Materiały źródłowe

• #1

  https://www.jaypeedigital.com/eReader/chapter/9789350257845/ch3

  The distribution of retinoblastoma is worldwide, affecting all racial groups without sex predilection. Retinoblastoma is a rare malignant tumor with a prevalence of about 1 in 15,00023,000 live births. The incidence of retinoblastoma appears to be constant among the various populations of the world, suggesting that environmental influences play little role in its etiology. Understanding of pathogenesis of retinoblastoma has improved over last 100 years, with contributions from the field of genetics, cell biology, animal models, medical oncology and, finally, stem cell biology. The cumulative evidence from all these fields have made significant contributions to improve the survival of the patients affected with retinoblastoma. The mystery that makes the tumor cells escape the confines of the eye to spread to extraocular sites, resist the chemotherapeutic drugs and to recur, is still not understood and warrants many more years of vigorous research.

• #2 EPIDEMIOLOGY

  https://www.aao.org/education/topic-detail/retinoblastoma–asia-pacific

  The disease is caused by a mutation in the RB1 gene located on the long arm of chromosome 13 (13q14). […] RB1 is a tumor suppressor gene and both copies of the gene must be affected for the tumor to form. […] The lack of a functioning RB1 tumor suppressor gene in a cell leads to retinoblastoma tumor formation. […] Retinoblastoma can be caused by germline or non-germline mutations. […] 95% of cases are sporadic; 5% have a family history of retinoblastoma. […] With a positive family history and germline mutation, the penetrance is approximately 90%.

• #3 Retinoblastoma – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/pediatric-cancers/retinoblastoma

  Retinoblastoma occurs in 1/15,000 to 1/30,000 live births and represents approximately 2% of childhood cancers. […] The pathogenesis of inheritance appears to involve mutational deactivation of both alleles of a retinoblastoma suppressor gene (RB1) located on chromosome 13q14. In the hereditary form, a germline mutation alters one allele in all cells, and a later somatic mutation alters the other allele in the retinal cells (the second hit in this 2-hit model), resulting in the cancer. […] The nonhereditary form probably involves somatic mutation of both alleles in a retinal cell. Although the term „sporadic” can be used to describe nonhereditary forms of retinoblastoma, it is technically a misnomer because many sporadic cases are due to de novo germline mutations and are therefore also subsequently heritable.

• #4 Recent progress in retinoblastoma: Pathogenesis, presentation, diagnosis and management – PubMed

  https://pubmed.ncbi.nlm.nih.gov/38615905/

  Retinoblastoma, the primary ocular malignancy in pediatric patients, poses a substantial threat to mortality without prompt and effective management. […] Notably, retinoblastoma has played a crucial role in unraveling the genetic foundations of oncogenesis. The process of tumorigenesis commonly begins with the occurrence of biallelic mutation in the RB1 tumor suppressor gene, which is then followed by a cascade of genetic and epigenetic alterations that correspond to the clinical stage and pathological features of the tumor. The RB1 gene, recognized as a tumor suppressor, encodes the retinoblastoma protein, which plays a vital role in governing cellular replication through interactions with E2F transcription factors and chromatin remodeling proteins. […] This review has systematically compiled and categorized the latest developments in the diagnosis and treatment of retinoblastoma which enhanced the quality of care for this pediatric malignancy.

• #5 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  Retinoblastoma arises from RB1 gene mutations on chromosome 13q14, leading to uncontrolled retinal cell proliferation in early childhood. […] Retinoblastoma is primarily caused by mutations in the RB1 tumor suppressor gene located on chromosome 13q14. The RB1 gene encodes the retinoblastoma protein (pRB), a key regulator of the cell cycle. Under normal conditions, pRB prevents uncontrolled cell proliferation by inhibiting the transition from the G1 phase to the S phase. When both alleles of RB1 are mutated or inactivated, pRB loses its regulatory function, leading to unchecked retinal cell growth and tumor formation. […] The development of retinoblastoma follows Alfred Knudson’s 2-hit hypothesis. In hereditary cases, the 1st „hit” occurs when an individual inherits a defective RB1 allele as a germline mutation in all body cells. The 2nd „hit” is a somatic mutation that inactivates the remaining functional RB1 allele within retinal cells, triggering tumor formation. In nonhereditary cases, both mutations arise sporadically within retinal cells, leading to tumorigenesis.

• #6 Molecular Biological Research on the Pathogenic Mechanism of Retinoblastoma

  https://www.mdpi.com/1467-3045/46/6/317

  Retinoblastoma (RB) is the most common intraocular malignant tumor in children, primarily attributed to the bi-allelic loss of the RB1 gene in the developing retina. […] Despite significant progress in understanding the basic pathogenesis of RB, comprehensively unravelling the intricate network of genetics and epigenetics underlying RB tumorigenesis remains a major challenge. […] The pathogenesis of retinoblastoma involves abnormalities in multiple genes. The bi-allelic inactivation of the RB1 gene is a major driving force in RB development, referred to as the “two-hit theory”, involving two successive mutations. […] The “two-hit theory” indicates that the inactivation of two alleles of the tumor suppressor gene is necessary for cancer, leading to uncontrolled cell differentiation and tumor formation.

• #7 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  Retinoblastoma arises from RB1 gene mutations on chromosome 13q14, leading to uncontrolled retinal cell proliferation in early childhood. […] Retinoblastoma is primarily caused by mutations in the RB1 tumor suppressor gene located on chromosome 13q14. The RB1 gene encodes the retinoblastoma protein (pRB), a key regulator of the cell cycle. Under normal conditions, pRB prevents uncontrolled cell proliferation by inhibiting the transition from the G1 phase to the S phase. When both alleles of RB1 are mutated or inactivated, pRB loses its regulatory function, leading to unchecked retinal cell growth and tumor formation. […] The development of retinoblastoma follows Alfred Knudson’s 2-hit hypothesis. In hereditary cases, the 1st „hit” occurs when an individual inherits a defective RB1 allele as a germline mutation in all body cells. The 2nd „hit” is a somatic mutation that inactivates the remaining functional RB1 allele within retinal cells, triggering tumor formation. In nonhereditary cases, both mutations arise sporadically within retinal cells, leading to tumorigenesis.

• #8 Retinoblastoma – EyeWiki

  https://eyewiki.org/Retinoblastoma

  Retinoblastoma is an intraocular malignancy with primitive neuroendocrine origins that primarily affects young children. […] The retinoblastoma susceptibility gene RB1 is a tumor-suppressing gene with a regulatory function in the cell division cycle. The RB1 gene encodes a protein Rb which, when activated, targets the E2F family of transcription factors and prevents the transcription of genes necessary for G1 to S phase transition. […] Knudson described the „two-hit” mechanism for tumorigenesis in patients with retinoblastoma. Two active copies of the retinoblastoma gene are normally carried in human cells. Both copies must be mutated to lead to the development of retinoblastoma. The initial mutation inactivates one copy of the gene. This mutation may occur in somatic or germline cells. The second mutation occurs in somatic cells. In the majority of cases, this occurs through loss of heterozygosity.

