Identification of Susceptibility Loci for Cutaneous Squamous Cell Carcinoma

Abstract

We report a genome-wide association study of cutaneous squamous cell carcinoma conducted among non-Hispanic white members of the Kaiser Permanente Northern California health care system. The study includes a genome-wide screen of 61,457 members (6,891 cases and 54,566 controls) genotyped on the Affymetrix Axiom European array and a replication phase involving an independent set of 6,410 additional members (810 cases and 5,600 controls). Combined analysis of screening and replication phases identified 10 loci containing single-nucleotide polymorphisms (SNPs) with P-values < 5 × 10(-8). Six loci contain genes in the pigmentation pathway; SNPs at these loci appear to modulate squamous cell carcinoma risk independently of the pigmentation phenotypes. Another locus contains HLA class II genes studied in relation to elevated squamous cell carcinoma risk following immunosuppression. SNPs at the remaining three loci include an intronic SNP in FOXP1 at locus 3p13, an intergenic SNP at 3q28 near TP63, and an intergenic SNP at 9p22 near BNC2. These findings provide insights into the genetic factors accounting for inherited squamous cell carcinoma susceptibility.

Figure 1

Manhattan plot showing −log₁₀ P-values of squared Cochran-Armitage trend statistics. The horizontal line represents the threshold P-value of 5×10^-8. Markers within 50 kb of SNPs with P-values < 5×10^-8 are indicated with black asterisks for those in pigment-related regions and in red triangles for those in other regions. The y-axis is truncated at P = 10^-30, although three SNPs at the 6p25 locus have P-values between 10^-30 and 10^-97, and 72 SNPs at the 16q24 locus have P-values between 10^-30 and 10^-44.

Figure 2

Manhattan plot enlargement showing 0.7 Mb region at the 16q24 locus. The upper panel shows the name and location of genes in the region, with an arrow indicating the transcribed strand of a gene and ticks indicating exons. The genes DEF8 (containing the top SNP rs4268748) and MC1R (associated with skin pigmentation and skin cancer) are shown in boxes. The lower panel shows the significance levels of the SNPs in this region, with labels for the three SNPs that are independently associated with SCC risk.