<p>Germline Sequencing Identifies Rare Variants in Finnish Subjects with Familial Germ Cell Tumors</p>

Abstract

Purpose: 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.

A Role of the TEX101 Interactome in the Common Aetiology Behind Male Subfertility and Testicular Germ Cell Tumor

“…Increased levels of CD109 transcript expression levels have been seen in the squamous cell cancers of the oesophagus, cervix, and lung ( 72 , 73 ). Recent germline sequencing research has shown the presence of CD109 in paediatric germ cell tumours arising from gonadal tissues, and several subtypes of paediatric germ cell tumours are shared with testicular germ cell tumours that arise after puberty, for example: teratoma, yolk sac tumour, embryonal carcinoma, and choriocarcinoma ( 74 ). A potential autosomal recessive variant of CD109 was discovered in a patient with malignant ovarian teratoma, with an increase in minor allele frequency compared to the control population ( 74 ).…”

“…Furthermore, the gene BSG, when present in non-small cell lung cancer is associated with increased metastatic potential ( 60 ). The interactome gene CD109 has shown oncogenic potential in some subtypes of TGCT, as well as other types of cancer ( 74 ). Thus, some genes within the interactome of TEX101 are related to tumour suppression, and some are associated with oncogenesis.…”