles/eye2012255

  In most UM, the retinoblastoma (Rb) and p53 pathways are functionally inhibited, although actual mutations in the RB1 and TP53 genes are rare. […] The PI3K/AKT pathway is constitutively activated in most UM. […] The mitogen-activated protein kinase/extracellular signal-related kinase pathway (MAPK/ERK) pathway is essential for mediating cell-cycle progression, and in several types of cancer mutations in this pathway result in it being constitutively activated, producing inappropriate and autonomous proliferation of neoplastic cells. […] This puzzle concerning the MAPK pathway, and the mechanisms by which it was constitutively activated, persisted until the recent discovery of mutations in GNAQ in almost half of UM. […] GNAQ and GNA11 mutations are also found in uveal naevi and in most UM regardless of their tumour stage, chromosomal constellation or other outcome predictors.

• #10 Novel Genetic Mutation that Causes the Most Common form of Eye Cancer Discovered | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/news-releases/novel-genetic-mutation-causes-most-common-form-eye-discovered

  An international, multi-center study has revealed the discovery of a novel oncogene that is associated with uveal melanoma, the most common form of eye cancer. Researchers have isolated an oncogene called GNA11 and have found that it is present in more than 40 percent of tumor samples taken from patients with uveal melanoma. […] These findings are significant because we now have a much better understanding of the precise mechanism of this disease, which may yield targets and treatments in the future. […] Currently, once this type of melanoma has spread beyond the eye, therapeutic options are extremely limited, added Dr. Bastian. […] Previous studies from this group have revealed another oncogene associated with uveal melanoma, called GNAQ. […] Based on this latest research and recent studies, 83 percent of uveal melanomas are now known to have an active mutation in the GNAQ or GNA11 oncogenes. […] In addition, said Dr. Bastian, since the large majority of uveal melanomas harbor mutations in these two oncogenes, this suggests that the activation of the Gq/11 pathway is the main route to the development of uveal melanoma and identifies a brand new target for therapeutic intervention.

• #11 Molecular pathology of uveal melanoma | Eye

  https://www.nature.com/articles/eye2012255

  These mutations appear to be necessary but not sufficient for complete malignant transformation to melanoma. […] These data suggest that GNAQ and GNA11 mutations are early events in the molecular pathogenesis of UM. […] The most striking abnormality in UM is the complete or partial loss of chromosome 3. […] The above-mentioned chromosomal alterations in primary UM are clinically relevant because of their correlation with the risk of metastatic death. […] Chromosome 3 loss is associated with a reduction of the 5-year survival probability from approximately 100% to 50%. […] Although considerable work has demonstrated that the hallmarks of cancer are applicable to UM, the identification of the genetic pathways associated with UM oncogenesis and particularly those with metastasis is still at a preliminary stage.

• #12 Melanoma of the eye caused by two gene mutations | ScienceDaily

  https://www.sciencedaily.com/releases/2014/05/140529132004.htm

  The two genes implicated — GNAQ and GNA11 — code for proteins (known as G proteins) that normally function as molecular on-off switches, regulating the passage of information from the outside to the inside of a cell. […] In their experiments, the scientists showed that mutations in these genes shift the G proteins to a permanent „on” or active status, which results in over-activation the Yes-associated protein (YAP). The activation of the YAP protein induces uncontrolled cell growth and inhibits cell death, causing malignancies. […] „We have a cancer that is caused by a very simple genetic mechanism,” Guan said. „And we have a drug that works on this mechanism. The clinical applications are very direct.”

• #13 Molecular pathology of uveal melanoma | Eye

  https://www.nature.com/articles/eye2012255

  Like other cancers, uveal melanomas (UM) are characterised by an uncontrolled, clonal, cellular proliferation, occurring as a result of numerous genetic, and epigenetic aberrations. […] Signalling pathways known to be disrupted in UM include: (1) the retinoblastoma pathway, probably as a result of cyclin D1 overexpression; p53 signalling, possibly as a consequence of MDM2 overexpression; and the P13K/AKT and mitogen-activated protein kinase/extracellular signal-related kinase pathway pathways that are disturbed as a result of PTEN and GNAQ/11 mutations, respectively. […] The identification of abnormal signalling pathways, genes and proteins in UM opens the way for target-based therapies, improving prospects for conserving vision and prolonging life. […] Intense efforts have been made in the last decades to understand the molecular genetics involved in the development and the progression of UM, to recognise those that are likely to metastasise, and to identify signalling pathways and possible druggable molecules in the neoplastic melanocytes, which can be targeted using systemic therapies.

