NEW YORK (GenomeWeb) – Two new studies published today in Nature Genetics have delivered a multitude of new markers linked to testicular cancer, as well as a better understanding of the genetic architecture of the disease.
Testicular cancer is the most common form of cancer among men aged 20 to 39, and its incidence has been rising, especially among males of Northern European ancestry, who are four and a half times more likely to get the disease than men of African descent. According to the American Cancer Society, about 8,850 cases are diagnosed in the US each year.
Based on previous research, scientists have estimated that heritability ranges from anywhere between a third and half of new testicular cancer cases. Yet linkage- and candidate gene-based approaches have failed to produce actionable loci.
Genome-wide association studies have been another story, though. Members of the international Testicular Cancer Consortium (TECAC) recently carried out a meta-analysis of five separate association studies, analyzing SNP microarray data from 3,558 cases and 113,970 controls, including X chromosome data. As detailed in their new paper published today, the consortium identified eight new susceptibility loci with genome-wide significance, as well as four new signals in previously identified regions.
"Our findings substantially increase the number of known [testicular germ cell tumor] susceptibility alleles, move the field closer to a comprehensive understanding of the underlying genetic architecture of TGCT, and provide further clues to the etiology of TGCT," wrote corresponding author Katherine Nathanson, a professor of medicine at the University of Pennsylvania's Perelman School of Medicine, one of TECAC's members.
According to the authors, several of the identified loci include "biologically plausible candidate genes" that are part of pathways relevant to male germ cell development and pluripotency, such as TFCP2L1 and ZFP42; DNA damage response, such as TIPIN; and metabolic mitochondrial function, such as ZWILCH.
Theidentified loci bring the total of independent susceptibility alleles for TGCT to date to 40 markers. Additionally, the authors looked at the prevalence of the new loci in 1000 Genomes Project data, noting ancestral differences in risk allele frequencies that parallel the incidence of the disease among different population groups.
In terms of heritability, the TECAC team found that the dozen markers identified in their meta-analysis accounted for 5.3 percent of the genetic risk to the brothers of testicular cancer patients, and 8 percent of the risk to their sons, increasing the respective estimates of heritability to 25 percent and 37 percent for risk to brothers and sons of those with the disease.
"In comparison with other cancer types, we have accounted for a high proportion of site-specific heritability with fewer loci," the authors wrote.
While TECAC's efforts netted them a dozen new markers, another project led by investigators at the Institute of Cancer Research in London, some of whom also participate in TECAC, were able to identify 19 new susceptibility loci for the disease using Illumina's Infinium OncoArray-500K BeadChip. None of the reported loci overlapped with those reported in the TECAC study.
As detailed in a paper published today describing that study, Clare Turnbull, a senior researcher at ICR, and colleagues also showed evidence for a network of chromatin interactions between TGCT risk variants and target genes. The findings revealed, according to the authors, the "widespread disruption of developmental transcriptional regulators in TGCT susceptibility," which they said is consistent with failed primordial germ cell differentiation as a primary step in oncogenesis.
"Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT," Turnbull and colleagues wrote.
The researchers carried out their GWAS on the OncoArray platform, running 3,206 TGCT cases and 7,422 controls on the array, all sourced from the British population. They followed this with a meta-analysis on two large datasets, adding roughly 2,300 more cases and more than 11,000 more controls to the analysis. Finally, they imputed more than 10 million SNPs using the 1000 Genomes Project as a reference. They replicated an initial cache of 37 SNPs in 1,801 more TGCT cases and 4,027 controls, all from the UK, identifying genome-wide significant associations at 19 new loci.
In addition, the authors used capture Hi-C to draft a chromatin interaction map for TGCT, demonstrating direct interactions between DNA containing the newly identified SNPs and target gene promoters. Subsequent integration of the data, together with ChIP-seq chromatin profiling and RNA-seq analysis, enabled the authors to obtain "preliminary but unbiased tissue-specific insight into the biological basis of TGCT susceptibility," leading them to propose a model of susceptibility based on transcriptional dysregulation contributing to the developmental arrest of primordial germ cells, among other causes.
Like the TECAC study, the ICR-led research team acknowledged its findings had explained more of the heritability for testicular cancer, noting that, when combined with previously reported markers, the cumulative 44 disease-associated loci account for 34 percent of father-to-son familial risk, and "have potential clinical utility for personalized risk profiling."