Identification of 22 susceptibility loci associated with testicular germ cell tumors.

Pluta, John; Pyle, Louise C.; Nead, Kevin T.; Wilf, Rona; Li, Mingyao; Mitra, Nandita; Weathers, Benita; D'Andrea, Kurt; Almstrup, Kristian; Anson-Cartwright, Lynn; Benitez, Javier; Brown, Christopher D.; Chanock, Stephen; Chen, Chu; Cortessis, Victoria K.; Ferlin, Alberto; Foresta, Carlo; Gamulin, Marija; Gietema, Jourik A.; Grasso, Chiara

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation. Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.

GERM cell tumors; TERATOCARCINOMA; GENOME-wide association studies; GERM cell differentiation; CHROMOSOME structure; GERM cells

Nature Communications, 2021, Vol 12, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-021-24334-y