Abstract LB-088: Ptch1 heterozygosity predisposes mice to developing IR-induced BCCs

Abstract

Abstract Basal cells nevus syndrome (BCNS, Gorlin syndrome) patients carry heterozygous germline mutations in PATCHED1 (PTCH1) gene, which encodes a receptor of hedgehog (HH) ligands and represses HH signaling in the absence of ligands. Mutated PTCH1 leads to aberrant activation of the HH signaling pathway, which is the pivotal driver underlying BCC carcinogenesis in both sporadic and BCNS BCCs. BCNS (PTCH1+/-) individuals are very susceptible to developing more BCCs at an earlier age but the mechanism for this genetic predisposition to BCCs remains elusive. In this study, we assessed how heterozygosity of the murine Ptch1 gene contributes to IR-induced BCC carcinogenesis. Specifically, we treated Ptch1fl/+ K14CreER2 mice with tamoxifen either at age 4 weeks (group A) or at 9 weeks (group B) to delete one copy of Ptch1 in K14-expressing keratinocytes. We irradiated both groups of mice with IR at mouse age 8 weeks so that at the time of IR, keratinocytes in group A mice, like those in BCNS patients, were Ptch1+/-, and mice in group B remained Ptch1+/+ but subsequent to recovery from acute damage all mice had Ptch1+/- keratinocytes. We found that mice in both groups developed similar amounts of microscopic BCCs at age either 7- or 9-months. However, only mice of group A (3 out of 13 mice) developed visible BCCs; none of the mice of group B (n = 30) developed visible BCCs by age 18-months, the longest time point monitored based on our studies of Ptch1+/- mice. The difference is statistically significant (p = 0.03). Histologically, these visible BCCs closely resemble human BCCs. This finding indicates (i) that heterozygosity of the Ptch1 gene limited to keratinocytes (without gene deletion in stromal cells) is sufficient to produce susceptibility to IR-induced visible BCC development and (ii) surprisingly that heterozygosity of the Ptch1 gene during acute mutagenic damage dramatically increases eventual conversion of microscopic to visible BCCs, probably by affecting acute repair of this damage. To gain further insights into this possible mechanism, we are culturing keratinocytes from these mice and performing cell cycle and apoptosis analysis upon IR treatment in vitro. Citation Format: Grace Y. Wang, Eileen Libove, Danielle Tucker, Ervin Epstein. Ptch1 heterozygosity predisposes mice to developing IR-induced BCCs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-088. doi:10.1158/1538-7445.AM2015-LB-088