Variants at the 9p21 locus and melanoma risk

Abstract

Background: The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS).

Methods: In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region.

Results: All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3' UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14-2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A-allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54).

Conclusions: Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes.

Figure 1

Linkage disequilibrium map of chromosome 9p21 from 21697000 bp to 22124000 bp. The linkage disequilibrium map derived from HapMap (release #27) shows the SNPs associated with cutaneous nevi or melanoma risk or both in GWAS.

Figure 2

Linkage disequilibrium map of chromosome 9p21 from 21956221 bp to 22003411 bp. The map derived from HapMap (release #27) reports the genotyped tagging SNPs.

Figure 3

Linkage disequilibrium map of the genotyped polymorphisms on chromosome 9p21 in the Spanish population. *CDKN2A isoform 1 encodes p16^INK4A ;**CDKN2A isoform 4 (CDKN2A/ARF) encodes p14^ARF.

Figure 4

Linkage disequilibrium map of chromosome 9p21 from 21697000 bp to 22124000 bp. The map derived from HapMap (release #27) shows the SNPs associated in GWAS with several cancers including melanoma and other diseases. T2D Type II diabetes, MI myocardialinfarction, CVD cardiovascular disease, CAD coronary artery disease, BCC Basal cell carcinoma, IA Intracranial aneurism, ALL Acute lymphoblastic leukemia.