Abstract
Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline
RB1
mutations. To further our understanding of the association of parental age and risk of
de novo
germline Rb mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 retinoblastoma patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We built two sets of hierarchical stepwise logistic regression models to detect an increased odds of a
de novo
germline mutation related to older parental age compared to sporadic and familial Rb. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and five-year age increases adjusted for the age of the other parent. Mean maternal ages for patients with
de novo
germline mutations and sporadic Rb were similar (28.3 and 28.5 respectively) as were mean paternal ages (31.9 and 31.2 respectively), and all were significantly higher than the weighted general U.S. population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted U.S. general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of having a
de novo
germline mutation for each five-year increase in paternal age, but these findings were not statistically significant (
de novo
versus sporadic ORs: 30-34 = 1.65 [0.69-4], ≥35 = 1.34 [0.54-3.3];
de novo
versus familial ORs: 30-34 = 2.82 [0.95 – 8.4], ≥35 = 1.61 [0.57-4.6]). Our study suggests a weak paternal age effect for Rb resulting from
de novo
germline mutations consistent with the paternal origin of most of these mutations.
