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RB1 – Melanoma

Retinoblastoma 1 (RB1) is infrequently implicated in melanoma pathogenesis. A single patient with a 9-year history of chronic lymphocytic leukemia and a cutaneous collision tumor harbored a constitutional t(12;17)(p13;p13) disrupting RB1, suggesting a possible germline predisposition to melanoma ([PMID:29371889]). In a clonal architecture study of 124 metastatic melanomas, truncating RB1 mutations were identified in multiple patients, indicating recurrent somatic loss of function in melanoma genomes ([PMID:25393105]). Functional assays demonstrate that RB1 represses cell cycle progression and transcriptional activation of oncogenic promoters such as IL6, consistent with a tumor suppressor mechanism in diverse cell types ([PMID:1652755]).

Integration & Clinical Utility: The current evidence supports a Limited clinical validity for RB1 in melanoma, based on one germline case and several somatic studies without segregation data. Genetic evidence is Limited: somatic truncating mutations are observed but familial segregation is unproven. Functional evidence is Moderate: RB1’s role in cell-cycle control and promoter repression is well established. Further family-based investigations and segregation analyses are required to define RB1 as a melanoma predisposition gene. Key Take-home: RB1 functions as a somatic tumor suppressor in melanoma with moderate mechanistic support but limited germline evidence for clinical genetic testing.

References

  • Molecular cytogenetics • 2018 • Cytogenetic/mutation profile of chronic lymphocytic leukemia/malignant melanoma collision tumors of the skin. PMID:29371889
  • PloS one • 2014 • Clonal architectures and driver mutations in metastatic melanomas. PMID:25393105
  • Oncology reports • 2007 • Mutational analysis of Chk1, Chk2, Apaf1 and Rb1 in human malignant melanoma cell lines. PMID:17143490
  • Proceedings of the National Academy of Sciences of the United States of America • 1991 • Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. PMID:1652755

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

One germline case of constitutional RB1 disruption in a CLL/MM collision tumour (PMID:29371889) and recurrent somatic truncating mutations in metastatic melanomas (PMID:25393105)

Genetic Evidence

Limited

Somatic RB1 truncating mutations observed in multiple melanoma genomes without germline segregation data

Functional Evidence

Moderate

RB1 represses cell-cycle genes and oncogenic promoters such as IL6, supporting a tumor suppressor mechanism (PMID:1652755)