Combined analysis of keratinocyte cancers identifies novel genome-wide loci.

Scott Gordon,Stuart Macgregor,Puya Gharahkhani,Xikun Han,Catherine M Olsen,Rachel E Neale,David C Whiteman,Jiyuan An,Jue-Sheng Ong,Matthew H Law,Upekha E Liyanage

doi:10.1093/hmg/ddz121

Scott Gordon, Stuart Macgregor + Show 9 more

Open Access

https://doi.org/10.1093/hmg/ddz121

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Abstract

The keratinocyte cancers (KC), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers in fair-skinned people. KC treatment represents the second highest cancer healthcare expenditure in Australia. Increasing our understanding of the genetic architecture of KC may provide new avenues for prevention and treatment. We first conducted a series of genome-wide association studies (GWAS) of KC across three European ancestry datasets from Australia, Europe and USA, and used linkage disequilibrium (LD) Score regression (LDSC) to estimate their pairwise genetic correlations. We employed a multiple-trait approach to map genes across the combined set of KC GWAS (total N = 47 742 cases, 634 413 controls). We also performed meta-analyses of BCC and SCC separately to identify trait specific loci. We found substantial genetic correlations (generally 0.5–1) between BCC and SCC suggesting overlapping genetic risk variants. The multiple trait combined KC GWAS identified 63 independent genome-wide significant loci, 29 of which were novel. Individual separate meta-analyses of BCC and SCC identified an additional 13 novel loci not found in the combined KC analysis. Three new loci were implicated using gene-based tests. New loci included common variants in BRCA2 (distinct to known rare high penetrance cancer risk variants), and in CTLA4, a target of immunotherapy in melanoma. We found shared and trait specific genetic contributions to BCC and SCC. Considering both, we identified a total of 79 independent risk loci, 45 of which are novel.

Highlights

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers of the skin
Using LDSC we found moderate or high genetic correlations between SCC, basal cell carcinoma (BCC) and combined keratinocyte cancers (KC) phenotypes (Fig. 1, Supplementary Material, Table S1)
UK Biobank (UKBB) BCC genome-wide association studies (GWAS) versus the 23andMe SCC GWAS Rg = 0.79 (CI 0.54–1.03, P-value = 2.6 × 10−10), while the QSkin BCC GWAS versus the UKBB SCC GWAS was Rg = 0.56 (CI 0.11–1.00, P-value = 0.01). These correlations indicated that a multivariate analysis using multiple trait analysis of GWAS (MTAG) was likely to be more powerful for identifying loci than separate analyses of BCC or SCC

Summary

Introduction

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common cancers of the skin. Together, they are known as keratinocyte carcinomas (KC), so named because the cells of origin are the abundant, keratin-producing cells of the epidermis. BCC and SCC both arise in the epidermis but are histologically and clinically distinct from each other (Supplementary Material, Fig. S1) [1]. BCC and SCC tend to be slow growing skin cancers when compared with melanoma, which is the most aggressive form [2]. SCC has a lower prevalence than BCC, but accounts for the most KC-related deaths [2]. In the USA the average annual cost of skin cancer (melanoma and keratinocyte cancers) treatment was $8.1 billion, with ∼4.9 million patients treated for skin cancer from 2007 to 2011 [5]

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