• #9 Retinoblastoma | PPT

  https://www.slideshare.net/slideshow/retinoblastoma-226548886/226548886

  Two mutations are required for the development of retinoblastoma. Child starts with two wild type alleles (RB+/RB+). Both alleles must mutate to produce the disease (RB/RB). Probability of both mutations occurring in the same cell is low; only one tumor forms (e.g., one eye). […] First hit occurs after conception in utero or in early or in early childhood in retinal cells. All cells in body are not affected as germ cells are not involved. Second somatic mutation results in loss of other normal allele. […] Child starts with heterozygous alleles (RB/RB+). Only one mutation is required to produce disease (RB/RB). Mutations resulting in loss of heterozygosity (LOH) are more probable in rapidly dividing cells, and multiple tumors occur (e.g., both eyes). […] RB1 protein: cell cycle regulator, checkpoint between G1 S-phase. Key factor in RB protein functioning is the phosphorylation status. Normally unphosphorylated and suppresses entry into S-phase by binding to E2F (transcription apparatus). Phosphorylation by cyclin/cdks abolishes inhibition causes dissociation of E2F which binds to DNA promotes progression through cell cycle.

• #10 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  Retinoblastoma arises from RB1 gene mutations on chromosome 13q14, leading to uncontrolled retinal cell proliferation in early childhood. […] Retinoblastoma is primarily caused by mutations in the RB1 tumor suppressor gene located on chromosome 13q14. The RB1 gene encodes the retinoblastoma protein (pRB), a key regulator of the cell cycle. Under normal conditions, pRB prevents uncontrolled cell proliferation by inhibiting the transition from the G1 phase to the S phase. When both alleles of RB1 are mutated or inactivated, pRB loses its regulatory function, leading to unchecked retinal cell growth and tumor formation. […] The development of retinoblastoma follows Alfred Knudson’s 2-hit hypothesis. In hereditary cases, the 1st „hit” occurs when an individual inherits a defective RB1 allele as a germline mutation in all body cells. The 2nd „hit” is a somatic mutation that inactivates the remaining functional RB1 allele within retinal cells, triggering tumor formation. In nonhereditary cases, both mutations arise sporadically within retinal cells, leading to tumorigenesis.

• #11 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  The molecular mechanisms underlying retinoblastoma involve several disrupted pathways that contribute to tumor progression. Loss of RB1 function results in the uncontrolled activity of the E2F transcription factor, which drives the expression of genes involved in DNA synthesis and cell cycle progression. This unchecked activity leads to the proliferation of immature retinal cells. […] Furthermore, the absence of functional RB1 impairs chromosomal stability, accumulating additional genetic alterations that contribute to tumor progression. […] Retinoblastoma tumors also exhibit increased angiogenesis, driven by factors like vascular endothelial growth factor (VEGF), which supports tumor growth and sustains the metabolic needs of rapidly dividing cancer cells. […] Additionally, retinoblastoma cells acquire the ability to evade programmed cell death (apoptosis), often through mechanisms such as overexpression of antiapoptotic proteins like the Bcl-2 family and activation of survival pathways, such as the PI3K/Akt signaling pathway. These molecular alterations further facilitate the growth and persistence of the tumor.

• #12 Retinoblastoma: present scenario and future challenges | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01223-z

  Studies have shown that inactivation of RB1 enables constitutive expression of E2F protein, causing a halt in the cell cycle control. […] A number of studies linked dysregulation of Rb signaling pathway to the acquisition of multiple cellular status, as an undifferentiated stem-like phenotype, the activation of EMT program, or metabolic rewiring. […] The p53 signalling pathway responds to various intrinsic and extrinsic stress signals by monitoring DNA replication, chromosome segregation and cell division. […] Studies conducted over the years show that retinoblastoma caused due to RB1 mutations usually bypass the p53 pathway as they are already death resistant. […] The Wnt signaling is one of the major signaling pathways known to maintain the tissue morphogenesis during embryogenesis, stem-like properties, and DNA repair.

• #13 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  Retinoblastoma arises from RB1 gene mutations on chromosome 13q14, leading to uncontrolled retinal cell proliferation in early childhood. […] Retinoblastoma is primarily caused by mutations in the RB1 tumor suppressor gene located on chromosome 13q14. The RB1 gene encodes the retinoblastoma protein (pRB), a key regulator of the cell cycle. Under normal conditions, pRB prevents uncontrolled cell proliferation by inhibiting the transition from the G1 phase to the S phase. When both alleles of RB1 are mutated or inactivated, pRB loses its regulatory function, leading to unchecked retinal cell growth and tumor formation. […] The development of retinoblastoma follows Alfred Knudson’s 2-hit hypothesis. In hereditary cases, the 1st „hit” occurs when an individual inherits a defective RB1 allele as a germline mutation in all body cells. The 2nd „hit” is a somatic mutation that inactivates the remaining functional RB1 allele within retinal cells, triggering tumor formation. In nonhereditary cases, both mutations arise sporadically within retinal cells, leading to tumorigenesis.

• #14

  https://journals.lww.com/ijo/fulltext/2023/71070/retinoblastoma__a_review_of_the_molecular_basis_of.9.aspx

  Retinoblastoma is a retinal cancer that affects children and is the most prevalent intraocular tumor worldwide. […] The root cause of retinoblastoma is the biallelic inactivation of the RB1 gene, but additional genomic alterations such as genomic gain of 1q, 2p, and 6p, along with the genomic loss of 16q may also contribute to the progression of the tumor. […] Advanced techniques such as high-throughput screening (HTS), next-generation sequencing (NGS), and gene expression analysis, in addition to RB1 inactivation, have identified various genetic targets that play crucial roles in retinoblastoma progression. […] In 1971, Alfred Knudson proposed the two-hit hypothesis that suggested the necessity of two mutational hits for the progression of retinoblastoma tumors. […] Various genetic, transcriptomic, and epigenetic events that play important roles in the growth, development, and progression of retinoblastoma have been discovered.

• #15 Molecular Biological Research on the Pathogenic Mechanism of Retinoblastoma

  https://www.mdpi.com/1467-3045/46/6/317

  Retinoblastoma (RB) is the most common intraocular malignant tumor in children, primarily attributed to the bi-allelic loss of the RB1 gene in the developing retina. […] Despite significant progress in understanding the basic pathogenesis of RB, comprehensively unravelling the intricate network of genetics and epigenetics underlying RB tumorigenesis remains a major challenge. […] The pathogenesis of retinoblastoma involves abnormalities in multiple genes. The bi-allelic inactivation of the RB1 gene is a major driving force in RB development, referred to as the “two-hit theory”, involving two successive mutations. […] The “two-hit theory” indicates that the inactivation of two alleles of the tumor suppressor gene is necessary for cancer, leading to uncontrolled cell differentiation and tumor formation.

• #16 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  Retinoblastoma arises from RB1 gene mutations on chromosome 13q14, leading to uncontrolled retinal cell proliferation in early childhood. […] Retinoblastoma is primarily caused by mutations in the RB1 tumor suppressor gene located on chromosome 13q14. The RB1 gene encodes the retinoblastoma protein (pRB), a key regulator of the cell cycle. Under normal conditions, pRB prevents uncontrolled cell proliferation by inhibiting the transition from the G1 phase to the S phase. When both alleles of RB1 are mutated or inactivated, pRB loses its regulatory function, leading to unchecked retinal cell growth and tumor formation. […] The development of retinoblastoma follows Alfred Knudson’s 2-hit hypothesis. In hereditary cases, the 1st „hit” occurs when an individual inherits a defective RB1 allele as a germline mutation in all body cells. The 2nd „hit” is a somatic mutation that inactivates the remaining functional RB1 allele within retinal cells, triggering tumor formation. In nonhereditary cases, both mutations arise sporadically within retinal cells, leading to tumorigenesis.

