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Two New Studies Uncover a Dozen New Testicular Cancer Risk Loci

NEW YORK (GenomeWeb News) – Two studies appearing in Nature Genetics this week have uncovered about a dozen new loci linked to testicular cancer risk.

The novel susceptibility loci are located near genes known to be involved in spermatogenesis, chromosomal segregation, and DNA damage response as well as germ cell specification and telomerase regulation — pathways that have possible biological connections to the development of testicular germ cell tumors.

"As we continue to cast a wider net, we identify additional genetic risk factors, which point to new mechanisms for disease," Katherine Nathanson from the University of Pennsylvania and a corresponding author on one study, which identified four new loci, said in a statement.

Other genes have previously been linked to testicular cancer, including KITLG and SPRY4, which were identified by Nathanson and colleagues back in 2009. However, they suspected that there may be many more susceptibility loci waiting to be uncovered.

In their study, Nathanson and her colleagues performed a meta-analysis that combined three genome-wide association studies of testicular cancer, totaling 931 cases and 1,975 controls. From this, they identified a number of SNPs for follow-up, though they excluded previously reported loci. The follow-up replication study of those 19 SNPs was conducted in a set of six other samples, including 3,211 cases and 7,591 controls.

Four loci — 4q22, 7p22, 16q22.3, and 17q22 — were significantly associated with testicular cancer, the researchers reported.

In a separate paper, also appearing online in Nature Genetics this week, Clare Turnbull from the Institute of Cancer Research in the UK and her colleagues reported on their finding of nine new loci for testicular cancer risk — 1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22, and 21q22.3 — through a genome-wide study of 986 cases and 4,946 controls and a follow-up study of 1,064 cases and 10,082 controls.

Together, the known loci and the susceptibility loci from these two new studies bring the total number of known testicular cancer risk loci to nearly 20.

These new loci also implicate a number of pathways in the development of testicular cancer.

For example, the marker at 4q22.2 that Nathanson and her colleagues identified is located within an intron of HPGDS, a gene that encodes hematopoietic prostaglandin D synthase. In mice, the researchers noted, HPGDS is expressed in the early embryonic male gonad and appears to regulate the localization of the Sox9 protein to the nucleus.

Similarly, the 7p22.3 locus they linked to disease includes the MAD1L1 gene. And MAD1, the researchers noted, is a spindle assembly checkpoint protein that works to prevent aneuploidy and ensure genomic stability.

This, the researchers said, indicates that testicular cancer may be a disorder of primordial germ cells, as many of the genes associated with the disease are linked to male germ cell development and differentiation. Further, as testicular cancers are marked by a chromosomal aberration, a gain of 12p, they underscored that their findings implicating a gene variation within a gene involved in chromosomal segregation.

"[Testicular germ cell tumors are] unique in that many of the loci are very good biological candidates due to their role in male germ cell development," Nathanson said. "Disruptions in male germ cell development lead to tumorigenesis, and presumably also to infertility."

In addition, the team led by Turnbull found that one loci they identified, 8q13.3, was near the PRDM14 gene, which is necessary for early germ cell specification, while another loci, 3p24.3 is near DAZL, which is needed for germ cell development regulation.

Further, the 5q31.1 loci they identified is linked to PITX1, which regulates TERT expression. TERT is a telomerase reverse transcriptase, making the 5q31.1 loci the third testicular cancer-related locus associated with telomerase regulation, the researchers noted.

"Integration of these genetic variants together with non-genetic [testicular germ cell tumors] risk factors into risk models may enable clinically useful risk profiling for TGCT in unaffected men, which in turn may provide a rational basis for applying strategies for the screening and targeted prevention of TGCT," Turnbull et al. added.

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