Abstract 5243: Functional characterization of genetic loci in basal cell carcinoma

Abstract Background: Genome-wide association studies (GWAS) have identified over 30 loci associated with basal cell carcinoma (BCC) susceptibility. However, the causal variants and mechanisms at these loci remain unknown. We performed statistical fine mapping and functional enrichment to identify credible causal variants at 31 established BCC risk loci. Methods: We performed statistical fine mapping by applying the sum of single effects (SuSiE) method to a previously published GWAS from 12,945 BCC cases and 274,252 controls. To identify genomic annotations enriched for BCC-associated variants, we compared high Posterior Inclusion Probability (PIP) variants from SuSIE to low PIP variants: we performed multivariable logistic regression of high-PIP status on 17 variant annotations from the Functional Annotation of Variants Online Resources (FAVOR) database, including sequence-contextual and functional annotations. Results: We identified 6 variants with PIP>0.99: rs1126809 (TYR), rs1805007 (MC1R), rs78378222 (TP53), rs12203592 (IRF4), rs35407(SLC45A2 a.k.a. MATP), rs12916300 (HERC2). Five of these six variants are in pigmentation genes; the sixth is in the tumor suppressor TP53. At a seventh region, the 95% credible set contained two variants in or upstream of RALY, which has previously been shown to be associated with pigmentation traits and multiple non-skin cancers. Another four regions had fewer than 10 variants in the credible set; the median size of the credible set was 11 (range: 1-76). After adjusting for sequence context (including location relative to exons, introns, UTRs; GC content; local mutation density, and nucleotide diversity) variants in active chromatin regions (as determined from multi-tissue methylation marks), variants in transcription factor binding sites, and skin eQTLs were significantly more likely to be high-PIP variants. Conclusions: Our results identify candidate variants, genes, and mechanisms for further study in BCC carcinogenesis. Citation Format: Mingyue Li, Constance Turman, Peter Kraft, Jiali Han. Functional characterization of genetic loci in basal cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5243.