The impact of RB1 genotype on incidence of second tumours in heritable retinoblastoma.

Abstract Background Patients with heritable retinoblastoma are at risk for bilateral retinoblastoma and second primary malignancies (SPMs). The incidence of SPM is significantly raised after radiotherapy. We analysed the impact of the class of constitutional RB1 variant on the incidence of SPM in survivors with and without previous radiotherapy. Methods From 1940 to 2008, 655 national patients were treated for heritable retinoblastoma at the German referral centre. Data on SPM, therapy and constitutional RB1 variant were available for 317 patients (48.3%). Heterozygous RB1 variants were classified into variants with regular and incomplete penetrance for retinoblastoma. Results SPM occurred in 51 of 317 survivors of heritable retinoblastoma. The incidence rate (IR) of SPM per 1000 person years was 8.4 (95% confidence interval (CI): 6.3–11.1) in individuals heterozygous for an oncogenic RB1 variant and 2.1 (95% CI: 0.0–11.4) with RB1 mosaicism. The incidence of SPM was higher in patients with regular penetrance compared with incomplete penetrance RB1 variants (IR 10.3 [95% CI: 7.5–13.8] vs. IR 3.2 [95% CI: 1.0–7.5]; p  Conclusions Patients heterozygous for regular penetrance RB1 variants had a higher risk to develop SPM than patients with incomplete penetrance variants. Increased knowledge on genotype-phenotype relation regarding SPM may influence screening recommendations for SPM in survivors of heritable retinoblastoma.