Testicular germ cell tumours (TGCTs) are the most common form of cancer in young adult men, with a peak incidence among those between 25 and 34 years of age.

by ecancer reporter Clare Sansom

This is one of the most easily treated of all cancers, with over 90% of all testicular cancers and approaching 100% of those diagnosed in the early stages completely cured; the main treatment is surgery, with adjuvant chemotherapy or radiotherapy used only if the tumour has spread.

Testicular cancer has a marked familial component, with brothers and sons of diagnosed testicular cancer patients known to be at greatly enhanced risk of the disease; it has been estimated that about 25% of the risk is due to genetic factors.

Two extensive, independent genome-wide association studies (GWAS) of testicular cancer have now identified a total of twelve new genetic susceptibility loci for testicular germ cell tumours.

A large, mainly US-based group of researchers led by Katherine Nathanson of the University of Pennsylvania, Philadelphia, USA, conducted a meta-analysis of three genome-wide association studies of testicular cancer [1].

These studies included six independent sample sets, together comprising a total of 3,211 TGCT patients and 7,591 unaffected controls.

The researchers combined data from 340 SNPs that these three studies had identified as being associated with increased incidence of TGCT, and selected forty of these from nine loci with combined P values below 1 x 10-4; twelve of these were localized to the same gene locus, the MAD1L1 locus on chromosome 7.

A total of seventeen SNPs, including the most significant from each of these nine loci, were selected for replication, and these loci were also genotyped in individuals from four further case-control studies of TGCT.

This combined analysis included 4,142 TGCT cases and 9,566 controls, and enabled the identification of four new loci that were significantly associated with the disease with P values of less than 5 x 10-8.

The most significantly correlated of these loci was at chromosome 4q22, and the most significant SNP marker at this locus was found within the gene that encodes hematopoietic prostaglandin D synthase; this protein is known to be expressed in the early embryonic male gonad, at least in mice.

Further SNPs were localized to the MAD1L1 locus at 7p22.3, which encodes the protein MAD1 (mitotic arrest deficient like 1), a cell cycle checkpoint protein that is involved in maintaining genomic stability.

The other two loci identified as including SNPs significantly associated with TGCT risk were the RFWD3 locus on chromosome 16q22.3, which encodes a protein that regulates the stability of p53, and a region on chromosome 17q22 that includes at least three genes encoding proteins with plausible links to testicular cancer.

The second study, by Clare Turnbull of the Institute of Cancer Research, Sutton, UK and co-workers, and the UK Testicular Cancer Collaboration (UKTCC), was a single, wide-ranging genome wide association study of a total of 307,291 SNPs in 986 TGCT cases and 4,946 controls [2].

The researchers selected the most significant 1,050 SNPs from this study and genotyped a further 1,094 UK-based TGCT cases and 10,082 controls.

A total of nine new loci that were associated with increased risk of TGCT with P values of less than 5 x 10-8 were identified from the combined studies.

The researchers estimated that these nine loci together account for approximately 4-6% of the total familial risk of the disease.

The complete list of TGCT risk loci identified by Turnball and colleagues is 1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22 and 21q22.3.

One of these regions, 17q22, was seen to overlap with one of the four regions identified in Nathanson’s study [1]; only one other, 1q24.1, has been highlighted in a further concurrent independent study of TGCT.

Several of these loci encode genes that can be plausibly linked to TGCT development.

Proteins encoded by genes located in two of these regions - DAZL at 3p24.3 and PRDM14 at 8q13.3 – are known to be involved in the development of male germ cells.

Furthermore, the locus 5q31.1 contains the gene PITX1 which encodes a transcription factor that regulates the expression of the telomerase reverse transcriptase, TERT; this is the third identified TGCT-associated locus to include a gene involved in telomerase regulation.

These two studies, therefore, identify a total of twelve new genetic loci that have significant associations with an increased risk of developing TGCT, and these all may be usefully included in models for profiling the risk of this common, tractable tumour.

References

[1] Chung, C.C., Kanetsky, P.A., Wang, Z. and 27 others (2013). Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nature Genetics, published online ahead of print 12 May 2013. doi:10.1038/ng.2634

[2] Ruark, E., Seal, S., McDonald, H., the UK Testicular Cancer Collaboration (UKTCC) and 17 others (2013). Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14.  Nature Genetics, published online ahead of print 12 May 2013. doi:10.1038/ng.2635