• #17 Retinoblastoma – EyeWiki

  https://eyewiki.org/Retinoblastoma

  Retinoblastoma is an intraocular malignancy with primitive neuroendocrine origins that primarily affects young children. […] The retinoblastoma susceptibility gene RB1 is a tumor-suppressing gene with a regulatory function in the cell division cycle. The RB1 gene encodes a protein Rb which, when activated, targets the E2F family of transcription factors and prevents the transcription of genes necessary for G1 to S phase transition. […] Knudson described the „two-hit” mechanism for tumorigenesis in patients with retinoblastoma. Two active copies of the retinoblastoma gene are normally carried in human cells. Both copies must be mutated to lead to the development of retinoblastoma. The initial mutation inactivates one copy of the gene. This mutation may occur in somatic or germline cells. The second mutation occurs in somatic cells. In the majority of cases, this occurs through loss of heterozygosity.

• #18 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  Retinoblastoma arises from RB1 gene mutations on chromosome 13q14, leading to uncontrolled retinal cell proliferation in early childhood. […] Retinoblastoma is primarily caused by mutations in the RB1 tumor suppressor gene located on chromosome 13q14. The RB1 gene encodes the retinoblastoma protein (pRB), a key regulator of the cell cycle. Under normal conditions, pRB prevents uncontrolled cell proliferation by inhibiting the transition from the G1 phase to the S phase. When both alleles of RB1 are mutated or inactivated, pRB loses its regulatory function, leading to unchecked retinal cell growth and tumor formation. […] The development of retinoblastoma follows Alfred Knudson’s 2-hit hypothesis. In hereditary cases, the 1st „hit” occurs when an individual inherits a defective RB1 allele as a germline mutation in all body cells. The 2nd „hit” is a somatic mutation that inactivates the remaining functional RB1 allele within retinal cells, triggering tumor formation. In nonhereditary cases, both mutations arise sporadically within retinal cells, leading to tumorigenesis.

• #19 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.

• #20 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  The molecular mechanisms underlying retinoblastoma involve several disrupted pathways that contribute to tumor progression. Loss of RB1 function results in the uncontrolled activity of the E2F transcription factor, which drives the expression of genes involved in DNA synthesis and cell cycle progression. This unchecked activity leads to the proliferation of immature retinal cells. […] Furthermore, the absence of functional RB1 impairs chromosomal stability, accumulating additional genetic alterations that contribute to tumor progression. […] Retinoblastoma tumors also exhibit increased angiogenesis, driven by factors like vascular endothelial growth factor (VEGF), which supports tumor growth and sustains the metabolic needs of rapidly dividing cancer cells. […] Additionally, retinoblastoma cells acquire the ability to evade programmed cell death (apoptosis), often through mechanisms such as overexpression of antiapoptotic proteins like the Bcl-2 family and activation of survival pathways, such as the PI3K/Akt signaling pathway. These molecular alterations further facilitate the growth and persistence of the tumor.

• #21 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  The molecular mechanisms underlying retinoblastoma involve several disrupted pathways that contribute to tumor progression. Loss of RB1 function results in the uncontrolled activity of the E2F transcription factor, which drives the expression of genes involved in DNA synthesis and cell cycle progression. This unchecked activity leads to the proliferation of immature retinal cells. […] Furthermore, the absence of functional RB1 impairs chromosomal stability, accumulating additional genetic alterations that contribute to tumor progression. […] Retinoblastoma tumors also exhibit increased angiogenesis, driven by factors like vascular endothelial growth factor (VEGF), which supports tumor growth and sustains the metabolic needs of rapidly dividing cancer cells. […] Additionally, retinoblastoma cells acquire the ability to evade programmed cell death (apoptosis), often through mechanisms such as overexpression of antiapoptotic proteins like the Bcl-2 family and activation of survival pathways, such as the PI3K/Akt signaling pathway. These molecular alterations further facilitate the growth and persistence of the tumor.

• #22 Retinoblastoma: present scenario and future challenges | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01223-z

  Studies have shown that inactivation of RB1 enables constitutive expression of E2F protein, causing a halt in the cell cycle control. […] A number of studies linked dysregulation of Rb signaling pathway to the acquisition of multiple cellular status, as an undifferentiated stem-like phenotype, the activation of EMT program, or metabolic rewiring. […] The p53 signalling pathway responds to various intrinsic and extrinsic stress signals by monitoring DNA replication, chromosome segregation and cell division. […] Studies conducted over the years show that retinoblastoma caused due to RB1 mutations usually bypass the p53 pathway as they are already death resistant. […] The Wnt signaling is one of the major signaling pathways known to maintain the tissue morphogenesis during embryogenesis, stem-like properties, and DNA repair.

• #23 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  The molecular mechanisms underlying retinoblastoma involve several disrupted pathways that contribute to tumor progression. Loss of RB1 function results in the uncontrolled activity of the E2F transcription factor, which drives the expression of genes involved in DNA synthesis and cell cycle progression. This unchecked activity leads to the proliferation of immature retinal cells. […] Furthermore, the absence of functional RB1 impairs chromosomal stability, accumulating additional genetic alterations that contribute to tumor progression. […] Retinoblastoma tumors also exhibit increased angiogenesis, driven by factors like vascular endothelial growth factor (VEGF), which supports tumor growth and sustains the metabolic needs of rapidly dividing cancer cells. […] Additionally, retinoblastoma cells acquire the ability to evade programmed cell death (apoptosis), often through mechanisms such as overexpression of antiapoptotic proteins like the Bcl-2 family and activation of survival pathways, such as the PI3K/Akt signaling pathway. These molecular alterations further facilitate the growth and persistence of the tumor.

• #24 The pathways of cell cycle regulation in retinoblastoma – Revista RBAC

  https://www.rbac.org.br/artigos/the-pathways-of-cell-cycle-regulation-in-retinoblastoma/

  The RB protein (pRB) acts as a regulator of G1/S phases of the cell cycle and has the ability to regulate the gene transcription of genes that participate in apoptosis, differentiation and cell adhesion. […] The inactivation of pRB promotes genomic instability and results in deletions, duplications and chromosomal rearrangements and compromises the ability of cells to terminate the cell cycle, being highly susceptible to oncogenic gene proliferation. […] The literature shows that pRB is functionally impaired in many tumors as a result of RB1 mutations or mutations that increase phosphorylation of the protein or by the expression of viral oncoproteins targeting pRB. […] In most cancers, these pathways are impaired by mutations in TP53, inactivation of the CDKN2A gene or amplification of MDM2. […] Many functions of pRB are related to genomic instability, cancer associated with poor prognosis, tumor heterogeneity and development of therapeutic resistance.

