Large-scale Analysis Demonstrates Familial Testicular Cancer to have Polygenic Aetiology

Chey Loveday,Philip Law,Kevin Litchfield,Max Levy,Amy Holroyd,Peter Broderick,Zsofia Kote-Jarai,Alison M Dunning,Kenneth Muir,Julian Peto,Rosalind Eeles,Douglas F Easton,Darshna Dudakia,Nick Orr,Nora Pashayan,Alison Reid,Robert A Huddart,Richard S Houlston,Clare Turnbull

doi:10.1016/j.eururo.2018.05.036

Abstract

Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. Early linkage analysis and recent large-scale germline exome analysis in TGCT cases demonstrate absence of major high-penetrance TGCT susceptibility gene(s). Serial genome-wide association study analyses in sporadic TGCT have in total reported 49 independent risk loci. To date, it has not been demonstrated whether familial TGCT arises due to enrichment of the same common variants underpinning susceptibility to sporadic TGCT or is due to shared environmental/lifestyle factors or disparate rare genetic TGCT susceptibility factors. Here we present polygenic risk score analysis of 37 TGCT susceptibility single-nucleotide polymorphisms in 236 familial and 3931 sporadic TGCT cases, and 12 368 controls, which demonstrates clear enrichment for TGCT susceptibility alleles in familial compared to sporadic cases (p=0.0001), with the majority of familial cases (84–100%) being attributable to polygenic enrichment. These analyses reveal TGCT as the first rare malignancy of early adulthood in which familial clustering is driven by the aggregate effects of polygenic variation in the absence of a major high-penetrance susceptibility gene. Patient summaryTo date, it has been unclear whether familial clusters of testicular germ cell tumour (TGCT) arise due to genetics or shared environmental or lifestyle factors. We present large-scale genetic analyses comparing 236 familial TGCT cases, 3931 isolated TGCT cases, and 12 368 controls. We show that familial TGCT is caused, at least in part, by presence of a higher dose of the same common genetic variants that cause susceptibility to TGCT in general.

Highlights

Testicular germ cell tumour (TGCT) is the most common cancer in young men
To explore the role of polygenic susceptibility in the aetiology of familial TGCT, we studied 236 familial and 3931 sporadic TGCT cases, and 12 368 healthy population controls derived from two previously published genome-wide association studies (GWAS)
We extracted the genotypes of tag single-nucleotide polymorphisms (SNPs) for 37 risk loci (Supplementary Table 2) which have been robustly associated with TGCT and for which high-quality direct or imputed genotypes were available for both GWAS datasets

Summary

Introduction

Testicular germ cell tumour (TGCT) is the most common cancer in young men. Multiplex TGCT families have been well reported and analyses of population cancer registries have demonstrated a four- to eightfold risk to male relatives of TGCT patients. In the 2000s, systematic family studies, including in population-based registries, confirmed that first-degree relatives of patients with TGCT, have four- to eight-fold higher risk for TGCT. While the identification of such risk alleles proves the existence of inherited susceptibility, the genetic basis of familial TGCT is unclear.

Results

Conclusion