• #14 The pathology of ocular cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3574240/

  As discussed previously, the prognosis of uveal melanoma is most accurately determined using molecular biological techniques to assess tumors for nonrandom chromosomal abnormalities or GEP. Patients (50%) who have monosomy 3 in their tumor cells will die within 3 years. […] Uveal melanoma typically metastasizes to the liver, which is involved in 90% of cases. Studies based on tumor doubling times suggest that uveal melanomas destined to metastasize already have spawned clinically unapparent distant micrometases before the patient becomes symptomatic and consults an ophthalmologist. […] The genetics of retinoblastoma actually are more complicated than initially thought. Dimaras et al have shown that both copies of the RB1 gene are also lost or inactivated in well-differentiated, benignly-behaving precursor tumors called retinomas or retinocytomas, which typically exhibits advanced degrees of photoreceptor differentiation. A number of additional mutations are required for malignant transformation into retinoblastoma.

• #15 The pathology of ocular cancer | Eye

  https://www.nature.com/articles/eye2012237

  The expression of genes in uveal melanomas changes as tumors undergo malignant transformation. Gene expression profile (GEP) analysis has identified two classes of tumors that differ markedly in their metastatic potential. The GEP of low-grade (Class I) melanomas resembles melanocytes. Class I tumor rarely metastasize (5%). In contrast, the GEP of class 2 tumors, which have more than a 90% risk for metastasis, resembles that of primitive neural or ectodermal stem cells. In addition, class 2 tumors typically have major chromosomal abnormalities such as loss of chromosome 3 (monosomy 3) and/or amplification of the long arm of chromosome 8 (8Q), which are important prognostic indicators. […] As discussed previously, the prognosis of uveal melanoma is most accurately determined using molecular biological techniques to assess tumors for nonrandom chromosomal abnormalities or GEP. Patients (50%) who have monosomy 3 in their tumor cells will die within 3 years. Patients with disomy 3 have a poorer prognosis if there is amplification of 8q.

• #16 Eye Cancer: Unique Insights into Oncogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1769553/

  Uveal melanomas (and many other solid tumors) do not completely abolish Rb activity, but rather, they appear to cause partial inactivation of Rb, to allow cell division without inducing the excessive apoptosis that can accompany complete Rb loss. […] If Rb pathway alterations occur early in uveal melanoma pathogenesis, what are the later events that determine whether these tumors will metastasize? […] The discovery that uveal melanomas form a binary classification of low- and high-risk tumors, rather than a continual spectrum of tumors of intermediate metastatic risks, will profoundly affect future research directions, the design of clinical trials, and the management of patients.

• #17 The pathology of ocular cancer | Eye

  https://www.nature.com/articles/eye2012237

  The expression of genes in uveal melanomas changes as tumors undergo malignant transformation. Gene expression profile (GEP) analysis has identified two classes of tumors that differ markedly in their metastatic potential. The GEP of low-grade (Class I) melanomas resembles melanocytes. Class I tumor rarely metastasize (5%). In contrast, the GEP of class 2 tumors, which have more than a 90% risk for metastasis, resembles that of primitive neural or ectodermal stem cells. In addition, class 2 tumors typically have major chromosomal abnormalities such as loss of chromosome 3 (monosomy 3) and/or amplification of the long arm of chromosome 8 (8Q), which are important prognostic indicators. […] As discussed previously, the prognosis of uveal melanoma is most accurately determined using molecular biological techniques to assess tumors for nonrandom chromosomal abnormalities or GEP. Patients (50%) who have monosomy 3 in their tumor cells will die within 3 years. Patients with disomy 3 have a poorer prognosis if there is amplification of 8q.

• #18 Uveal melanoma – Wikipedia

  https://en.wikipedia.org/wiki/Uveal_melanoma

  The most important genetic alteration associated with poor prognosis in uveal melanoma is inactivation of BAP1, which most often occurs through mutation of one allele and subsequent loss of an entire copy of chromosome 3 (monosomy 3) to unmask the mutant copy. […] The most accurate prognostic factor is molecular classification by gene expression profiling of uveal melanomas. This analysis has been used to identify two subclasses of uveal melanomas: class 1 tumors that have a very low risk of metastasis, and class 2 tumors that have a very high risk of metastasis.

