Abstract 2497: Inherited copy number variants that increase risk of developing pediatric germ cell tumors with a particular focus on the X chromosome

Abstract Pediatric malignant germ cell tumors (GCTs) are heterogeneous but are grouped together due to the presumed common cell of origin, the primordial germ cell (PGC). Little is known about etiology; however, evidence supporting in utero origins of pediatric and adult GCT suggests that disruptions in normal germ cell development are likely to be highly relevant. Germline copy number variants (CNVs) are a plausible source of inherited genetic variation and have not been thoroughly evaluated to date. CNVs on the X chromosome are of particular interest because individuals with both Klinefelter syndrome (47, XXY) and Turner syndrome (45, X) are at increased risk of pediatric GCT, suggesting that alterations in X chromosome dosage contribute to etiology. A family study of adult testicular cancer where at least one member had bilateral cancer identified a significant linkage peak at Xq27 (hLOD=4.7). In addition, somatic copy number gains of chromosome X are frequently seen in adult testicular germ cell tumors. Given these findings in adult GCT, similar aberrations may also be relevant risk factors for the pediatric group. Pediatric GCT samples were obtained from a Children’s Oncology Group study and state biobank programs in Michigan and California. Genotyping array data were generated using the Illumina HumanCoreExome Beadchip (Illumina, San Diego). CNV calls were made for 2,002 GCT cases and 1,402 controls with high quality intensity data using Genvisis, which has specialized algorithms to make CNV calls on the X chromosome. Klinefelter syndrome cases (n=27) were excluded from the analyses. No study sample had classic Turner syndrome; however, one female case had a giant 51Mb deletion of Xq. Analyses were performed for females-only, males-only, and everyone together. We identified two regions that are study-wide significant on chromosome X at Xq27.1 and Xp11.2 and one nominally significant near Xq28. The most significant finding was identified in females-only and is located within a region that encodes genes within the SPANX family. Evidence suggests these genes affect germ cells; however, supporting data is reported in spermatozoa rather than oocytes. The events in our study were large (240kb), had similar breakpoints, and appear to be flanked by repetitive DNA that might lead to recurrent events at the same region. The variant was present in the control samples within gnomAD at a low allele frequency (0.18%). In our study, both deletions and duplications were noted: 11 female cases (1 or 2 expected based on gnomAD allele frequencies) and 0 female controls (0-1 expected). The finding was not replicated in males (6 male cases and 5 male controls harbored similar CNVs). We are in the process of validating these in silico and potentially via quantitative PCR. Findings may shed light on disruptions in normal development that may increase risk of GCT. Citation Format: Shannon S. Cigan, John J. Meredith, John Zaharick, Erica Langer, Anthony J. Hooten, John A. Lane, Nathan Pankratz, Jenny N. Poynter. Inherited copy number variants that increase risk of developing pediatric germ cell tumors with a particular focus on the X chromosome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2497.