• #25 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  The molecular mechanisms underlying retinoblastoma involve several disrupted pathways that contribute to tumor progression. Loss of RB1 function results in the uncontrolled activity of the E2F transcription factor, which drives the expression of genes involved in DNA synthesis and cell cycle progression. This unchecked activity leads to the proliferation of immature retinal cells. […] Furthermore, the absence of functional RB1 impairs chromosomal stability, accumulating additional genetic alterations that contribute to tumor progression. […] Retinoblastoma tumors also exhibit increased angiogenesis, driven by factors like vascular endothelial growth factor (VEGF), which supports tumor growth and sustains the metabolic needs of rapidly dividing cancer cells. […] Additionally, retinoblastoma cells acquire the ability to evade programmed cell death (apoptosis), often through mechanisms such as overexpression of antiapoptotic proteins like the Bcl-2 family and activation of survival pathways, such as the PI3K/Akt signaling pathway. These molecular alterations further facilitate the growth and persistence of the tumor.

• #26 Retinoblastoma – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK545276/

  The molecular mechanisms underlying retinoblastoma involve several disrupted pathways that contribute to tumor progression. Loss of RB1 function results in the uncontrolled activity of the E2F transcription factor, which drives the expression of genes involved in DNA synthesis and cell cycle progression. This unchecked activity leads to the proliferation of immature retinal cells. […] Furthermore, the absence of functional RB1 impairs chromosomal stability, accumulating additional genetic alterations that contribute to tumor progression. […] Retinoblastoma tumors also exhibit increased angiogenesis, driven by factors like vascular endothelial growth factor (VEGF), which supports tumor growth and sustains the metabolic needs of rapidly dividing cancer cells. […] Additionally, retinoblastoma cells acquire the ability to evade programmed cell death (apoptosis), often through mechanisms such as overexpression of antiapoptotic proteins like the Bcl-2 family and activation of survival pathways, such as the PI3K/Akt signaling pathway. These molecular alterations further facilitate the growth and persistence of the tumor.

• #27 Retinoblastoma: present scenario and future challenges | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01223-z

  Studies have shown that inactivation of RB1 enables constitutive expression of E2F protein, causing a halt in the cell cycle control. […] A number of studies linked dysregulation of Rb signaling pathway to the acquisition of multiple cellular status, as an undifferentiated stem-like phenotype, the activation of EMT program, or metabolic rewiring. […] The p53 signalling pathway responds to various intrinsic and extrinsic stress signals by monitoring DNA replication, chromosome segregation and cell division. […] Studies conducted over the years show that retinoblastoma caused due to RB1 mutations usually bypass the p53 pathway as they are already death resistant. […] The Wnt signaling is one of the major signaling pathways known to maintain the tissue morphogenesis during embryogenesis, stem-like properties, and DNA repair.

• #28 Structural Insights into the Mechanism of Phosphoregulation of the Retinoblastoma Protein | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058463

  The retinoblastoma susceptibility protein RB1 is a key regulator of cell proliferation and fate. […] Phosphorylation of RB1 by cyclin-dependent kinases leads to conformational alterations and inactivates the capability of RB1 to bind partner protein. […] Phosphorylation of RB1 by members of the proline-directed family of cyclin-dependent Serine (Ser) Threonine (Thr) protein kinases inactivates the ability of RB1 to interact with partner proteins, presumably instigating fragmentation of the RB1-containing protein assemblies. […] Although atomic resolution structures of the various RB1 functional domains have been determined, how these domains and their respective protein interaction surfaces are arranged in the active molecule is not known. […] The work allows the deduction of the domain arrangement in the active unphosphorylated form and permits prediction of the cause and mechanics of the conformational response leading to functional inactivation by cyclin-dependent kinase phosphorylation.

• #29 Structural Insights into the Mechanism of Phosphoregulation of the Retinoblastoma Protein | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058463

  RB1 is inactivated by phosphate modification on proline-directed sites, with phosphorylation disabling the ability of RB1 to sustain interaction with partner proteins. […] Comparison of the domain arrangements in the active unmodified MBP-ddRB1-NP modelled using the crystal structures of the unmodified individual domains and the phosphate-modified RB-NP-domain assembly allows us to propose a mechanism by which the active conformation is converted into the inactive conformation. […] Together these observations support a quite detailed model for the regulation by phosphorylation whereby domain rearrangement culminates in generating the inactive conformation of RB1.

• #30 Retinoblastoma | PPT

  https://www.slideshare.net/slideshow/retinoblastoma-226548886/226548886

  Hypo-phosphorylated or un-phosphorylated pRb inhibits the cell from entering a new cell cycle. […] Hypo-phosphorylated Rb inhibits activity of the E2F family of transcription factors. Hyper-phosphorylation of Rb sequesters Rb, and releases E2Fs. E2Fs are needed for transcription of genes that are essential for the cell to enter the cell cycle. […] Rb, the retinoblastoma protein regulates the cell cycle. Cell cycle = OFF Rb binds to E2F: no transcription, no entry into S phase. Cell cycle = ON Rb does not bind to E2F: transcription and entry into S phase w/o 2 copies of Rb: no cell cycle. […] Rb activity is tightly regulated by the cell cycle clock. Hypo-phosphorylation is catalyzed by cycD-CDK4/6. Hyper-phosphorylation is catalyzed by cycE-CDK2. […] The presence of vitreous seeding. Multiple tumors may arise from a primary retinoblastoma. Tumor could spread via subretinal space. […] Chemotherapy (debated) * Massive choroidal involvement /or * Retrolaminar involvement of optic nerve /or * Anterior chamber involvement. […] Chemoreduction averts the development of TRB.

• #31 Retinoblastoma | PPT

  https://www.slideshare.net/slideshow/retinoblastoma-226548886/226548886

  Hypo-phosphorylated or un-phosphorylated pRb inhibits the cell from entering a new cell cycle. […] Hypo-phosphorylated Rb inhibits activity of the E2F family of transcription factors. Hyper-phosphorylation of Rb sequesters Rb, and releases E2Fs. E2Fs are needed for transcription of genes that are essential for the cell to enter the cell cycle. […] Rb, the retinoblastoma protein regulates the cell cycle. Cell cycle = OFF Rb binds to E2F: no transcription, no entry into S phase. Cell cycle = ON Rb does not bind to E2F: transcription and entry into S phase w/o 2 copies of Rb: no cell cycle. […] Rb activity is tightly regulated by the cell cycle clock. Hypo-phosphorylation is catalyzed by cycD-CDK4/6. Hyper-phosphorylation is catalyzed by cycE-CDK2. […] The presence of vitreous seeding. Multiple tumors may arise from a primary retinoblastoma. Tumor could spread via subretinal space. […] Chemotherapy (debated) * Massive choroidal involvement /or * Retrolaminar involvement of optic nerve /or * Anterior chamber involvement. […] Chemoreduction averts the development of TRB.

• #32

  https://journals.lww.com/ijo/fulltext/2016/64050/genetic_perspective_of_retinoblastoma__from.2.aspx

  Recurrent genetic changes in addition to RB1 inactivation happens in human RB tumors. […] Recent evidence point out the importance of p16INK4A in RB progression. […] The study demonstrated that the p53 pathway was inactivated in RB1 deficient cells due to amplification of MDMX and MDM2. […] The tireless efforts of scientist to understand the events that follow RB1 inactivation for tumor progression have laid a foundation to recognize the probable pathogenic signature of this tumor. […] Identifying the cell of origin of RB may help to answer questions regarding phenotype variability and progression of the tumor. […] Improvement in our understanding on the molecular wiring of RB would result in a better treatment option in the future.

• #33 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. […] 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.

