High parental age is associated with sporadic hereditary retinoblastoma: the Dutch retinoblastoma register 1862-1994

Abstract

We wished to determine the influence of parental age at the birth of a retinoblastoma patient on the risk of sporadic hereditary retinoblastoma. The parental age at birth of 941 patients of the Dutch retinoblastoma register was identified and compared between sporadic hereditary and nonhereditary patients. In a subcohort , a comparison was made with parental age at birth in the general population, as obtained from the Central Bureau of Statistics. Missing birth dates of the parents of retinoblastoma patients were traced with the help of the municipal registries and the Central Bureau of Genealogy. The mean paternal age was 10.7 months higher and the mean maternal age was 11.0 months higher in the sporadic hereditary retinoblastoma patients than in parents of nonhereditary patients. In the subcohort, the mean paternal and maternal ages of sporadic hereditary patients were also higher (12.4 and 11.5 months, respectively) than those of the general population. All differences were statistically significant. This study shows that a high parental age is associated with an enhanced risk of sporadic hereditary retinoblastoma. IntroductionRetinoblastoma is a malignant pediatric tumor affecting the retina and occurring about once in 20 000 live births. Retinoblastoma occurs in a hereditary form (30%-40% of the patients) and a nonhereditary form (60%-70%; Vogel 1979). It develops following at least two (Knudson 1971; DerKinderen 1987) mutational events, namely, inactivation of both alleles of the retinoblastoma (RB1) gene at 13q14 (Cavenee et al. 1983;Dryja et al. 1986).The hereditary form results from a germline mutation which is present in all body cells. Among hereditary cases, a familial hereditary form and a sporadic hereditary form may be distinguished. An indication for the familial hereditary form is a parent with retinoblastoma or a family member with this disease, indicating that one of the parents must be a carrier of the RB1 gene. In the sporadic hereditary form, no other family members are affected, and the patient is the first person in the family with retinoblastoma. In the nonhereditary form, the retinoblastoma mutation is exclusively found in the tumor cells of the retina (Knudson 1971;Vogel 1979).Epidemiological observations suggest that parental age is related to the genesis of sporadic hereditary disorders such as Down's syndrome and achondroplasia. This is understandable, since the number of new mutations in germline cells increases with age (Penrose 1955;Vogel and Rathenberg 1975;Vogel 1979). The existence of an association of sporadic hereditary retinoblastoma with parental age is still controversial (Falls and Neel 1951;Stevenson and Martin 1957;Smith and Sorsby 1958;Macklin 1960;Matsunaga 1965;Fraser and Friedmann 1967;Tünte 1972;Pellié et al. 1973;Bunin et al. 1989;Matsunaga et al. 1990; DerKinderen et al. 1990). Furthermore, DNA investigations on some patients suggest that new germline mutations are principally of paternal orgin (Ejima et al. 1988;Dryja et al. 1989;Zhu et al. 1989). Th...

Quantification of the paternal allele bias for new germline mutations in the retinoblastoma gene

“…In our study, new germline mutations arose from fathers who were, on average, no older than fathers of children with maternally derived germline mutations or somatic initial mutations. Other, more formal studies of this issue involving greater numbers of cases have found a small paternal age effect (Vogel and Rathenberg 1975;der Kinderen et al 1990;Moll et al 1996), but at least two studies have not (Matsunaga et al 1990;Sasaki et al 1991). Additional research will probably be necessary to resolve this issue.…”

Paternal age and reproduction

“…Nonetheless, children of older fathers are not only more likely to have several diseases of clear genetic cause (Kühnert and Nieschlag, 2004;Lambert et al, 2006), they show also an increased risk for multifactorial diseases such as birth defects (Olshan et al, 1994;McIntosh et al, 1995;Kazaura et al, 2004;Bille et al, 2005;Zhu et al, 2005a, b;Archer et al, 2007;Yang et al, 2007), childhood cancers (Moll et al, 1996;Hemminki et al, 1999;Sharpe et al, 1999;Murray et al, 2002;Yip et al, 2006), prostate cancer (Zhang et al, 1999), breast cancer (controversial) (Colditz et al, 1991;Choi et al, 2005), diabetes mellitus type l (Bingley et al, 2000;Cardwell et al, 2005), multiple sclerosis (Montgomery et al, 2004), some forms of cerebral palsy (Fletcher and Foley, 1993), schizophrenia (Malaspina, 2001), bipolar disorder (Frans et al, 2008), autism (Reichenberg et al, 2006), epilepsy (Vestergaard et al, 2005), Alzheimer disease (Whalley et al, 1995) and lower intelligence quotients (Malaspina et al, 2005;Saha et al, 2009). However, some of the reported associations need to be considered with caution for methodological reasons in the statistical analysis, especially in regard to the validity of the data sources (Kirby, 2007) (Fig.…”

Osteosarcoma following retinoblastoma: Age at onset and latency period

“…[1][2][3][4][5] Patients with retinoblastoma during early childhood are at risk of developing osteosarcoma during adolescence, [6][7][8] and, as radiotherapy is frequently used for the treatment of retinoblastoma, a high proportion of osteosarcomas are observed within the radiation field. [6][7][8] Most cases of osteosarcoma occurring in retinoblastoma survivors are either bilateral or associated with a familial predisposition, i.e. in subjects presumably heterozygous for an RB1 gene germline mutation.…”