New common variants affecting susceptibility to basal cell carcinoma

Abstract

In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 x 10(-9)). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 x 10(-9)), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 x 10(-10)). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.

Figure 1

Schematic view of the LD structure of the 9p21 CDKN2A/B region, locations of relevant genes and genome-wide association data for BCC and coronary artery disease (CAD). (a) Pairwise correlation structure of a 300-kb interval from 21.9 Mb to 22.2 Mb (NCBI Build 36) on 9p21. The upper plot (blue) shows the pairwise D′ values for SNPs with minor allele frequencies >5% from the HapMap v22 CEU dataset. The lower plot shows the corresponding r² values. (b) Estimated recombination rates (saRR) in cM/Mb from the HapMap Phase II data. (c) Location of RefSeq genes and the ANRIL transcript. (d) Locations of the SNPs giving the most significant signals for BCC, CAD and T2D. (e) Illumina chipderived genome-wide association data for BCC (red dots) and CAD (blue dots). Note that the overall most significant CAD SNP rs10757278 is not represented on the Illumina chip but is highly correlated with rs10116277 (D′ = 0.96, r² = 0.90 in HapMap CEU).