• #34

  https://journals.lww.com/ijo/fulltext/2023/71070/retinoblastoma__a_review_of_the_molecular_basis_of.9.aspx

  Retinoblastoma is a retinal cancer that affects children and is the most prevalent intraocular tumor worldwide. […] The root cause of retinoblastoma is the biallelic inactivation of the RB1 gene, but additional genomic alterations such as genomic gain of 1q, 2p, and 6p, along with the genomic loss of 16q may also contribute to the progression of the tumor. […] Advanced techniques such as high-throughput screening (HTS), next-generation sequencing (NGS), and gene expression analysis, in addition to RB1 inactivation, have identified various genetic targets that play crucial roles in retinoblastoma progression. […] In 1971, Alfred Knudson proposed the two-hit hypothesis that suggested the necessity of two mutational hits for the progression of retinoblastoma tumors. […] Various genetic, transcriptomic, and epigenetic events that play important roles in the growth, development, and progression of retinoblastoma have been discovered.

• #35 Retinoblastoma: Etiology, Modeling, and Treatment

  https://www.mdpi.com/2072-6694/12/8/2304

  Retinoblastoma is a retinal cancer that is initiated in response to biallelic loss of RB1 in almost all cases, together with other genetic/epigenetic changes culminating in the development of cancer. […] RB1 deficiency makes the retinoblastoma cell-of-origin extremely susceptible to cancerous transformation, and the tumor cell-of-origin appears to depend on the developmental stage and species. […] The cellular consequences of RB1 inactivation have been associated with multiple forms of genomic instability, which fuels tumorigenesis by eliminating safeguards that limit oncogenic transformation. […] However, compared with other cancers including RB1-deficient malignancies, retinoblastoma exhibits minimal genomic instability because of unique cell type-specific circuitry. […] Genomic alterations in retinoblastoma are unique with common gains at 1q, 2p, and 6p and loss at 16q.

• #36

  https://journals.lww.com/ijo/fulltext/2023/71070/retinoblastoma__a_review_of_the_molecular_basis_of.9.aspx

  Retinoblastoma is a retinal cancer that affects children and is the most prevalent intraocular tumor worldwide. […] The root cause of retinoblastoma is the biallelic inactivation of the RB1 gene, but additional genomic alterations such as genomic gain of 1q, 2p, and 6p, along with the genomic loss of 16q may also contribute to the progression of the tumor. […] Advanced techniques such as high-throughput screening (HTS), next-generation sequencing (NGS), and gene expression analysis, in addition to RB1 inactivation, have identified various genetic targets that play crucial roles in retinoblastoma progression. […] In 1971, Alfred Knudson proposed the two-hit hypothesis that suggested the necessity of two mutational hits for the progression of retinoblastoma tumors. […] Various genetic, transcriptomic, and epigenetic events that play important roles in the growth, development, and progression of retinoblastoma have been discovered.

• #37 Retinoblastoma: Etiology, Modeling, and Treatment

  https://www.mdpi.com/2072-6694/12/8/2304

  Retinoblastoma is a retinal cancer that is initiated in response to biallelic loss of RB1 in almost all cases, together with other genetic/epigenetic changes culminating in the development of cancer. […] RB1 deficiency makes the retinoblastoma cell-of-origin extremely susceptible to cancerous transformation, and the tumor cell-of-origin appears to depend on the developmental stage and species. […] The cellular consequences of RB1 inactivation have been associated with multiple forms of genomic instability, which fuels tumorigenesis by eliminating safeguards that limit oncogenic transformation. […] However, compared with other cancers including RB1-deficient malignancies, retinoblastoma exhibits minimal genomic instability because of unique cell type-specific circuitry. […] Genomic alterations in retinoblastoma are unique with common gains at 1q, 2p, and 6p and loss at 16q.

• #38 Retinoblastoma | Hereditary Ocular Diseases

  https://disorders.eyes.arizona.edu/disorders/retinoblastoma

  Among these is an upregulation of spleen tyrosine kinase (SYK) required for tumor cell survival which, if inhibited, leads to retinoblastoma cell death in vivo and in vitro. […] However, two thirds of cases are of non-germinal origin with both somatic mutations occurring in a single retinal progenitor cell. […] Because this is a highly unlikely event, these cases are generally unilateral and unifocal with an average age of onset of 24 months. […] To further complicate the story, recent evidence suggests that retinoblastoma is genetically heterogeneous. […] About 6% of patients have no RB1 mutation. […] In one study, about half of such individuals have up-regulation of the MYCN oncogene (2p24.3) suggesting a second mechanism leading to clinical retinoblastoma.

• #39 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. […] 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). […] 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. […] 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. […] 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.

• #40 Molecular Biological Research on the Pathogenic Mechanism of Retinoblastoma

  https://www.mdpi.com/1467-3045/46/6/317

  RB is thought to be related to the mutation or inactivation of two copies of the retinoblastoma gene (RB1), the tumor suppressor gene, and caused by a mutation of RB1 programming retinoblastoma protein (pRB). […] In recent years, many studies have shown that changes in RB genes, other than those causing RB gene inactivation, are common in RB patients and promote tumor progression, also known as subtype 2. […] Epigenetics refers to heritable changes in gene expression that occur without alterations in the DNA sequence. These changes primarily include DNA methylation, histone modifications, and the expression of non-coding RNAs. […] Aberrations in epigenetics can lead to the activation of oncogenes and the silencing of tumor suppressor and DNA repair genes, thereby initiating and promoting tumorigenesis.

• #41 Molecular Biological Research on the Pathogenic Mechanism of Retinoblastoma

  https://www.mdpi.com/1467-3045/46/6/317

  RB is thought to be related to the mutation or inactivation of two copies of the retinoblastoma gene (RB1), the tumor suppressor gene, and caused by a mutation of RB1 programming retinoblastoma protein (pRB). […] In recent years, many studies have shown that changes in RB genes, other than those causing RB gene inactivation, are common in RB patients and promote tumor progression, also known as subtype 2. […] Epigenetics refers to heritable changes in gene expression that occur without alterations in the DNA sequence. These changes primarily include DNA methylation, histone modifications, and the expression of non-coding RNAs. […] Aberrations in epigenetics can lead to the activation of oncogenes and the silencing of tumor suppressor and DNA repair genes, thereby initiating and promoting tumorigenesis.

• #42 Retinoblastoma (hereditary predisposition)

  https://atlasgeneticsoncology.org/cancer-prone-disease/10031/retinoblastoma-(hereditary-predisposition)

  Predisposition to retinoblastoma is transmitted as an autosomal dominant trait trait with incomplete penetrance; it is caused by mutations in the RB1 gene; there is also a non-hereditary form of retinoblastoma that is caused by RB1-mutations confined to somatic cells. […] Tumor foci are initiated by the second mutation in somatic retinal cells. […] Many children with hereditable RB have new germinal mutations, and both parents are normal. […] In the majority of retinoblastoma tissues, the mutations that result in biallelic inactivation of the RB1 gene are accompanied by loss of constitutional heterozygosity, originating from deletions and several chromosomal mechanisms such as mitotic recombination and nondisjunction. […] RB1 promoter hypermethylation is observed in about 13% of retinoblastomas. […] In retinoblastoma tissues methylation of a CpG island encompassing the promoter region of RB1 is a quite frequent mechanism inactivating one copy of the gene.

