Prospectively Identified Incident Testicular Cancer Risk in a Familial Testicular Cancer Cohort

Abstract

Background Human testicular germ cell tumors (TGCT) have a strong genetic component and a high familial relative risk. However, linkage analyses have not identified a rare, highly-penetrant familial TGCT (FTGCT) susceptibility locus. Currently, multiple low-penetrance genes are hypothesized to underlie the familial multiple-case phenotype. The observation that two is the most common number of affected individuals per family presents an impediment to FTGCT gene discovery. Clinically, the prospective TGCT risk in the multiple-case family context is unknown. Methods We performed a prospective analysis of TGCT incidence in a cohort of multiple-affected-person families and sporadic-bilateral-case families; 1,260 men from 140 families (10,207 person-years of follow-up) met our inclusion criteria. Age-, gender-, and calendar time-specific standardized incidence ratios (SIR) for TGCT relative to the general population were calculated using SEER*Stat. Results Eight incident TGCTs occurred during prospective FTGCT cohort follow-up (versus 0.67 expected; SIR=11.9; 95% confidence interval [CI]=5.1–23.4; excess absolute risk=7.2/10,000). We demonstrate that the incidence rate of TGCT is greater among bloodline male relatives from multiple-case testicular cancer families than that expected in the general population, a pattern characteristic of adult-onset Mendelian cancer susceptibility disorders. Two of these incident TGCTs occurred in relatives of sporadic-bilateral cases (0.15 expected; SIR=13.4; 95%CI=1.6–48.6). Conclusions Our data are the first indicating that despite relatively low numbers of affected individuals per family, members of both multiple-affected-person FTGCT families and sporadic-bilateral TGCT families comprise high-risk groups for incident testicular cancer. Impact Men at high TGCT risk might benefit from tailored risk stratification and surveillance strategies.

The genomic landscape of testicular germ cell tumours: from susceptibility to treatment

“…However, coding variants conferring intermediate-to-high risk of TGCT might still exist, but they are likely to each only account for a small proportion of cases of multiple occurrence TGCT families. A number of additional strands of evidence also support an alternative, highly polygenic model of TGCT susceptibility, with disease risk determined by the co-inheritance of multiple risk variants, many of which are common 18 . Heritability estimates using genomic datasets suggest that over three-quarters of the inherited genetic risk is transmitted through common variation 12 .…”

Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer

“…Circles, females; squares, males. TGCT cases and family members of whom DNA samples were available for sequencing are numbered . Risk factors and age of onset (dx; in parentheses) are shown for each TGCT case.…”

“…Testicular Germ cell tumor (TGCT) is a frequent disease among adult males aged 15–40, with >52,000 new cases annually diagnosed worldwide . TGCT accounts for 98% of all testicular cancer, and is mainly subdivided into two histological subtypes, the seminoma and non‐seminoma tumors, each of them represent around 50% of the TGCT cases. The seminoma is a uniform tumor, while the non‐seminomas are more aggressive and heterogeneous .…”

“…The seminoma is a uniform tumor, while the non‐seminomas are more aggressive and heterogeneous . The remaining 2% of all Testicular Cancers are the Sex Cord Stromal testis tumors, which arise from the supporting tissues of the testis, include Leydig and Sertoli cells …”

“…Family history is one of the strongest known risk factors for TGCT, and relatively high compared to other cancer types which have familial relative risks between 1.5 and 2.5. Retrospective cohort studies have demonstrated that sons of men with TGCT have a four‐ to six‐fold increased risk of TGCT compared to the general population, while brothers of affected men have an 8‐ to 14‐fold increased risk . These risks increase to 37‐fold and 76‐fold in dizygotic and monozygotic twins, respectively .…”