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.

Fig. 1

Flow chart showing reasons for inclusion and exclusion of retinoblastoma patients with hereditary retinoblastoma from our cohort. In the total group of 410 hereditary retinoblastoma patients from our cohort, 99 primary tumors (SPT) have been diagnosed. In the flow chart is also depicted in which in- or excluded group these SPT’s have occurred. Percentage is calculated from the total of 99 SPT’s

Fig. 2

Graphical representation of RB1 and mutations found among hereditary retinoblastoma subjects diagnosed with a second primary malignancy (n = 44). Exons 1 through 27 are not drawn to scale. Every symbol represents a retinoblastoma subject diagnosed with a second primary malignancy. Black symbols represent sporadic hereditary retinoblastoma subjects. Greyscale coloured symbols represent subjects with familial retinoblastoma. Downward-pointing symbols represent mutations in exons, and upward-pointing symbols represent mutations in introns. The horizontal lines below depict large rearrangements