In this analysis, we did not observe any significant associations between GCT in girls or boys and family history of cancer overall; but we did observe some interesting results by age at diagnosis in the relatives. A family history of cancer with an early age of onset is suggestive of genetic susceptibility to disease. In our study, male children displayed a statistically significant increased risk of GCT if they had a family history of cancer in a relative diagnosed before the age of 40 years. In contrast, we observed a significant inverse association in girls with a family history of cancer diagnosed before age 40. We also observed a significant association between GCT in boys and melanoma in a family member, suggesting that these cancers may share common genetic or environmental risk factors.
Our results on the overall association between family history of cancer and risk of pediatric GCT are consistent with the few studies that have evaluated this relationship. A study of 41 GCT cases reported similar numbers of neoplasms in relatives of case and control children; however, they observed an excess of first- and second-degree case relatives with multiple tumors [4
]. A study of 73 cases with ovarian GCT reported no excess diagnoses of any cancer, breast and cervical cancer, or ovarian cysts among mothers of cases compared with mothers of controls [5
]. A third study of 105 cases of pediatric GCT reported a nonsignificant increase in risk of malignant GCT in children with a family history of cancer in a first-degree relative (OR = 2.9, 95% CI 0.9–9.1)[6
]. Taken together, these results suggest that a family history of cancer in general is not strongly associated with the risk of pediatric GCT, although the small sample size of these studies limits the power to detect associations.
The evidence for a heritable component of ovarian GCT has not been conclusive [30
]. In our study, we observed a statistically significant inverse association between family history of ovarian or uterine cancer and risk of GCT in girls. The explanation for this association is not obvious. We did observe a slightly elevated, although non-significant, association between family history of other benign reproductive organ disorders and GCT in girls. Previous studies have demonstrated that family history of female reproductive cancers is not accurately reported in case–control studies [34
]; therefore, it is possible that history of cancer is inaccurately reported as reproductive organ disease in these families. We were unable to account for female relatives who had hysterectomies or oophorectomies and were subsequently not at risk for uterine or ovarian cancer.
In contrast to the limited studies of family history in pediatric GCT and adult ovarian GCT, numerous studies have evaluated the association with adult testicular GCT. The strong family history of testicular cancer in fathers and brothers of testicular cancer cases suggests that there is a heritable component of this disease [15
], although a positive family history represents only 1–3% of all cases [38
]. The association between family history of testicular cancer and risk of pediatric GCT in boys was of interest in our study; however, we could not test the hypothesis that pediatric GCT in boys was associated with a family history of testicular cancer because of the small number of reported cases of testicular cancer in family members (n
A family history of other types of cancers in relatives of testicular cancer patients could suggest common genetic or environmental risk factors. Because of the limited numbers of cancers reported in relatives, we were able to evaluate site specific associations only between family history of melanoma, lung, breast, prostate, and uterine/ovarian and GCT in boys. Melanoma was the only cancer for which a family history was significantly associated with GCT in boys. A possible association between family history of melanoma and risk of testicular GCT has been reported previously in an analysis from the Swedish Family-Cancer database [25
]; however, the reported associations were not consistent across all types of relatives. In another study, an increased number of testicular cancers was not observed in relatives of 4,079 cases of melanoma; however, there was an increased number of testicular cancers when second cancers were evaluated in the melanoma cases themselves [39
]. Hormonal and reproductive factors have been suggested to play a role both in testicular cancer and melanoma [5
], which could provide one potential explanation for this relationship. However, the role of hormonal and reproductive factors in the pathogenesis of melanoma has been controversial, and a recent review of the literature suggested that there is no conclusive evidence to suggest that pregnancy or hormonal factors influence the development of melanoma in women [40
]. The potential relationship between family history of melanoma and GCT should be evaluated in future studies.
A major strength of this study was the relatively
large number of pediatric GCT cases assembled; however, several limitations must also be considered. First, family history of disease was obtained by self-report. Validation studies have shown that reporting of family history of cancer is relatively accurate, especially for the more common cancer sites [34
]. However, studies have shown that reporting may be less accurate for several of the cancers of interest here, including testicular cancer [47
], melanoma [48
], and cancer of the female reproductive organs [34
]. As expected, a higher reliability of report has been observed for first-degree relatives compared with more distant relatives [34
]. Although we evaluated associations between both first (parents) and second (grandparents and aunts/uncles) degree relatives of the cases, it is important to note that family history information was provided by the parents about their first degree relatives. We might then expect the information about children's second degree relatives to be more accurate than in comparable studies of adult cancers. Parents of cases might also be expected to give a more thorough history than control parents, although there was no difference in sensitivity of reporting between cases and controls in two previous studies [35
]. There was not a tendency for parents of cases to report more cancers among family members in our study, and significant associations of GCT with a positive family history of cancer and reproductive organ disease differed by sex.
Another limitation that must be considered is the lower participation rate among controls (66.6%) compared with cases (80.8%) in this study. Significant differences between cases and controls for family income, race and parental education have been reported in this study population [8
]. In order to account for these potential variations among the groups, we adjusted our analyses for annual family income, maternal education, maternal race, and maternal age at birth of the index child; however, we must consider the possibility of residual confounding by SES. The young age of the relatives of our study population is also a limitation as most of these individuals have not reached the peak age for risk of cancer. Lastly, we cannot rule out chance as an explanation for these results due to the many comparisons we made between family history of cancer and GCT.
In conclusion, we did not find strong evidence that a family history of cancer in general is associated with pediatric GCT in boys or girls. We did find evidence that having a relative with an early age at diagnosis may be associated with childhood GCTs in a sex-specific manner, although these results should be evaluated in additional studies. Analysis of family history of other cancers may provide clues to mechanistic pathways involved in GCT and could also be used to help define cancer screening practices for relatives of children with GCT.