Simple SummaryAlthough granulosa cell tumors can occur in rare syndromes and one familial case of a granulosa cell tumor has been described, a genetic predisposition for granulosa cell tumors has... Show moreSimple SummaryAlthough granulosa cell tumors can occur in rare syndromes and one familial case of a granulosa cell tumor has been described, a genetic predisposition for granulosa cell tumors has not been identified. Through our collaborations with patients, we identified four families in which two women of each family were diagnosed with an adult granulosa cell tumor. Although predicted deleterious variants in PIK3C2G, BMP5, and LRP2 were found, we could not identify an overlapping genetic variant or affected locus that may explain a genetic predisposition for granulosa cell tumors. The age of onset in the familial patients was significantly lower (median 38 years, range from 17 to 60) than in sporadic patients (median between 50 and 55 years). Furthermore, breast cancer, polycystic ovary syndrome, and subfertility were seen in these families.Adult granulosa cell tumor (AGCT) is a rare ovarian cancer subtype, with a peak incidence around 50-55 years. Although AGCT can occur in specific syndromes, a genetic predisposition for AGCT has not been identified. The aim of this study is to identify a genetic variant in families with AGCT patients, potentially contributing to tumor evolution. We identified four families, each including two women diagnosed with AGCT. Whole-genome sequencing was performed to identify overlapping germline variants or affected genes. Familial relationship was evaluated using genealogy and genomic analyses. Patient characteristics, medical (family) history, and pedigrees were collected. Findings were compared to a reference group of 33 unrelated AGCT patients. Mean age at diagnosis was 38 years (range from 17 to 60) versus 51 years in the reference group, and seven of eight patients were premenopausal. In two families, three first degree relatives were diagnosed with breast cancer. Furthermore, polycystic ovary syndrome (PCOS) and subfertility was reported in three families. Predicted deleterious variants in PIK3C2G, BMP5, and LRP2 were identified. In conclusion, AGCTs occur in families and could potentially be hereditary. In these families, the age of AGCT diagnosis is lower and cases of breast cancer, PCOS, and subfertility are present. We could not identify an overlapping genetic variant or affected locus that may explain a genetic predisposition for AGCT. Show less
