Association of Y-chromosomal gr/gr deletions with testicular germ cell tumor: whole-genome analysis of 198,306 individuals
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Purpose: Germline deletions affecting the Y-chromosomal gr/gr region were reported in 2005 as associated with susceptibility to testicular germ cell tumor (TGCT), a highly heritable tumor type that is the most common cancer type affecting adult men under the age of 45. Attempts to replicate this association have been equivocal, primarily due to limited power. Methods: Here, we compare and validate two computational approaches to gr/gr deletion calling in high-, low- and ultra-low-coverage whole genome sequencing data, applying these to two datasets from UK Biobank and the TECAC consortium. We generate dataset-specific effect size estimates for the gr/gr deletion-TGCT association using Firth's bias-reduced logistic regression across a total of 198,306 men of European-like ancestry (2231 with and 196,075 without TGCT). Results: Upon random-effects meta-analysis of estimated effect sizes in the two datasets, we found no significant association between gr/gr deletion status and TGCT risk (combined odds ratio=1.24, 95% CI=0.74-2.07, p=0.42), nor upon stratification of seminoma and non-seminoma/mixed histological subtypes. Conclusion: Our analysis suggests gr/gr deletion status alone is likely not predictive of TGCT risk in population-scale analyses of European-like individuals; however, the importance of other proposed determinants of gr/gr deletion impact, including Y-haplogroups and semen phenotype, remains unexplored at scale.
Source: medRxiv
Authors: Subin Choi, Maria Santa Rocca, Cinzia Vinanzi, John Pluta, Zeid Kuzbari, Chey Loveday, Sophie Allen, Beth Torr, Benita Weathers, Lynn Anson-Cartwright, Darren R. Feldman, Jourik A. Gietema, Anna Gonzalez-Neira, Robert J. Hamilton, Csilla Krausz, Giovenale Moirano, Kevin T. Nead, Jérémie Nsengimana, Jenny N. Poynter, David J. Vaughn, Peter A. Kanetsky, Katherine L. Nathanson, Alberto Ferlin, Clare Turnbull, Charlie F. Rowlands
Institutions: Institute of Cancer Research, University of Padua, University of Pennsylvania, University of Toronto, Princess Margaret Cancer Centre, Memorial Sloan Kettering Cancer Center, University Medical Center Groningen, University of Groningen, Spanish National Cancer Research Centre, Centre for Biomedical Network Research on Rare Diseases, University of Florence, Piedmont Reference Center for Epidemiology and Cancer Prevention, University of Turin, The University of Texas MD Anderson Cancer Center, Newcastle University, University of Minnesota, Abramson Cancer Center, Moffitt Cancer Center, Royal Marsden NHS Foundation Trust
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G5174455661, G9000050107
OpenAlex ID: W7128034796