Identifying Susceptibility Loci for Cutaneous Squamous Cell Carcinoma Using a Fast Sequence Kernel Association Test.

Manyan Huang,Ming Li,Chen Lyu,Xin Li,Jiali Han,Abrar A Qureshi

doi:10.3389/fgene.2021.657499

Abstract

Cutaneous squamous cell carcinoma (cSCC) accounts for about 20% of all skin cancers, the most common type of malignancy in the United States. Genome-wide association studies (GWAS) have successfully identified multiple genetic variants associated with the risk of cSCC. Most of these studies were single-locus-based, testing genetic variants one-at-a-time. In this article, we performed gene-based association tests to evaluate the joint effect of multiple variants, especially rare variants, on the risk of cSCC by using a fast sequence kernel association test (fastSKAT). The study included 1,710 cSCC cases and 24,304 cancer-free controls from the Nurses’ Health Study, the Nurses’ Health Study II and the Health Professionals Follow-up Study. We used UCSC Genome Browser to define gene units as candidate loci, and further evaluated the association between all variants within each gene unit and disease outcome. Four genes HP1BP3, DAG1, SEPT7P2, and SLFN12 were identified using Bonferroni adjusted significance level. Our study is complementary to the existing GWASs, and our findings may provide additional insights into the etiology of cSCC. Further studies are needed to validate these findings.

Highlights

Cutaneous squamous cell carcinoma is the second most common type of non-melanoma skin cancers, accounting for about 20% of all skin cancers and the majority of deaths attributable to non-melanoma skin cancers (Chitsazzadeh et al, 2016; Motaparthi et al, 2017; Parekh and Seykora, 2017; Que et al, 2018a)
We evaluated the association between genomic regions and Cutaneous squamous cell carcinoma (cSCC) using the fastSKAT, a region-based association test that is computationally efficient for large-scale genomic datasets (Lumley et al, 2018)
For a total of 18 SNPs identified by previous Genomewide association studies (GWAS), we used fastSKAT to test each variant for association with the disease outcome and compared the testing p-values with those reported in previous publications

Summary

Introduction

Cutaneous squamous cell carcinoma (cSCC) is the second most common type of non-melanoma skin cancers, accounting for about 20% of all skin cancers and the majority of deaths attributable to non-melanoma skin cancers (Chitsazzadeh et al, 2016; Motaparthi et al, 2017; Parekh and Seykora, 2017; Que et al, 2018a). The incidence of cSCC in the United States has been increasing over the last few decades, with over 1 million annual cases in recent years (Nguyen et al, 2014; Muzic et al, 2017; Que et al, 2018a,b). The increase is expected to continue because of the longer life expectancy, aging population and chronic ultraviolet exposure (Nguyen et al, 2014; Motaparthi et al, 2017; Waldman and Schmults, 2019). It is of crucial importance to understand the pathogenesis of cSCC and to reduce the public health impact of the disease

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