• #19 Uveal Melanoma: Comprehensive Review of Its Pathophysiology, Diagnosis, Treatment, and Future Perspectives

  https://www.mdpi.com/2227-9059/12/8/1758

  Uveal melanoma (UM) is the most common intraocular malignancy in adults. Recent advances highlight the role of tumor-derived extracellular vesicles (TEV) and circulating hybrid cells (CHC) in UM tumorigenesis. […] Frequent mutations in the BAP1 (i.e., BRCA-1 associated protein 1), EIF1AX (i.e., eukaryotic translation initiation factor 1A X-linked), GNA11 (i.e., guanosine nucleotide-binding protein alpha-11), GNAQ (i.e., guanosine nucleotide-binding protein Q), and SF3B1 (i.e., splicing factor 3b subunit 1) genes were shown to occur in the majority of UM cases, as well as contribute on different levels to the metastatic risk. […] Furthermore, recent studies have underscored the importance of circulating neoplastic-immune hybrid cells (CHCs) in the blood—corresponding to dual nature hybrid cells (DNCs) in the primary tumor—and tumor-derived extracellular vesicles (TEVs) in the pathogenesis of metastatic UM.

• #20 The pathology of ocular cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3574240/

  As discussed previously, the prognosis of uveal melanoma is most accurately determined using molecular biological techniques to assess tumors for nonrandom chromosomal abnormalities or GEP. Patients (50%) who have monosomy 3 in their tumor cells will die within 3 years. […] Uveal melanoma typically metastasizes to the liver, which is involved in 90% of cases. Studies based on tumor doubling times suggest that uveal melanomas destined to metastasize already have spawned clinically unapparent distant micrometases before the patient becomes symptomatic and consults an ophthalmologist. […] The genetics of retinoblastoma actually are more complicated than initially thought. Dimaras et al have shown that both copies of the RB1 gene are also lost or inactivated in well-differentiated, benignly-behaving precursor tumors called retinomas or retinocytomas, which typically exhibits advanced degrees of photoreceptor differentiation. A number of additional mutations are required for malignant transformation into retinoblastoma.

• #21 The pathology of ocular cancer | Eye

  https://www.nature.com/articles/eye2012237

  Uveal melanoma typically metastasizes to the liver, which is involved in 90% of cases. Studies based on tumor doubling times suggest that uveal melanomas destined to metastasize already have spawned clinically unapparent distant micrometases before the patient becomes symptomatic and consults an ophthalmologist.

• #22 Uveal Melanoma: Comprehensive Review of Its Pathophysiology, Diagnosis, Treatment, and Future Perspectives

  https://www.mdpi.com/2227-9059/12/8/1758

  The majority (90%) of UMs arise from the choroid of the uveal tract. The eye is in fact an immune privileged site; ocular immune privilege is defined by the presence of local and systemic mechanisms to limit local inflammation. Dysregulations of the immune system are directly associated with the development of malignancies. […] The inflammatory phenotype of UM, which is defined as a lymphocytic inflammatory process, is known to be associated with a poor prognosis. […] Activation of the NFκB pathway was found to occur in primary and metastatic UM, subsequently upregulating UM cell proliferation and inhibiting apoptosis. […] A major constituent of the TME are TEVs, which are known to bridge the communication between tumor cells and their microenvironment. TEVs favor tumorigenesis through the transfer of their material to neighboring cells.

• #23 Uveal Melanoma: Comprehensive Review of Its Pathophysiology, Diagnosis, Treatment, and Future Perspectives

  https://www.mdpi.com/2227-9059/12/8/1758

  The oncogenic potential of TEVs in metastatic disease has been proposed as a mechanism for UM dissemination. […] CHCs are a novel tumor cell population found within the TME recently identified in the blood of patients with UM. They result from the fusion of tumor cells with leucocytes and form the backbone of tumor heterogeneity.

• #24 Doctors identify molecular cause of eye cancer

  https://medicalxpress.com/news/2021-09-doctors-molecular-eye-cancer.html?deviceType=mobile

  Researchers have identified a molecular mechanism that drives the progression of uveal melanoma (UM), an often lethal eye cancer in adults. […] The finding, published in the journal Nature Communications, may offer an opportunity to develop treatments to suppress earlier a lethal type of tumor that spreads to other parts of the body. […] It also represents a breakthrough in understanding cancer biology, linking two hallmarks of cancer—chromosomal instability (errors in chromosome segregation during cell division) and epigenetic alterations (changes in gene regulation)—that interact to advance disease progression. […] The researchers integrated a variety of genetic and other analyses at the single-cell level to demonstrate that UM progression is propelled by the loss of Polycomb Repressive Complex 1—proteins that regulate gene expression. This loss leads to aberrant gene expression and errors in the way chromosomes segregate during cell division. Eventually, this leads to an inflammatory response that makes the tumor more aggressive. […] „By uncovering key steps involved in tumor progression, our work highlights an opportunity for earlier therapeutic intervention to suppress tumor evolution,” Bakhoum said.

