Germline Sequencing Identifies Rare Variants in Finnish Subjects with Familial Germ Cell Tumors

Erin L Crowgey,1 Tea Soini,2 Nidhi Shah,1 Satu-Liisa Pauniaho,2,3 Pekka Lahdenne,2 David B Wilson,4 Markku Heikinheimo,2,4 Todd E Druley4 1Nemours Center for Cancer and Blood Disorders, Nemours Alfred I. duPont Hospital for Children, Wilmington, DE, USA; 2Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 3Tampere Center for Child Health Research, University of Tampere, Tampere University Hospital, Tampere, Finland; 4Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, MO, USACorrespondence: Todd E DruleyDepartment of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 4515 McKinley Avenue, Campus Box 8510, St. Louis, MO 63108, USAEmail druley_t@wustl.eduPurpose: Pediatric germ cell tumors are rare, representing about 3% of childhood malignancies in children less than 15 years of age, presenting in neonates or adolescents with a greater incidence noted in older adolescents. Aberrations in primordial germ cell proliferation/differentiation can lead to a variety of neoplasms, including teratomas, embryonal carcinoma, choriocarcinoma, and yolk sac tumors.Patients and Methods: Three Finnish families with varying familial germ cell tumors were identified, and whole-genome sequencing was performed using an Illumina sequencing platform. In total, 22 unique subjects across the three families were sequenced. Family 1 proband (female) was affected by malignant ovarian teratoma, Family 2 proband (female) was affected by sacrococcygeal teratoma with yolk sac tumor in the setting of Cornelia de Lange syndrome, and Family 3 proband (male) was affected by malignant testicular teratoma. Rare variants were identified using an autosomal recessive or de novo model of inheritance.Results: For family 1 proband (female), an autosomal recessive or de novo model of inheritance identified variants of interest in the following genes: CD109, IKBKB, and CTNNA3, SUPT6H, MUC5AC, and FRG1. Family 2 proband (female) analysis identified gene variants of interest in the following genes: LONRF2, ANO7, HS6ST1, PRB2, and DNM2. Family 3 proband (male) analysis identified the following potential genes: CRIPAK, KRTAP5-7, and CACNA1B.Conclusion: Leveraging deep pedigrees and next-generation sequencing, rare germline variants were identified that were enriched in three families from Finland with a history of familial germ cell tumors. The data presented support the importance of germline mutations when analyzing complex cancers with a low somatic mutation landscape.Keywords: genomics, familial germ cell tumors, next generation sequencing, germline analysis