Increasing Paternal Age Associated With Elevated Risk of De Novo Mutations in Offspring Diagnosed With Sporadic...

The impact of paternal exposures on de novo germline mutations leading to bilateral sporadic retinoblastoma in offspring is largely unknown. This malignancy results from mutations of both alleles of the RB1 tumor suppressor gene in a retinal cell. Hence, in this study we aimed to investigate the role of paternal age, gonadal radiation exposure, and smoking on different types of de novo RB1 mutations in a cohort of children with bilateral sporadic retinoblastoma.

We utilized data from two multi-institutional studies consisted of 172 children diagnosed with sporadic bilateral retinoblastoma who had available information on paternal de novo RB1 mutations. Information on paternal radiation exposure, paternal smoking, and paternal age were obtained from structured questionnaires. Exact logistic regression was utilized to estimate the association between each paternal characteristic and the risk of various types of de novo mutations in offspring.

The results revealed a significant association between young paternal age (< 25) and decreased risk of any type of de novo RB1 mutations in offspring compared to children with no mutation detected (adjusted odds ratio [OR] 0.19; 95% confidence interval [CI] 0.04-0.98). In addition, a significant trend toward elevated risk of de novo mutations in offspring with increasing paternal age was detected (adjusted OR 4.01; 95% CI 1.07-15.76). No statistically significant association was identified for the other investigated paternal characteristics.

Our study suggests a significant role for increasing paternal age in the development of sporadic bilateral retinoblastoma by elevating the risk of de novo RB1 mutations in offspring. These findings shed light on the potential causal mechanisms underlying the development of sporadic retinoblastoma.