• #25 Doctors identify molecular cause of eye cancer

  https://medicalxpress.com/news/2021-09-doctors-molecular-eye-cancer.html?loadCommentsForm=1&deviceType=mobile

  Researchers have identified a molecular mechanism that drives the progression of uveal melanoma (UM), an often lethal eye cancer in adults. […] The finding, published in the journal Nature Communications, may offer an opportunity to develop treatments to suppress earlier a lethal type of tumor that spreads to other parts of the body. […] The researchers integrated a variety of genetic and other analyses at the single-cell level to demonstrate that UM progression is propelled by the loss of Polycomb Repressive Complex 1—proteins that regulate gene expression. This loss leads to aberrant gene expression and errors in the way chromosomes segregate during cell division. Eventually, this leads to an inflammatory response that makes the tumor more aggressive. […] „By uncovering key steps involved in tumor progression, our work highlights an opportunity for earlier therapeutic intervention to suppress tumor evolution,” Bakhoum said.

• #26 Retinoblastoma – Wikipedia

  https://en.wikipedia.org/wiki/Retinoblastoma

  Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cases are first detected in those under 3 years old. […] Almost half of children with retinoblastoma have a hereditary genetic defect associated with it. In other cases, retinoblastoma is caused by a congenital mutation in the chromosome 13 gene 13q14 (retinoblastoma protein). […] Mutation of genes, found in chromosomes, can affect the way in which cells grow and develop within the body. Alterations in RB1 or MYCN can give rise to retinoblastoma. […] In children with the heritable genetic form of retinoblastoma, a mutation occurs in the RB1 gene on chromosome 13. RB1 was the first tumor suppressor gene cloned. Although RB1 interacts with over 100 cell proteins, its negative regulator effect on the cell cycle principally arises from binding and inactivation of the transcription factor E2F, thus repressing the transcription of genes which are required for the S phase.

• #27 Retinoblastoma: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1222849-overview

  Retinoblastoma is the most common primary ocular malignancy (eye cancer) of childhood. […] The most widely held concept of histogenesis of retinoblastoma holds that it generally arises from a multipotential precursor cell (mutation in the long arm of chromosome 13 band 13q14) that could develop into almost any type of inner or outer retinal cell. Intraocularly, it exhibits a variety of growth patterns, which have been described as outlined below. […] In 1970, Tso and colleagues established that the tumor arises from photoreceptor precursors. […] In October of 2007, a team of investigators at St. Jude Children’s Research Hospital (Memphis, Tenn) claimed to have identified the specific cell that gives rise to retinoblastoma. The major importance of this discovery is the idea that retinoblastoma can arise from fully matured nerves in the retina called horizontal interneurons, disproving the long-held scientific principle that fully formed, mature nerves cannot multiply like young immature cells.

• #28 Retinoblastoma – Wikipedia

  https://en.wikipedia.org/wiki/Retinoblastoma

  Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cases are first detected in those under 3 years old. […] Almost half of children with retinoblastoma have a hereditary genetic defect associated with it. In other cases, retinoblastoma is caused by a congenital mutation in the chromosome 13 gene 13q14 (retinoblastoma protein). […] Mutation of genes, found in chromosomes, can affect the way in which cells grow and develop within the body. Alterations in RB1 or MYCN can give rise to retinoblastoma. […] In children with the heritable genetic form of retinoblastoma, a mutation occurs in the RB1 gene on chromosome 13. RB1 was the first tumor suppressor gene cloned. Although RB1 interacts with over 100 cell proteins, its negative regulator effect on the cell cycle principally arises from binding and inactivation of the transcription factor E2F, thus repressing the transcription of genes which are required for the S phase.

• #29 Retinoblastoma (Eye Cancer in Children) | Children’s Hospital of Philadelphia

  https://www.chop.edu/conditions-diseases/retinoblastoma

  Retinoblastoma is a rare eye cancer found in children. It originates in the part of the eye called the retina. […] Hereditary retinoblastoma is caused by alterations, also known as mutations, to specific areas within an individuals genetic information. […] In patients with hereditary retinoblastoma, the disorder develops as the result of alterations in a specific gene known as RB1, which is located on chromosome 13 at position q14.1-q14.2. RB1 is the only gene known to be associated with hereditary retinoblastoma. The protein produced by the RB1 gene acts as a tumor suppressor, which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death. […] Individuals with hereditary retinoblastoma are also at a slightly increased risk to develop tumors of the pineal gland. Later in life, patients may develop other tumors, most commonly bone or muscle tumors. […] It is believed that most children with non-hereditary disease develop a retinoblastoma tumor because both RB1 gene copies become damaged within a single developing retinal cell.

