RB1 – Hereditary Retinoblastoma

The retinoblastoma 1 gene RB1 is a classic autosomal dominant tumor suppressor mutated in Hereditary Retinoblastoma. Germline loss-of-function variants in RB1 predispose to bilateral or multifocal disease by a two-hit mechanism, with somatic inactivation of the second allele required for tumorigenesis. Penetrance is generally high but variable, reflecting both complete loss and hypomorphic alleles.

Robust genetic evidence includes 180 unrelated retinoblastoma patients screened, with germline RB1 mutations identified in 77 of 85 bilateral cases (PMID:15884040) and segregation across 29 low-penetrance families (PMID:7927327). Additional affected relatives were documented in these families, confirming dominant transmission. A retrospective cohort of 199 survivors demonstrated genotype–phenotype correlations, including elevated second malignancy risk for recurrent nonsense alleles (HR=3.53) and reduced risk for low-penetrance mutations (HR=0.19) (PMID:22205104).

The RB1 variant spectrum comprises premature truncations (nonsense, frameshift, splice site), in-frame indels, and missense changes affecting functional domains. A representative hypomorphic allele, c.1448A>T (p.His483Leu), segregates with reduced expressivity in a low-penetrance pedigree (PMID:21538077). Over 99 unique germline mutations have been catalogued, including recurrent CGA>TGA transitions at methylated CpG hotspots.

Clinically, carriers present with unilateral or bilateral retinoblastoma in infancy and require lifelong surveillance for second primary tumors (osteosarcoma, soft tissue sarcomas, melanoma), especially after radiotherapy. Case reports describe osteosarcoma in a 24-year-old survivor (PMID:8217129) and leiomyosarcoma of the bladder (PMID:32197986). Low-penetrance families may present with mild or unilateral disease or benign acral fibromas as cutaneous markers (PMID:11069472).

Functional studies support RB1 haploinsufficiency and loss-of-function as the pathogenic mechanism. Low-penetrant alleles retain partial E2F1 binding and nuclear localization, with intermediate cyclin-dependent kinase phosphorylation profiles (PMID:9342358). Mutation of the bipartite nuclear localization signal disrupts nuclear import and growth suppressor activity, confirming domain-specific requirements for tumor suppression (PMID:8336704).

Integrating genetic and experimental data, RB1 mutation analysis achieves definitive clinical validity and guides early detection, surveillance, and risk stratification. Genetic counselling should address variable penetrance and second malignancy risk, informing personalized management. Key take-home: RB1 testing is essential for diagnosis and lifelong monitoring of hereditary retinoblastoma carriers.

References

• Human mutation • 2005 • Sensitive multistep clinical molecular screening of 180 unrelated individuals with retinoblastoma detects 36 novel mutations in the RB1 gene. PMID:15884040
• Human genetics • 1994 • Distinct RB1 gene mutations with low penetrance in hereditary retinoblastoma. PMID:7927327
• Familial cancer • 2011 • Low penetrance hereditary retinoblastoma in a family: what should we consider in the genetic counselling process and follow up? PMID:21538077
• Proceedings of the National Academy of Sciences of the United States of America • 1997 • Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result in partial loss of RB function. PMID:9342358
• Molecular and cellular biology • 1993 • A bipartite nuclear localization signal in the retinoblastoma gene product and its importance for biological activity. PMID:8336704

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