Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma.

Harvind S Chahal,Peter Kraft,Yuan Lin,Jean Y Tang,David A Hinds,Jiali Han,Wen-Qing Li,Hong-Ji Dai,Katherine J Ransohoff,Kavita Y Sarin,Abrar A Qureshi,Wenting Wu

doi:10.1038/ncomms12048

Abstract

Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7–11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 × 10−8) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma.

Highlights

Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7–11% of Caucasians in the United States
In stage 1, the most significant single-nucleotide polymorphism (SNP) at each locus associated with Squamous cell carcinoma (SCC) (Po10 À 5) was identified, yielding a list of 14 index SNPs (Fig. 1)
Stage 2 consisted of an independent genome-wide association study (GWAS) set of 825 adjudicated SCC cases and 11,518 controls of European ancestry from the Nurses’ Health Study and Health Professionals Follow-Up Study (HPFS) (Table 1) to confirm the index SNPs identified in stage 1

Summary

Introduction

Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7–11% of Caucasians in the United States. We report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in antiapoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma. QQ plots, forest plots and misclassification analysis are provided in Supplementary Figs 1–8

Methods

Results

Conclusion