Significantly increased load of hereditary cancer-linked germline variants in infertile men.

study questionWhat is the load and profile of hereditary cancer-linked germline variants in infertile compared to fertile men? SUMMARY ANSWER: This study showed almost 5-fold enrichment of disease-causing findings in hereditary cancer genes in infertile compared to fertile men (6.9% vs 1.5%, WHAT IS KNOWN ALREADY: Epidemiological studies have revealed that men with low sperm count have a 2-fold higher risk of developing cancer during their lifetime. Our recent study observed a 4-fold increased prevalence of cancer in men with monogenic infertility compared to the general male population (8% vs 2%). Shared molecular etiologies of male infertility and cancer have been proposed. STUDY DESIGN SIZE DURATION: This retrospective study analyzed germline likely pathogenic and pathogenic (LP/P) variants in 157 hereditary cancer genes in 522 infertile and 323 fertile men recruited to the ESTonian ANDrology (ESTAND) cohort. PARTICIPANTS/MATERIALS SETTING

methodsAll study participants (n = 845) had been recruited and phenotyped at an Andrology Clinic. Identification of LP/P variants in the cancer gene panel was performed from an exome sequencing dataset generated for the study cohort. All variants passed an automated filtering process, final manual assessment of pathogenicity, and experimental confirmation using Sanger sequencing. Retrospective general health records were available for 36 out of 41 (88%) men with LP/P findings. MAIN RESULTS AND THE ROLE OF CHANCE: Infertile men presented a nearly 5-fold higher load of LP/P findings (36 of 522 cases, 6.9%) compared to fertile subjects (5 of 323, 1.5%; odds ratio (OR) = 4.7, 95% CI 1.81-15.5; LARGE SCALE DATA: All hereditary cancer-linked variants identified in this study have been submitted to the National Center for Biotechnology Information (NCBI) ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/). LIMITATIONS REASONS FOR CAUTION: All recruited participants were of white European ancestry and living in Estonia. Thus, the results might not apply to other ethnic groups. Due to the young age of study participants (median age 34.4 years), the true incidence of cancer during lifetime could not be assessed. As retrospective clinical data were not available for all men, it was not possible to evaluate all possible genotype-phenotype links. The absence of genetic data from family members precluded the assessment of the hereditary nature of the variants or their potential WIDER IMPLICATIONS OF THE

findingsInfertility affects about 7-10% of men worldwide. In this study, one in 15 men with spermatogenic failure carried germline LP/P variants in hereditary cancer genes. As exome sequencing is gradually entering the molecular diagnostics setup in andrology, analyzing hereditary cancer-linked variants in the workup of infertile men will offer additional clinical benefits. Male factor infertility is typically diagnosed in men in their 30s, often before the onset of cancer or its symptoms. Early knowledge of germline predisposition to cancer enables timely screening and multidisciplinary management options, potentially improving the prognosis. The study data provide support for the shared monogenic etiologies of hereditary cancer and spermatogenic failure. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Estonian Research Council grant PRG1021 (M.L. and M.P.). The authors declare no conflicts of interest.