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Meta-Analysis Uncovers Five Additional Susceptibility Loci for Cutaneous Malignant Melanoma

NEW YORK (GenomeWeb) – Researchers have linked five novel susceptibility loci to cutaneous malignant melanoma, bringing the total number of susceptibility loci associated with the disease to 20.

An international team led by the University of Leeds' Mark Iles conducted a two-stage meta-analysis of CMM genome-wide association studies, examining nearly 16,000 cases and more than 26,400 controls. As the researchers reported in Nature Genetics today, they replicated all previously known 13 susceptibility loci, replicated two suspected susceptibility loci, and uncovered five novel ones, including ones involved in the metabolism of hormones and telomere maintenance.

"We have used the power of this large collection of CMM cases and controls to identify five new susceptibility loci, none of which are significantly associated with classical CMM risk factors and thus highlight new disease pathways," Ives and his colleagues wrote in their paper.

For the first stage of their study, the researchers pulled together 12,874 cases and 23,203 controls from all six published CMM GWAS and five unpublished ones, while in the second stage, they genotyped disease-linked SNPs in 3,116 CMM cases and 3,206 controls from a further three datasets. This, they noted, reflects a four-fold increase in sample size compared to previous studies of melanoma risk.

In the first stage, the researchers found that all 13 previously reported CMM susceptibility loci reached genome-wide significance, as did two other loci whose link to melanoma hadn't before been replicated. In addition, they noted a further three loci linked to CMM with genome-wide significance as well as SNPs in another 11 regions that didn't quite reach significance, but were associated with telomere genes, which are thought to play a role in melanoma.

Eighteen SNPs were carried through to the second stage of the study for genotyping in 3,116 CMM cases and 3,206 controls, the researchers said. A meta-analysis of the two stages of the study uncovered two new regions with genome-wide significance as well as confirmed the association of five of the SNPs with melanoma.

The association signals at 2p22.2, which reached genome-wide significance in the first stage and in the overall meta-analysis, encompass the 3'UTR region of RMDN2 and the whole CYP1B1 gene, the researchers reported. These SNPs are situated near potential enhancers active in both keratinocytes and melanocytes, they noted.

The CYP1B1 gene encodes a metabolizer of endogenous hormones and exogenous chemicals and is regulated by ARNT, which is itself located at a melanoma-associated locus, the researchers noted. This, they suggested, could be how CYP1B1 influences melanoma risk.

Mutations in the CYP1B1 gene have also been linked to other cancers, particularly hormonal ones like breast and ovarian cancer.

Another SNP of interest to the researchers — rs7776158 at 6p22.3 — was in a melanocyte enhancer that binds IRF4, and a SNP in IRF4 has been linked to nevus count, skin pigmentation, and tanning response, all related to melanoma risk.

Meanwhile, another signal at 10q24.33 was also strongly associated with telomere length, Ives and his colleagues reported. The signal there, they added, spans both the OBFC1 gene and the promoter of the SH3PXD2A gene. As OBFC1 is part of the telomere maintenance complex, the researchers said it was the more promising candidate. Three other loci, they said, are also in telomere-associated regions.

"This gives further evidence that the telomere pathway, with its effect on the growth and senescence of cells, may be important in understanding the development of melanoma," Ives and his colleagues said.

The 13 previously known loci, the researchers added, explain nearly 17 percent of the familial relative risk for CMM. By adding the seven loci they confirmed or newly uncovered in this study, they could explain 19.2 percent of the familial relative risk.

They noted that there are likely more loci remaining to be uncovered that contribute to disease risk.