RB1 mutations and second primary malignancies after hereditary retinoblastoma

Abstract

Survivors of hereditary retinoblastoma have a high risk of second primary malignancies, but it has not been investigated whether specific RB1 germline mutations are associated with greater risk of second primary malignancies in a large cohort. We conducted a retrospective cohort study of 199 survivors of hereditary retinoblastoma with a documented RB1 germline mutation diagnosed between 1905 and 2005. In total, 44 hereditary retinoblastoma survivors developed a second primary malignancy after a median follow-up of 30.2 years (range 1.33–76.0). A significantly increased risk of second primary malignancy was observed among carriers of one of the 11 recurrent CGA>TGA nonsense RB1 mutations (hazard ratio (HR) = 3.53; [95% confidence interval (CI) = 1.82–6.84]; P = .000), and there was a significantly lower risk for subjects with a low penetrance mutation (HR = .19; [95% CI = .05–.81]; P = .025). Our findings suggest a genotype-phenotype correlation for second primary cancers of retinoblastoma survivors and may impact on long-term surveillance protocols of patients with hereditary retinoblastoma, if confirmed by future studies.

RB1mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients

“…In three of these families, one of the RB1 carriers without Rb had developed a sarcoma that may be RB1 -related. In a previous study, we have shown that the risk of a second cancer for carriers of a incomplete penetrance RB1 mutation is much lower than for carriers of a mutation with high penetrance 20. Nevertheless, awareness of a possible increased risk is important, and therefore RB1 mutation testing of family members can be useful even when they will not develop Rb anymore.…”

“…Therefore, all newly diagnosed Rb patients have been offered DNA testing since the beginning of the 1990s and extensive follow-up procedures have led to the testing of virtually all Rb patients still living from the Dutch National Retinoblastoma Register 20. Our study cohort thus forms a unique unbiased nationwide group of Rb patients.…”

“…Throughout the years, the information has been updated regularly with clinical and genetic data 4 20. Since 1992, all newly diagnosed Rb patients are treated in the National Retinoblastoma Treatment Center at the VU University Medical Center.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…Now, with improved therapy and better survival for their RBs it has become clear that these individuals have an increased risk of other cancers later in life as well. 107 Somatic alterations of RB1, including large deletions and promoter methylations, have been detected in different cancer forms, including breast cancer (see references in Berge et al 108 ). In a recent paper, Witkiewicz et al 109 found an RB-deficiency gene expression signature to be associated with increased chance of a pathological complete response among breast cancer patients receiving primary chemotherapy with 5-fluorouracil, adriamycin and cyclophosphamide, but also patients treated with combined anthracycline-and taxane-containing regimens.…”

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

“…Intra-and interfamily variation in phenotypic expressivity suggests there may be other modifying factors (32,33). In a large retrospective cohort of RB survivors, individuals with lower penetrance mutations were also found to have a lower risk of second primary malignancies (34).…”