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UK Study Uncovers Four New Testicular Germ Cell Tumor Risk Loci

NEW YORK (GenomeWeb) – A UK-led research team has tracked down four previously unidentified loci with ties to testicular cancer, adding to what is known about genetic risk of the disease.

As they reported in Nature Communications, the researchers, led by the Institute of Cancer Research, focused on testicular germ cell tumor, carrying out a multi-stage genome-wide association study that included more than 6,000 individuals with the disease and nearly 19,100 unaffected controls. Their results pointed to four risk sites not found in the past, falling on chromosomes 3, 11, and 16.

The team's follow-up work suggests that testing at the four new loci — together with the 21 testicular cancer risk loci identified in the past — could eventually help find men at highest risk of testicular germ cell tumor.

"Applying these 25 variants, we found that men in the top one percent for testicular cancer risk were at a more than tenfold elevated risk of developing the disease compared with the average — although that still adds up to only around a five percent (one in twenty) chance of developing testicular cancer," senior author Clare Turnbull, a genetics and epidemiology researcher at the Institute of Cancer Research in London, said in a statement.

Testicular germ cell tumors typically respond well to standard platinum-based chemotherapy, somewhat diminishing the urgency in finding targetable testicular cancer mutations.

But because the disease appears to be on the rise in some Western countries, Turnbull and colleagues reasoned that there might be a benefit to using GWAS to delve into disease biology and search for variants common to those most susceptible to the disease.

"[I]f we can identify more of the genetic variation underlying testicular cancer, this sort of testing might be used clinically to help identify those at most risk of testicular cancer before they develop the disease, such that we can offer measures to help stop them from developing testicular cancer," Turnbull said.

For the first stage of the study, the researchers used Illumina HumanCNV370 Duo bead or Infinium 1.2M arrays to directly assess more than 300,000 SNPs in 986 cases and 4,946 controls, along with millions of additional imputed SNPs.

They followed up on that discovery-stage analysis by comparing SNP profiles in another 1,064 individuals with testicular germ cell tumor and 10,082 unaffected individuals who had been assessed with a custom Illumina Infinium iCOGS array, as well as a meta-analysis of the discovery and follow-up cohorts.

By scrutinizing tens of thousands of SNPs that had been tested in both groups, the team narrowed in on suspicious SNPs at a dozen loci, 10 of which were successfully genotyped in 4,009 more cases and 4,066 controls in the replication analysis.

Combined with a meta-analysis of individuals from all three stages of the study, the researchers used these data to verify testicular cancer associations at four loci.

In particular, their results suggest that those with testicular germ cell tumor tend to have particular variants in and around the chromosome 3 gene TFDP2 and the GAB2 gene on chromosome 11, along with independent chromosome 16 sites near the GSPT1 and ZFPM1 genes.

The testicular cancer-associated SNP at one of the chromosome 16 sites appeared to influence GSPT1 expression, the researchers reported. Their other analyses uncovered conservation for variants at two of the new risk loci.

Based on the new and known testicular cancer risk SNPs, the team estimated that the risk of testicular cancer comes in at just over 5 percent for men who scored in the top 1 percent of the polygenetic risk.