• #30 Retinoblastoma – Wikipedia

  https://en.wikipedia.org/wiki/Retinoblastoma

  The development of retinoblastoma can be explained by the two-hit model. According to the two-hit model, both alleles need to be affected, so two events are necessary for the retinal cell or cells to develop into tumors. The first mutational event can be inherited (germline or constitutional), which will then be present in all cells in the body. The second hit results in the loss of the remaining normal allele (gene) and occurs within a particular retinal cell. In the sporadic, nonheritable form of retinoblastoma, both mutational events occur within a single retinal cell after fertilization (somatic events); sporadic retinoblastoma tends to be unilateral. […] Not all retinoblastoma cases are with RB1 inactivation. There are cases reported with only one RB1 mutation or even two functional RB1 alleles, which indicates other oncogenic lesions of retinoblastoma. Somatic amplification of the MYCN oncogene is responsible for some cases of nonhereditary, early-onset, aggressive, unilateral retinoblastoma. MYCN can act as a transcription factor and promotes proliferation by regulating the expression of cell cycle genes.

• #31 Retinoblastoma: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/retinoblastoma/

  Retinoblastoma is a rare type of eye cancer that usually develops in early childhood, typically before the age of 5. This form of cancer develops in the retina, which is the specialized light-sensitive tissue at the back of the eye that detects light and color. […] Mutations in the RB1 gene are responsible for most cases of retinoblastoma. RB1 is a tumor suppressor gene, which means that it normally regulates cell growth and stops cells from dividing too rapidly or in an uncontrolled way. Most mutations in the RB1 gene prevent it from making any functional protein, so cells are unable to regulate cell division effectively. As a result, certain cells in the retina can divide uncontrollably to form a cancerous tumor. Some studies suggest that additional genetic changes can influence the development of retinoblastoma; these changes may help explain variations in the development and growth of retinoblastoma and other types of tumors in different people.

• #32 Retinoblastoma: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/retinoblastoma/

  Researchers estimate that one-third of all retinoblastomas are hereditary, which means that RB1 gene mutations are present in all of the body’s cells, including reproductive cells (sperm or eggs). People with hereditary retinoblastoma may have a family history of the disease, and they are at risk of passing on the mutated RB1 gene to the next generation. The other two-thirds of retinoblastomas are non-hereditary, which means that RB1 gene mutations are present only in cells of the eye and cannot be passed to the next generation.

• #33 The pathology of ocular cancer – ProQuest

  https://www.proquest.com/scholarly-journals/pathology-ocular-cancer/docview/1287507804/se-2

  Primary cancers of the eye are rare. These include uveal melanoma, a tumor that preferentially affects the choroid of light-eyed, fair-skinned Europeans, and the pediatric retinal neoplasm retinoblastoma, which is slightly more common worldwide. Uveal melanoma kills about half of affected patients. Most succumb to hepatic metastases, which are unresponsive to current therapy. Factors indicative of poor prognosis include tumor size, ciliary body involvement, epithelioid cells, extraocular extension, lymphocytic and melanophagic infiltration, mitotic activity, vascular mimicry patterns, and most importantly, the detection of monosomy 3 and class 2 gene expression profile in tumor cells using special tests. […] Most retinoblastomas are caused by sporadic somatic mutations in the RB1 gene, but about one-third arise in infants with germline mutations. The latter tend to develop earlier, are often bilateral and are transmissible to offspring as an autosomal dominant trait. Retinoblastoma displays varying degrees of differentiation including Homer Wright and Flexner-Wintersteiner rosettes and photoreceptor differentiation (eurettes).

• #34 Retinoblastoma – Wikipedia

  https://en.wikipedia.org/wiki/Retinoblastoma

  The development of retinoblastoma can be explained by the two-hit model. According to the two-hit model, both alleles need to be affected, so two events are necessary for the retinal cell or cells to develop into tumors. The first mutational event can be inherited (germline or constitutional), which will then be present in all cells in the body. The second hit results in the loss of the remaining normal allele (gene) and occurs within a particular retinal cell. In the sporadic, nonheritable form of retinoblastoma, both mutational events occur within a single retinal cell after fertilization (somatic events); sporadic retinoblastoma tends to be unilateral. […] Not all retinoblastoma cases are with RB1 inactivation. There are cases reported with only one RB1 mutation or even two functional RB1 alleles, which indicates other oncogenic lesions of retinoblastoma. Somatic amplification of the MYCN oncogene is responsible for some cases of nonhereditary, early-onset, aggressive, unilateral retinoblastoma. MYCN can act as a transcription factor and promotes proliferation by regulating the expression of cell cycle genes.

