Heterozygous Germline Fanconi Anemia-Related Gene Mutations Increase Susceptibility to Germ Cell Tumors.

Purpose: Germ cell tumors (GCTs) are a heterogeneous group of neoplasms that predominantly affect adolescents and young adults. Notably, geographical disparities in GCT incidence exist, with higher rates observed in East Asia. Although numerous studies have established links between heterozygous germline mutations in Fanconi anemia (FA) genes and the development of certain human cancers, the association between germline pathogenic or likely pathogenic (P/LP) variants in FA genes and the relative risk of developing GCTs remains incompletely characterized.

Methods: In this study, we used next-generation sequencing (NGS) to investigate the genetic susceptibility patterns of Chinese patients with GCTs for the first time. We investigated the association between germline P/LP variants in FA-related genes and the risk of developing GCTs. Furthermore, we compared clinical characteristics, mutational landscape, and mutational signatures between patients with and without germline P/LP variants in FA-related genes.

Results: We identified heterozygous germline P/LP variants in FA-related genes in 12.12% (8/66) of patients with GCTs, involving FANCA, BRCA2, FANCD2, FANCE, and SLX4. Our findings demonstrate a significant association between a subset of FA genes and an increased relative risk of GCTs, indicating a role for these variants in GCT predisposition. Furthermore, patients harboring these FA gene variants exhibited a higher number of mutations, increased propensity for gene fusions, and demonstrated a greater degree of genomic instability.

Conclusion: These results elucidate the contribution of FA-related germline variants to GCT pathogenesis and advance our understanding of the genetic determinants influencing GCT relative risk. This research provides a basis for developing more effective screening strategies, personalized treatment approaches, and improved patient management strategies for GCTs.