• #43

  https://www.omim.org/entry/180200

  Sakai et al. (1991) studied the methylation pattern at the 5-prime end of the RB gene, including its promoter region and exon 1, in DNA purified from 56 primary retinoblastomas. The purpose was to investigate the possibility that hypermethylation of the promoter region might be responsible for loss of function of the gene giving rise to tumor. In 5 of the tumors, they found evidence for hypermethylation; all tumors were from unilateral, 'simplex’ patients. […] […] A significant proportion of disease-causing mutations in the RB1 gene result in the premature termination of protein synthesis, and most of these mutations occur as C-to-T transitions at CpG dinucleotides. Mancini et al. (1997) presented evidence confirming the view that such recurring CpG mutations are the result of the deamination of 5-methylcytosine within these CpGs. […]

• #44 Retinoblastoma: present scenario and future challenges | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01223-z

  With an average incidence of 1 in every 18,000 live births, retinoblastoma is a rare type of intraocular tumour found to affect patients during their early childhood. […] According to the Knudson hypothesis, also known as the two hit hypothesis, two hits on the retinoblastoma susceptibility (RB) gene is often considered as the initiating event in the development of the disease. […] The major signaling pathways involved in retinoblastoma initiation and development are Rb, p53, Ras/MAPK and Notch pathways. […] The transcription of 190kbp RB1 gene leads to the formation of a 110 kDa nuclear phosphoprotein renowned for its role in cell cycle regulation. […] Mutations on the RB1 gene inhibit the Rb function, thus leading to the activation of E2F mediated transcription and hence, constant cell division leading to the retinoblastoma.

• #45 Retinoblastoma: present scenario and future challenges | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01223-z

  Studies have shown that inactivation of RB1 enables constitutive expression of E2F protein, causing a halt in the cell cycle control. […] A number of studies linked dysregulation of Rb signaling pathway to the acquisition of multiple cellular status, as an undifferentiated stem-like phenotype, the activation of EMT program, or metabolic rewiring. […] The p53 signalling pathway responds to various intrinsic and extrinsic stress signals by monitoring DNA replication, chromosome segregation and cell division. […] Studies conducted over the years show that retinoblastoma caused due to RB1 mutations usually bypass the p53 pathway as they are already death resistant. […] The Wnt signaling is one of the major signaling pathways known to maintain the tissue morphogenesis during embryogenesis, stem-like properties, and DNA repair.

• #46 The pathways of cell cycle regulation in retinoblastoma – Revista RBAC

  https://www.rbac.org.br/artigos/the-pathways-of-cell-cycle-regulation-in-retinoblastoma/

  The RB protein (pRB) acts as a regulator of G1/S phases of the cell cycle and has the ability to regulate the gene transcription of genes that participate in apoptosis, differentiation and cell adhesion. […] The inactivation of pRB promotes genomic instability and results in deletions, duplications and chromosomal rearrangements and compromises the ability of cells to terminate the cell cycle, being highly susceptible to oncogenic gene proliferation. […] The literature shows that pRB is functionally impaired in many tumors as a result of RB1 mutations or mutations that increase phosphorylation of the protein or by the expression of viral oncoproteins targeting pRB. […] In most cancers, these pathways are impaired by mutations in TP53, inactivation of the CDKN2A gene or amplification of MDM2. […] Many functions of pRB are related to genomic instability, cancer associated with poor prognosis, tumor heterogeneity and development of therapeutic resistance.

• #47

  https://journals.lww.com/ijo/fulltext/2016/64050/genetic_perspective_of_retinoblastoma__from.2.aspx

  Recurrent genetic changes in addition to RB1 inactivation happens in human RB tumors. […] Recent evidence point out the importance of p16INK4A in RB progression. […] The study demonstrated that the p53 pathway was inactivated in RB1 deficient cells due to amplification of MDMX and MDM2. […] The tireless efforts of scientist to understand the events that follow RB1 inactivation for tumor progression have laid a foundation to recognize the probable pathogenic signature of this tumor. […] Identifying the cell of origin of RB may help to answer questions regarding phenotype variability and progression of the tumor. […] Improvement in our understanding on the molecular wiring of RB would result in a better treatment option in the future.

• #48 Retinoblastoma | Cancer Genetics Web

  https://www.cancer-genetics.org/X1801.htm

  Retinoblastoma is a malignancy arising in the retina, mostly diagnosed in young children; two-thirds of all cases of retinoblastoma are diagnosed before age 2 years, and 95% before age 5 years. […] Between 25-30% of Retinoblastoma cases are heritable, having a germline mutation of the RB1 gene. […] The penetrance of the RB1 mutation in retinoblastoma is thought to be dependent on concurrent genetic modifiers, in particular MDM2 and MDM4. […] Isochromosome (6p) represents a highly characteristic cytogenetic abnormality of human retinoblastoma (RB) cells and may be important for tumor progression. […] Our results indicate that mitotic nondisjunction leading to trisomy 6 precedes the isochromosome formation. […] The isochromosome may then be formed by transverse division of the centromere or intrachromosomal chromatid exchange.

• #49 Retinoblastoma: present scenario and future challenges | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01223-z

  Studies on murine models showed that deletion of Rb homologs like p107 and p130 causes an increment in -catenin expression, indicating the crosstalk between Rb and Wnt pathway. […] Considered to be the best characterised signalling pathway in cell biology, Ras/Raf pathway transduces signals from the extracellular area to the nucleus and enables activation of cell growth, differentiation, and migration. […] The Notch signaling pathway has been found to be a critical player of cellular plasticity through the induction of EMT.

• #50 Retinoblastoma: present scenario and future challenges | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01223-z

  Studies on murine models showed that deletion of Rb homologs like p107 and p130 causes an increment in -catenin expression, indicating the crosstalk between Rb and Wnt pathway. […] Considered to be the best characterised signalling pathway in cell biology, Ras/Raf pathway transduces signals from the extracellular area to the nucleus and enables activation of cell growth, differentiation, and migration. […] The Notch signaling pathway has been found to be a critical player of cellular plasticity through the induction of EMT.

• #51 Retinoblastoma: present scenario and future challenges | Cell Communication and Signaling | Full Text

  https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01223-z

  Studies on murine models showed that deletion of Rb homologs like p107 and p130 causes an increment in -catenin expression, indicating the crosstalk between Rb and Wnt pathway. […] Considered to be the best characterised signalling pathway in cell biology, Ras/Raf pathway transduces signals from the extracellular area to the nucleus and enables activation of cell growth, differentiation, and migration. […] The Notch signaling pathway has been found to be a critical player of cellular plasticity through the induction of EMT.

• #52 An epigenomic mechanism in retinoblastoma: the end of the story? | Genome Medicine | Full Text

  https://genomemedicine.biomedcentral.com/articles/10.1186/gm314

  The discovery of its cause (biallelic loss of RB1) did not offer insight to improved management. […] The lack of new therapies, despite extensive characterization of the RB1 gene and its manifold functions, is likely to be due to rapid progression of malignancy changes that occur in intraocular retinoblastoma after tumor initiation. […] The molecular mechanism(s) behind these consistently observed phenotypic alterations are not understood. […] The authors then evaluated epigenetic deregulation as a possible mechanism for the rapid progression of malignancy changes, using an integrative approach involving chromatin immunoprecipitation (ChIP), DNA methylation and gene expression data analysis. […] The authors concluded that SYK could be a promising new therapeutic target for the disease.

