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

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.

Keywords:

• genomics
• familial germ cell tumors
• next generation sequencing
• germline analysis

Abbreviations

GCT, germ cell tumors; NGS, next-generation sequencing; WGS, whole-genome sequencing; GATK, genome analysis toolkit; VCF, variant call file; MAF, minor allele frequency; SISu, Sequencing Initiative Suomi.

Acknowledgments

The authors would like to thank the families for participating in this research effort. Furthermore, the authors acknowledge support from the McDonnell Genome Institute at Washington University for conducting the next-generation sequencing, and Krishna Kanchi for providing bioinformatics support for the raw data.

Author Contributions

All authors contributed to data analysis, drafting and/or revising the article, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Disclosure

Dr Todd E Druley reports ownership, salary from ArcherDX, Inc., outside the submitted work. In addition, Dr Todd E Druley has a patent #62/106,967 pending to Canopy Biosciences. The authors report no other conflicts of interest in this work.

Additional information

Funding

The authors acknowledge grant support to MH via Sigrid Jusélius Foundation, Leukemia Research Foundation of Delaware and the National Institute of General Medical Sciences of the National Institutes of Health grant number U54-GM104941 (PI: Binder-Macleod) for supporting ELC, and the Kellsie’s Hope Foundation to TED.