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

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