In this study, we have assessed the influence of older parental age on Rb caused by de novo autosomal dominant mutations using a cohort of Rb survivors diagnosed and treated at one institution. To our knowledge, this is the first study to evaluate parental age effects for three different categories of Rb (hereditary Rb resulting from a de novo germline mutation, sporadic Rb, and familial Rb inherited from an affected parent), and to investigate parental age differences between these three groups.
Although we found no significant differences between maternal and paternal ages when comparing between the three Rb groups, there was some evidence of a signal for older paternal age and the odds of a de novo
germline mutation based on the modeling. We also noted that mean parental ages related to de novo
germline mutations and sporadic Rb, but not familial Rb, were higher than the general population This finding supports the notion that, in general, those with familial Rb reproduce at ages similar to the general population, but have a 50/50 chance of passing on the mutated RB1
allele with each pregnancy. It was not surprising to find younger parental ages for familial Rb cases when compared with sporadic Rb because this was reported in a previous study (Yip et al. 2006
). However, the similarity of mean maternal and paternal ages for de novo
germline mutations and sporadic Rb was unexpected, because it has not been previously reported.
When comparing our study to previous studies regarding parental age data for Rb (see ), it is important to note that we compared our hospital-based cohort to the general population in our analysis of mean maternal and paternal age. We did not use matched general population controls for our logistic regression analysis nor did we use incidence data for Rb in the United States. Unlike previous studies, we compared the odds of being in the de novo
germline mutation classification group versus the sporadic and familial Rb groups given increasing parental age in our cohort of individuals. Our comparisons of parental age to general population means were similar to findings reported by DerKinderen et al. (1990)
and Moll et al. (1996)
for de novo
mutations, but in contrast to these studies, we also saw significant differences for sporadic non-hereditary Rb.
Comparison to previous studies of Retinoblastoma and parental age.
In our cohort we had relatively few parents over age 35 years making it difficult to estimate the odds of having a child with a Rb de novo
mutation for fathers of advanced paternal age (greater than 40-45 years of age) (). The theory behind de novo
mutations and advanced paternal age is that errors occur in mitotic divisions during male spermatogenesis (Thacker 2004
; Sartorius and Nieschlag 2010
). Although our results suggested a pattern of increased odds of a de novo
mutation with paternal age, we believe this is a preliminary finding that should be followed up with additional analysis with a greater number of Rb survivors with increased enrichment for advanced parental age. Only 65% of the cohort agreed to participate, and having more subjects would allow for statistical power to determine if the patterns we observed in this analysis are valid. In addition, more complete information on subject characteristics, such as race, would allow for a more detailed analysis of this potential confounder. Future research could consider the influence of other covariates such as environmental exposures of one or both parents that could increase the risk of de novo
retinoblastoma mutations (Bunin, et al. 2011
Future work regarding Rb and parental age should include mutation status gathered from genetic testing rather than by proxy with laterality and family history since some unilateral survivors in our cohort may have a de novo mutation that predisposed them to Rb. A dataset including mutation status and mutation type (missense versus nonsense, etc.) would allow for a more precise analysis of the differences in parental ages of the three Rb classification groups, given an adequate number of patients to achieve statistical power. Although prior studies have benefited from larger sample sizes, we believe this is the first study to include familial inherited Rb in an analysis of parental age.
Overall, our findings show that, as previously reported for other countries, the mean parental age of Rb survivors with a de novo mutation is statistically significantly higher than the mean age of the general U.S. population. The similarity of mean maternal and paternal ages for de novo germline mutations and sporadic Rb was unexpected and deserves further attention. Our study suggests a greater paternal rather than maternal contribution to RB1 mutations, perhaps during gametogenesis, for the de novo germline mutations, however we have insufficient data for investigating paternal age over age 40 years to test this hypothesis further. Our findings do not indicate statistically significant effects for advanced paternal age and thus would not be appropriate for use in genetic counseling at this time.