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

Authors Crowgey EL, Soini T, Shah N, Pauniaho SL, Lahdenne P, Wilson DB, Heikinheimo M, Druley TE

Received 7 January 2020

Accepted for publication 19 April 2020

Published 30 June 2020 Volume 2020:13 Pages 127—137


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Martin H. Maurer

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, USA

Correspondence: Todd E Druley
Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 4515 McKinley Avenue, Campus Box 8510, St. Louis, MO 63108, USA

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

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