• #53 Retinoblastoma | Hereditary Ocular Diseases

  https://disorders.eyes.arizona.edu/disorders/retinoblastoma

  Among these is an upregulation of spleen tyrosine kinase (SYK) required for tumor cell survival which, if inhibited, leads to retinoblastoma cell death in vivo and in vitro. […] However, two thirds of cases are of non-germinal origin with both somatic mutations occurring in a single retinal progenitor cell. […] Because this is a highly unlikely event, these cases are generally unilateral and unifocal with an average age of onset of 24 months. […] To further complicate the story, recent evidence suggests that retinoblastoma is genetically heterogeneous. […] About 6% of patients have no RB1 mutation. […] In one study, about half of such individuals have up-regulation of the MYCN oncogene (2p24.3) suggesting a second mechanism leading to clinical retinoblastoma.

• #54 Retinoblastoma Study Reveals Pathogenesis Gene Downstream of Mutated RB1 | GenomeWebRSS FeedsVisit GenomeWeb on TwitterVisit GenomeWeb on LinkedIn

  https://www.genomeweb.com/sequencing/retinoblastoma-study-reveals-pathogenesis-gene-downstream-mutated-rb1

  NEW YORK – Investigators at the University of Miami Miller School of Medicine, the University of Iowa, and the University of Texas Southwestern Medical Center turned to a multiomics approach to untangle the downstream consequences of RB1 tumor suppressor inactivation in retinoblastoma, a common and dangerous eye cancer that can occur in children. […] Their results suggested that the characteristic RB1 inactivation in retinoblastoma frees the estrogen-related receptor gamma (ESRRG) from its usual regulation by RB1, apparently boosting ESRRG expression, particularly under the oxygen-depleted, hypoxic conditions found in Rb tumor cells. […] „We found that the estrogen-related receptor (ESR) gamma (ESRRG) is an essential mediator of hypoxic adaptation and cell survival in Rb that is constitutively activated by RB1 loss and is subsequently affected by recurrent genomic aberrations in Rb,” the authors reported.

• #55 Retinoblastoma Study Reveals Pathogenesis Gene Downstream of Mutated RB1 | GenomeWebRSS FeedsVisit GenomeWeb on TwitterVisit GenomeWeb on LinkedIn

  https://www.genomeweb.com/sequencing/retinoblastoma-study-reveals-pathogenesis-gene-downstream-mutated-rb1

  „Together, these findings suggest that RB1 dampens the hypoxia-induced surge in ESRRG activity and that loss of RB1 abolishes this homeostatic mechanism, resulting in nascent Rb cells becoming increasingly dependent on ESRRG in the hypoxic tumor microenvironment,” adding that „[f]urther studies are warranted to investigate the potential role for inhibiting ESRRG in the management of Rb.”

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

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

  This study indicated that the verified DEGs are continuously and consistently expressed in different subtypes and stages of RB. These DEGs may be the key to understanding the development and invasion of RB. […] In addition, the 3 genes, CDK1, CDC20, and BUB1 were found to be the key genes in the PPI network. […] The positive regulatory cell cycle-related gene set was significantly enriched in the CDK1 high expression group; that is, CDK1 promoted the cell cycle in RB tissues. […] UHRF1 was identified as the only shared upregulated gene. […] It was further confirmed that UHRF1 promotes the proliferation and invasion of RB cells. On the contrary, CADM1, as a representative of 18 downregulated DEGs, was found to negatively regulate the phenotype of RB cells. […] This study reveals the key role of UHRF1 in RB from the perspective of bioinformatics, further supporting UHRF1 as a potential diagnostic and therapeutic biomarker for RB. […] Our results found evidence for the tumor-suppressing effect of CADM1 in RB and further suggested the possibility of CADM1 as a tumor suppressor.

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

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

  This study indicated that the verified DEGs are continuously and consistently expressed in different subtypes and stages of RB. These DEGs may be the key to understanding the development and invasion of RB. […] In addition, the 3 genes, CDK1, CDC20, and BUB1 were found to be the key genes in the PPI network. […] The positive regulatory cell cycle-related gene set was significantly enriched in the CDK1 high expression group; that is, CDK1 promoted the cell cycle in RB tissues. […] UHRF1 was identified as the only shared upregulated gene. […] It was further confirmed that UHRF1 promotes the proliferation and invasion of RB cells. On the contrary, CADM1, as a representative of 18 downregulated DEGs, was found to negatively regulate the phenotype of RB cells. […] This study reveals the key role of UHRF1 in RB from the perspective of bioinformatics, further supporting UHRF1 as a potential diagnostic and therapeutic biomarker for RB. […] Our results found evidence for the tumor-suppressing effect of CADM1 in RB and further suggested the possibility of CADM1 as a tumor suppressor.

• #58 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.

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

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

  This study indicated that the verified DEGs are continuously and consistently expressed in different subtypes and stages of RB. These DEGs may be the key to understanding the development and invasion of RB. […] In addition, the 3 genes, CDK1, CDC20, and BUB1 were found to be the key genes in the PPI network. […] The positive regulatory cell cycle-related gene set was significantly enriched in the CDK1 high expression group; that is, CDK1 promoted the cell cycle in RB tissues. […] UHRF1 was identified as the only shared upregulated gene. […] It was further confirmed that UHRF1 promotes the proliferation and invasion of RB cells. On the contrary, CADM1, as a representative of 18 downregulated DEGs, was found to negatively regulate the phenotype of RB cells. […] This study reveals the key role of UHRF1 in RB from the perspective of bioinformatics, further supporting UHRF1 as a potential diagnostic and therapeutic biomarker for RB. […] Our results found evidence for the tumor-suppressing effect of CADM1 in RB and further suggested the possibility of CADM1 as a tumor suppressor.

• #60 Mechanism study of isoflavones as an anti-retinoblastoma progression agent | Oncotarget

  https://www.oncotarget.com/article/19365/

  Isoflavones, bioactive soy compounds, are known to exhibit anticancer activities. […] The present study investigated the anticancer activities of isoflavones on human retinoblastoma Y79 cells in vitro and in vivo. […] Flow cytometry analysis indicated that isoflavones blocked G1/S progression. […] Western blot analysis demonstrated that the mammalian target of rapamycin (mTOR) pathway in Y79 cells was inhibited by isoflavones, with a concomitant decrease in cyclin E1, which accounted for the isoflavone-mediated G1 phase arrest. […] Isoflavones also inhibited human retinoblastoma growth in vivo; western blot analysis showed inhibition of mTOR and downregulation of cyclin E1 in an isoflavone-treated xenograft mouse model. […] Together, these results illustrate that isoflavones inhibit retinoblastoma tumour growth in vitro and vivo and that inactivation of the mTOR pathway and downregulation of cyclin E1 is involved in this action.

• #61

  https://journals.lww.com/ijo/fulltext/2016/64050/genetic_perspective_of_retinoblastoma__from.2.aspx

  Recurrent genetic changes in addition to RB1 inactivation happens in human RB tumors. […] Recent evidence point out the importance of p16INK4A in RB progression. […] The study demonstrated that the p53 pathway was inactivated in RB1 deficient cells due to amplification of MDMX and MDM2. […] The tireless efforts of scientist to understand the events that follow RB1 inactivation for tumor progression have laid a foundation to recognize the probable pathogenic signature of this tumor. […] Identifying the cell of origin of RB may help to answer questions regarding phenotype variability and progression of the tumor. […] Improvement in our understanding on the molecular wiring of RB would result in a better treatment option in the future.