• #35 Retinoblastoma: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1222849-overview

  Retinoblastoma is the most common primary ocular malignancy (eye cancer) of childhood. […] The most widely held concept of histogenesis of retinoblastoma holds that it generally arises from a multipotential precursor cell (mutation in the long arm of chromosome 13 band 13q14) that could develop into almost any type of inner or outer retinal cell. Intraocularly, it exhibits a variety of growth patterns, which have been described as outlined below. […] In 1970, Tso and colleagues established that the tumor arises from photoreceptor precursors. […] In October of 2007, a team of investigators at St. Jude Children’s Research Hospital (Memphis, Tenn) claimed to have identified the specific cell that gives rise to retinoblastoma. The major importance of this discovery is the idea that retinoblastoma can arise from fully matured nerves in the retina called horizontal interneurons, disproving the long-held scientific principle that fully formed, mature nerves cannot multiply like young immature cells.

• #36 The pathology of ocular cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3574240/

  As discussed previously, the prognosis of uveal melanoma is most accurately determined using molecular biological techniques to assess tumors for nonrandom chromosomal abnormalities or GEP. Patients (50%) who have monosomy 3 in their tumor cells will die within 3 years. […] Uveal melanoma typically metastasizes to the liver, which is involved in 90% of cases. Studies based on tumor doubling times suggest that uveal melanomas destined to metastasize already have spawned clinically unapparent distant micrometases before the patient becomes symptomatic and consults an ophthalmologist. […] The genetics of retinoblastoma actually are more complicated than initially thought. Dimaras et al have shown that both copies of the RB1 gene are also lost or inactivated in well-differentiated, benignly-behaving precursor tumors called retinomas or retinocytomas, which typically exhibits advanced degrees of photoreceptor differentiation. A number of additional mutations are required for malignant transformation into retinoblastoma.

• #37 Retinoblastoma: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1222849-overview

  Retinoblastoma is the most common primary ocular malignancy (eye cancer) of childhood. […] The most widely held concept of histogenesis of retinoblastoma holds that it generally arises from a multipotential precursor cell (mutation in the long arm of chromosome 13 band 13q14) that could develop into almost any type of inner or outer retinal cell. Intraocularly, it exhibits a variety of growth patterns, which have been described as outlined below. […] In 1970, Tso and colleagues established that the tumor arises from photoreceptor precursors. […] In October of 2007, a team of investigators at St. Jude Children’s Research Hospital (Memphis, Tenn) claimed to have identified the specific cell that gives rise to retinoblastoma. The major importance of this discovery is the idea that retinoblastoma can arise from fully matured nerves in the retina called horizontal interneurons, disproving the long-held scientific principle that fully formed, mature nerves cannot multiply like young immature cells.

• #38 New Drug Target for Childhood Eye Cancer Discovered | HHMI

  https://www.hhmi.org/news/new-drug-target-childhood-eye-cancer-discovered

  To our surprise and excitement, what we found was that instead of cancer genes having genetic mutations, they were being epigenetically regulated differently than normal cells, says Dyer. […] Even though there’s no mutation in SYK in retinoblastoma, Dyer says, RB1 influences the way cells turn genes on and off. […] In the case of retinoblastoma, scientists now know that it’s one gene mutation causing a plethora of epigenetic changes.

• #39 Exploration of retinoblastoma pathogenesis with bioinformatics – Zhang – Translational Cancer Research

  https://tcr.amegroups.org/article/view/54313/html

  Differentially expressed genes (DEGs) from retinoblastoma (RB) tissues play key roles in the progression of RB. […] The role of DEGs in different subtypes and stages of RB has not yet been systematically analyzed. […] Through comparison with adjacent tissues, a total of 78 upregulated genes and 155 downregulated genes from the RB tissues were identified across the 3 data sets. […] Gene set enrichment analysis (GSEA) showed that the 3 representative genes CDK1, CDC20, and BUB1, which were all upregulated, could promote the cell cycle in RB. […] Cell Counting Kit-8 (CCK-8) experiment and GSEA results showed that UHRF1 can promote the proliferation and invasion of RB. […] Conversely, the downregulated representative gene CADM1 is a tumor suppressor gene, which can inhibit the progression of RB.

• #40 Exploration of retinoblastoma pathogenesis with bioinformatics – Zhang – Translational Cancer Research

  https://tcr.amegroups.org/article/view/54313/html

  These DEGs may be the key to understanding the development and invasion of RB. […] The results revealed that CDK1, CDC20, and BUB1 are upregulated in RB and participate in the process of RB by promoting the cell cycle. […] The role of UHRF1 in RB was confirmed with bioinformatics, further suggesting that UHRF1 could be a potential diagnostic and therapeutic target for RB. […] CADM1 is downregulated in RB, which possibly increases the proliferation and invasion of RB cells.

