Combined analysis of keratinocyte cancers identifies novel genome-wide loci

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.

Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy

“…Previous studies have shown that variants in this region are associated with non-melanoma skin cancer. 37 The SNPs identified in these analyses include rs679677 which is in high linkage disequilibrium with rs2476601 (r 2 =0.97 in the European population of 1000 Genomes 38 ). We further investigated the direction of effect of the autoimmune risk variant rs2476601 in a non-melanoma skin cancer cohort of 17 426 cases and 319 712 controls defined by cancer ICD10 code C44 in the UK Biobank.…”

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

“…The melanoma GWAS dataset was obtained from the 2015 melanoma GWAS meta-analyses 50 comprising 12,874 cases and 23,203 controls from populations of European ancestry. For keratinocyte cancers (KC), we performed separate fixed effect inverse-variance-weighted squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) meta-analysis of GWAS summary data available in Liyanage and colleagues 51 , derived from 23andMe, Inc., a personal genetics company, and the QSkin 38 cohort. The UKB samples were excluded to ensure non-overlapping samples in the two-sample MR framework (see below).…”

“…QSkin data were collected from participants of European ancestry currently residing in Queensland, Australia and consist of 1995 BCC cases, 821 SCC cases and 4797 controls 38 . Detailed information about genotyping and quality control of QSkin BCC and SCC GWASs and cleaning of the 23andMe data were provided previously 51 , and the cohort description is outlined in supplementary methods.…”

Polygenic Risk Scores Allow Risk Stratification for Keratinocyte Cancer in Organ-Transplant Recipients

“…Its conventional risk factors include skin and hair pigmentation traits, sun exposure, age, sex, and chronic immunosuppression (Didona et al, 2018;Garrett et al, 2017;Neale et al, 2007;Park et al, 2019). GWASs have identified several genetic variants or SNPs associated with BCC and SCC Liyanage et al, 2019;Pardo et al, 2017). Despite the individual magnitude of association for each SNP being small, they can be used in aggregate to characterize the genetic liability toward disease outcomes through a polygenic risk score (PRS).…”