316 EPHB2 germline mutation in patients with high frequency basal cell carcinomas and prostate carcinoma

Basal cell cancer (BCC) is the most common cancer worldwide. While commonly linked to UV exposure, the formation of BCC can also be influenced by host genetics as seen in Basal Cell Nevus Syndrome (BCNS). However, there is a subset of patients without BCNS who develop a high frequency of BCCs (hfBCC) and have increased risk of internal cancers. As our innate DNA repair system is critical for preventing mutations, and skin is mutated more than any other organ from UV exposure, multiple skin cancers can indicate host genetic defects leading to inherited cancer risk. We conducted whole genome sequencing of 93 hfBCC patients, defined as ≥6 in a 10-year period (average 15), and identified a variant of EPHB2, a receptor tyrosine kinase regulator of cell proliferation, invasion, and signaling. EPHB2 D679N, which resides in the kinase domain of the EphB2 protein essential for receptor signaling, was identified in 5.7% of our cohort and enriched by 5.4-fold compared to the population mutation frequency. 60% of patients with this variant had an internal malignancy, of which two-thirds had prostate cancer. We assessed the impact of the mutation on EphB2 expression, which did not alter levels of tyrosine phosphorylated wildtype (WT) when transfected across BCC and prostate cancer cell lines, though we observed an increase in pAkt in D679N EphB2 (MUT) expressing cells compared to EphB2WT in all cell lines, and upregulation of pErk1/2 in BCC cells with EphB2MUT. Our results suggest that the D679N EphB2 mutant could provide survival and growth advantage by activating Akt signaling. We are pursuing mechanistic assays to dissect the mechanism by which this may occur with ongoing and future experiments.