• #41 The pathology of ocular cancer

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3574240/

  Primary cancers of the eye are rare. These include uveal melanoma, a tumor that preferentially affects the choroid of light-eyed, fair-skinned Europeans, and the pediatric retinal neoplasm retinoblastoma, which is slightly more common worldwide. Uveal melanoma kills about half of affected patients. Most succumb to hepatic metastases, which are unresponsive to current therapy. Factors indicative of poor prognosis include tumor size, ciliary body involvement, epithelioid cells, extraocular extension, lymphocytic and melanophagic infiltration, mitotic activity, vascular mimicry patterns, and most importantly, the detection of monosomy 3 and class 2 gene expression profile in tumor cells using special tests. […] Uveal melanoma’s propensity for lightly pigmented patients and the posterior part of the uveal tract suggests that UV light may have a role in its pathogenesis, but several studies in this regard are inconclusive.

• #42 Plant Compound Gives Hope Against Deadly Eye Cancer | Arizona Retinal Specialists

  https://www.arizonaretinalspecialists.com/blog/plant-compound-gives-hope-against-deadly-eye-cancer/

  The cancer starts at the layer of pigmented cells of the eye that includes the iris. It represents about three to five percent of all melanoma cases, and is fatal in about half of the patients who develop it. Uveal melanoma doesnt have a strong link to ultraviolet ray exposure, unlike skin melanoma. However, researchers say people with fair skin and blue or green eyes are at higher risk of developing the cancer. […] For decades, researchers have been analyzing the overactive signaling molecules in uveal melanoma but have had little clinical progress in shutting them down. The protein commonly found in this specific type of tumor is called G alpha q, which belongs to a class of molecules known as G proteins. When such substances develop genetic errors that switch them on permanently, cancer can result.

• #43 Retinoblastoma – Wikipedia

  https://en.wikipedia.org/wiki/Retinoblastoma

  Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cases are first detected in those under 3 years old. […] Almost half of children with retinoblastoma have a hereditary genetic defect associated with it. In other cases, retinoblastoma is caused by a congenital mutation in the chromosome 13 gene 13q14 (retinoblastoma protein). […] Mutation of genes, found in chromosomes, can affect the way in which cells grow and develop within the body. Alterations in RB1 or MYCN can give rise to retinoblastoma. […] In children with the heritable genetic form of retinoblastoma, a mutation occurs in the RB1 gene on chromosome 13. RB1 was the first tumor suppressor gene cloned. Although RB1 interacts with over 100 cell proteins, its negative regulator effect on the cell cycle principally arises from binding and inactivation of the transcription factor E2F, thus repressing the transcription of genes which are required for the S phase.

• #44 Retinoblastoma (Eye Cancer in Children) | Children’s Hospital of Philadelphia

  https://www.chop.edu/conditions-diseases/retinoblastoma

  Retinoblastoma is a rare eye cancer found in children. It originates in the part of the eye called the retina. […] Hereditary retinoblastoma is caused by alterations, also known as mutations, to specific areas within an individuals genetic information. […] In patients with hereditary retinoblastoma, the disorder develops as the result of alterations in a specific gene known as RB1, which is located on chromosome 13 at position q14.1-q14.2. RB1 is the only gene known to be associated with hereditary retinoblastoma. The protein produced by the RB1 gene acts as a tumor suppressor, which means that it helps to keep cells from growing and dividing too quickly and it promotes cell death. […] Individuals with hereditary retinoblastoma are also at a slightly increased risk to develop tumors of the pineal gland. Later in life, patients may develop other tumors, most commonly bone or muscle tumors. […] It is believed that most children with non-hereditary disease develop a retinoblastoma tumor because both RB1 gene copies become damaged within a single developing retinal cell.

• #45 New Drug Shows Promise for Treating Eye Cancer Called Uveal Melanoma | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/news/new-drug-shows-promise-treating-eye-cancer-called-uveal-melanoma

  Uveal melanoma (also called ocular melanoma) is a cancer that forms in the eye. Although rare, this malignancy is often fatal when it spreads to other parts of the body, which happens in about half of all cases. […] Most skin melanomas are triggered by exposure to sun and ultraviolet radiation, which causes DNA mutations. Compared with other cancer types, skin melanomas have very high rates of mutation. This provides more targets for immunotherapy drugs called checkpoint inhibitors, which have worked very well against skin melanomas. The mutations driving uveal melanomas are generally not caused by sun damage and are far fewer in number. Because uveal melanomas dont have as many mutations to target with immunotherapy, those treatments are generally less effective than they are for skin melanomas.