• #62 Retinoblastoma | Hereditary Ocular Diseases

  https://disorders.eyes.arizona.edu/disorders/retinoblastoma

  Retinoblastoma is a malignant tumor of the developing retinal cells caused in most cases by mutations in both copies of the RB1 gene. […] The RB1 gene is a tumor suppressor gene, located on chromosome 13q14 and is the first human cancer gene to be cloned. […] Recent evidence suggests that post-mitotic cone precursors are uniquely sensitive to pRB depletion and may be the cells in which retinoblastoma originates. […] However, more recent information suggests that the occurrence and viability of retinoblastic cells may be more complex than suggested by simple loss of function of the RB1 alleles. […] There is increasing evidence for the role of epigenetic factors such as DNA methylation impacting the differential expression of more than 100 additional genes which may be influencing the retinoblastoma phenotype.

• #63 Retinoblastoma: Etiology, Modeling, and Treatment

  https://www.mdpi.com/2072-6694/12/8/2304

  Interestingly, the 1q gain and 16q loss in tumors are indicative of increased levels of genomic instability and associated with late diagnosis and non-hereditary retinoblastoma. […] High MYCN amplification is proposed as a novel mechanism of disease initiation in retinoblastoma without RB1 mutation. […] Definitive determination of the cell-of-origin and understanding how tumor cells exploit the mechanisms of such susceptible cells for malignant transformation may facilitate development of treatments that specifically target tumor cells, while sparing normal retinal tissue. […] The intrinsic gene expression program of cone cells can be oncogenically activated in the absence of pRb. […] Cone-specific signal circuitry, including TRβ2, RXRγ, oncoprotein Mdm2 (MDM2), and N-myc proto-oncogene protein (MYCN), collaboratively supports the transition from premalignant to malignant lesions. […] If cone cells are the cell-of-origin, pRB depletion and cone-specific signal circuitry may enable proliferation in retinoblastoma.

• #64 Retinoblastoma: Etiology, Modeling, and Treatment

  https://www.mdpi.com/2072-6694/12/8/2304

  Interestingly, the 1q gain and 16q loss in tumors are indicative of increased levels of genomic instability and associated with late diagnosis and non-hereditary retinoblastoma. […] High MYCN amplification is proposed as a novel mechanism of disease initiation in retinoblastoma without RB1 mutation. […] Definitive determination of the cell-of-origin and understanding how tumor cells exploit the mechanisms of such susceptible cells for malignant transformation may facilitate development of treatments that specifically target tumor cells, while sparing normal retinal tissue. […] The intrinsic gene expression program of cone cells can be oncogenically activated in the absence of pRb. […] Cone-specific signal circuitry, including TRβ2, RXRγ, oncoprotein Mdm2 (MDM2), and N-myc proto-oncogene protein (MYCN), collaboratively supports the transition from premalignant to malignant lesions. […] If cone cells are the cell-of-origin, pRB depletion and cone-specific signal circuitry may enable proliferation in retinoblastoma.

• #65 Molecular Biological Research on the Pathogenic Mechanism of Retinoblastoma

  https://www.mdpi.com/1467-3045/46/6/317

  Retinoblastoma (RB) is the most common intraocular malignant tumor in children, primarily attributed to the bi-allelic loss of the RB1 gene in the developing retina. […] Despite significant progress in understanding the basic pathogenesis of RB, comprehensively unravelling the intricate network of genetics and epigenetics underlying RB tumorigenesis remains a major challenge. […] The pathogenesis of retinoblastoma involves abnormalities in multiple genes. The bi-allelic inactivation of the RB1 gene is a major driving force in RB development, referred to as the “two-hit theory”, involving two successive mutations. […] The “two-hit theory” indicates that the inactivation of two alleles of the tumor suppressor gene is necessary for cancer, leading to uncontrolled cell differentiation and tumor formation.

• #66

  https://www.jaypeedigital.com/eReader/chapter/9789350257845/ch3

  The distribution of retinoblastoma is worldwide, affecting all racial groups without sex predilection. Retinoblastoma is a rare malignant tumor with a prevalence of about 1 in 15,00023,000 live births. The incidence of retinoblastoma appears to be constant among the various populations of the world, suggesting that environmental influences play little role in its etiology. Understanding of pathogenesis of retinoblastoma has improved over last 100 years, with contributions from the field of genetics, cell biology, animal models, medical oncology and, finally, stem cell biology. The cumulative evidence from all these fields have made significant contributions to improve the survival of the patients affected with retinoblastoma. The mystery that makes the tumor cells escape the confines of the eye to spread to extraocular sites, resist the chemotherapeutic drugs and to recur, is still not understood and warrants many more years of vigorous research.

• #67 Emerging Developments in the Understanding and Treatment of Retinoblastoma – Retina Today

  https://retinatoday.com/articles/2010-mar/emerging-developments-in-the-understanding-and-treatment-of-retinoblastoma

  The paradigm of cancer treatment has experienced tremendous advancements, as treatments are now targeting not only hyperproliferative neoplastic cells but also the tumor microenvironment. This unique cancer stromal tissue is made up of a milieu of cytokines, growth factors, extracellular proteins, tumor cells, endothelial cells, fibroblasts, and inflammatory cells. Together, these components serve as key modulators in tumor development, growth, resistance to treatment, and metastasis. A more thorough understanding of the mechanisms that drive tumorigenesis is imperative to develop more targeted treatments for tumors. […] With a greater understanding of the pathogenesis of retinoblastoma tumors, novel drugs may be investigated to target important aspects of tumor progression. Combined with chemotherapy and focal consolidation with laser, adjuvant treatments that target tumor vasculature, hypoxia, macrophages, MMPs and specific genes and gene pathways, may lead to greater control rates for advanced tumors or less dependence on chemotherapy with systemic toxicities.

• #68 Molecular Biological Research on the Pathogenic Mechanism of Retinoblastoma

  https://www.mdpi.com/1467-3045/46/6/317

  The targeting of epigenetic modifications provides a unique opportunity to optimize therapeutic paradigms and develop novel treatment modalities. […] The pathogenesis of RB involves the complex regulation of multiple genes and pathways; however, the respective roles and interrelationships between this large, complex RNA regulatory network and protein-based regulatory mechanisms have not been clearly understood.

• #69

  https://journals.lww.com/ijo/fulltext/2023/71070/retinoblastoma__a_review_of_the_molecular_basis_of.9.aspx

  The downregulation of ARHGAP9 was found to significantly affect cancer cell susceptibility toward chemotherapeutic drugs, such as carboplatin and etoposide, leading to increased cancer cell migration, invasion, proliferation and chemoresistance. […] The probability of epigenetic dysregulation in retinoblastoma has been explored through integrative epigenome analysis. […] Epigenetic mechanisms such as hypermethylation, gene silencing, and large deletions have been found to be involved in retinoblastoma progression. […] MDM4 which is an inhibitor of p53 protein that disrupts the apoptotic pathway has been found to be highly upregulated in retinoblastoma with the help of immunoblotting and immunoprecipitation. […] Recent developments in our understanding of the molecular landscape of retinoblastoma has equipped us with a valuable list of potential targets for targeted therapy, thanks to the success of multi-omics technologies like NGS and proteomics.

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