Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

Kavita Y Sarin,Alice S Whittemore,Luba M Pardo,Guðmar Þorleifsson ,André G Uitterlinden ,Maryam M Asgari,Amanda E Toland,Adam J Rubin ,Jón Ólafsson ,Eric Jørgensen ,Yuan Lin,Andrey Ziyatdinov,Roxana Daneshjou,Wenting Wu,Paul A Khavari,Tamar Nijsten,Peter Kraft,Simon Stacey ,Kári Stefánsson ,Bárður Sigurgeirsson ,Kristin Thorisdottir,Jiali Han

doi:10.1038/s41467-020-14594-5

Abstract

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.

Highlights

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States
The novel single nucleotide polymorphisms (SNPs) occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility
The genome-wide association studies (GWAS) meta-analysis consisted of 19,149 SCC cases and 680,049 controls, including 2081 SCC cases and 296,015 controls from deCODE genetics in Iceland, 398 cases and 10,629 controls from Rotterdam, Netherlands, 6579 cases and 280,558 controls from 23andMe, 2287 cases and 30,966 controls from Nurses’ Health Study (NHS)/Health Professionals Follow-Up Study (HPFS), 103 cases and 1715 controls from Ohio State University Hospital, and 7701 cases and 60,166 controls from Kaiser Permanente

Summary

Introduction

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Three genome-wide association studies (GWAS) have identified 14 single-nucleotide polymorphisms (SNPs) associated with cutaneous SCC4–6 These studies include a GWAS in 7404 SCC cases and 292,106 controls in the 23andMe, the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) cohort[4], a GWAS in 7701 SCC cases and 60,186 controls from the Kaiser Permanente Northern California healthcare system[6], and a GWAS in 745 SCC cases and 12,805 controls from Rotterdam Study, NHS, and HPFS5. These 14 SNPs involve loci which affect skin pigmentation, and occur in loci associated with cell-mediated immunity, anti-apoptotic pathways and cellular proliferation. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility

Methods

Results

Conclusion