116 Identification of germline pathogenic mutations in patients with high-frequency basal cell carcinomas

Abstract

Basal cell carcinoma (BCC) is the most common malignancy worldwide with more than 4 million new cases annually in the US. Though BCCs develop from UV radiation, host genetics also play a role, as demonstrated by patients with Basal Cell Nevus Syndrome (BCNS), who carry germline PTCH1 mutations. Genome-wide association studies have also identified common genetic polymorphisms associated with BCC. Interestingly, frequent BCC development has been associated with risk of solid tumor malignancy. This study investigates germline variants that contribute to development of high-frequency BCCs (hfBCCs) in patients without BCNS. We performed germline whole genome sequencing in 88 patients with hfBCCs, defined as ≥6 in a 10-year period (mean 14.9 BCCs, range 6-98). 27.7% of hfBCC patients reported an internal malignancy. On average 2.2 pathogenic or likely pathogenic mutations per patient (range 0-11) were identified by ClinVar or InterVar. Recurrent mutations were seen in DNA repair, tumor suppressor, immune regulation, and pigmentation genes. Highly penetrant mutations included an EPHB2 variant, associated with prostate and brain cancer, in 5.7% of our cohort (enriched by 10.7-fold in comparison to Exome Aggregation Consortium Non-Finnish European (ExAC NFE) population frequency). In addition, 3.4% of patients had mutations in PADI3 (2.2-fold increase compared to ExAC NFE), associated with uncombable hair syndrome. Notably, 80% of patients with EPHB2 variant and 67% of patients with PADI3 mutations had a history of internal malignancy. Additional gene mutations identified include TYR, PRKN, MITF, EYS, JAK2, MLH3, and CHEK2. Our findings identify germline pathogenic mutations, some present in several patients with internal or hematopoietic cancers. We are currently exploring the functional implications of these genes in cell line assays to elucidate how they play a role in cancer susceptibility and development.