• #46 New Drug Shows Promise for Treating Eye Cancer Called Uveal Melanoma | Memorial Sloan Kettering Cancer Center

  https://www.mskcc.org/news/new-drug-shows-promise-treating-eye-cancer-called-uveal-melanoma

  Overall, for metastatic uveal melanoma, weve tried a variety of drugs with very modest success. The average survival time for metastatic uveal melanoma is between one and two years. Better treatments are urgently needed. […] Tebentafusp enables immune T cells to recognize and target the uveal melanoma cells by homing in on a protein on the cancer cells called gp100. The T cells normally ignore the protein, but tebentafusp acts as matchmaker like forcing an introduction at an awkward dinner party to make the immune cell recognize the cancer cell as a threat. […] Tebentafusp is the first systemic therapy proven to help people live longer with uveal melanoma. Its shattering the notion that theres not much that can be done when this disease spreads. Its also a symbol of how fast cancer research is progressing.

• #47 logo–sylvester

  https://umiamihealth.org/en/sylvester-comprehensive-cancer-center/treatments-and-services/eye-and-ocular-cancer

  Primary eye cancers are rare. They can occur within the eye, on the eye’s surface, in the skin cells around the eye, or in your glands that produce tears. Secondary eye cancers occur more frequently. These are tumors from other parts of the body that have spread to the eye. […] Ocular oncology experts at Sylvester Comprehensive Cancer Center and Bascom Palmer Eye Institute work to treat eye and ocular cancers from all sides: ophthalmology, dermatology, ocular oncology, radiation oncology, and pathology. […] Targeted, precise radiation therapy options. We are the only center in South Florida offering localized internal plaque radiation therapy. This treatment allows us to treat cancer without removing the eye preserving vision, independence, and quality of life. […] Leading-edge intra-arterial chemotherapy for children with retinoblastoma. Your child has twice the chance his or her eye will be spared. Using intra-arterial chemotherapy, we target chemotherapy directly to the eye tumor. This curative treatment has decreased the number of eye removals (for retinoblastoma) by half. It is also easier on developing bodies. Sylvester is the only center in the Southeastern U.S. and one of a few in the country that is highly skilled at this treatment. […] Safer, more accurate diagnosis. Sylvester and Bascom Palmer offer ultra-high frequency OCT (optical coherence tomography). This optical ultrasound diagnoses melanomas and inner eyelid (conjunctival) tumors without biopsy or radiation.

• #48 How to Detect Eye Cancer & How to Treat It | UTSW Medical Center Medblog

  https://utswmed.org/medblog/eye-cancer-treatment/

  Treatment for eye cancer may include chemotherapy, radiation, or surgery. […] One of these is brachytherapy, a type of radiation therapy that places tiny radioactive capsules, pellets, seeds, or wires in the body temporarily or permanently to provide direct, targeted treatment. […] Brachytherapy often can be used to treat uveal melanoma. […] This advanced treatment for retinoblastoma delivers concentrated doses of cancer-killing drugs directly to the affected part of the eye. […] Surgery required to remove cancers that occur on the surface of the eye can cause a loss of tissue, so its important to have specialists who can reconstruct the surface of the eye using stem cells to support the regrowth of the tissue. […] Ocular oncologists collaborate with specialists in many other areas of medicine to provide the depth and breadth of care eye cancers require.

• #49 Cancer pathogenesis and therapy – Leiden University

  https://www.universiteitleiden.nl/en/research-dossiers/cancer-pathogenesis-and-therapy

  A healthy cell divides only when it is necessary for either growth or repair. In contrast, cancer cells multiply much more frequently and have escaped the natural control mechanisms. Changes in genetic material, known as mutations, are at the root of unbridled cell division. A cancer cell develops in steps, through an accumulation of mutations in genes involved in cell division. […] Molecular and genetic research provides researchers with more insight into how tumours are formed, and this knowledge allows us to develop new medications and treatments. […] Over the last few years, an increasing number of medications have been appearing that target specific traits of cancer cells. For instance, there are now medicines that specifically inhibit the molecules responsible for uncontrolled cell growth.

• #50 Cancer pathogenesis and therapy – Leiden University

  https://www.universiteitleiden.nl/en/research-dossiers/cancer-pathogenesis-and-therapy

  What makes treating cancer so difficult is that a tumour often finds ways to escape the therapy and continue growing. Multiple strategies and combination therapies are needed to outwit such clever tumour cells, along with working together with different types of researchers to find an optimal treatment. […] More and more medicines are becoming available that target a tumours specific traits.

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