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

Abstract

Study question: What 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%, P = 2.3 × 10^-4).

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 methods: All 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; P = 2.3 × 10^-4) spanning over 24 hereditary cancer genes. The prevalence of findings was not significantly different between azoospermic and oligozoospermic cases. There was also no enrichment of findings in men with a history of cryptorchidism. By the time of the study, six men carrying hereditary cancer variants had been diagnosed with a tumor. Family members affected with cancer had been documented for 10 of 14 cases with available pedigree health data.Nearly half of the infertile men with LP/P findings (17 out of 36) carried variants in genes belonging to the Fanconi anemia (FA) pathway involved in the maintenance of genomic integrity in mitosis and meiosis, repair of DNA double-stranded breaks, and interstrand crosslinks. Overall, FA-pathway genes BRCA2 (monoallelic) and FANCM (biallelic) were the most frequently affected loci (five subjects per gene).LP/P findings in pleiotropic genes linked to human development and hereditary cancer (TSC1, PHOX2B, WT1, SPRED1, NF1, LZTR1, HOXB13) were identified in several patients with syndromic phenotypes. Four cryptorchid infertile men were carriers of MLH1, MSH2, and MSH6 variants implicated in Lynch syndrome. Future studies will reveal whether this observation is a by chance or replicable finding.Most hereditary cancer genes with LP/P variants show high expression in one or more testicular cell types, and mouse models for 15 of 24 affected genes have been reported to exhibit male sub- or infertility. These data support shared genetic etiology of impaired spermatogenesis and cancer. A significantly increased fraction of cancer-linked variants in infertile compared to fertile men could also explain the reported high prevalence of cancer as a comorbidity in male infertility.

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 de novo occurrence.

Wider implications of the findings: Infertility 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.