Genomic Stability in Syndromic Basal Cell Carcinoma

Abstract

Basal cell cancers (BCCs) are characterized by upregulation of Hedgehog pathway through loss of PTCH1 or activation of SMO, and SMO inhibitors, such as vismodegib, are effective therapies for advanced BCCs. Although most BCCs are sporadic, rare individuals with basal cell nevus syndrome (BCNS) harbor germline defects in PTCH1 and develop up to hundreds of tumors that are histopathologically indistinguishable from sporadic BCCs. Interestingly, BCNS-BCCs are more responsive to SMO inhibitors than sporadic BCCs, with minimal development of resistance. Given differences in clinical course and therapy response, we sought to characterize BCCs in the setting of BCNS. We found that BCNS individuals with low tumor burden demonstrated significantly fewer UV signature somatic mutations and lower overall somatic mutational load compared to BCNS individuals with high burden, supporting a role of UV exposure in driving BCC development in BCNS individuals. However, compared with sporadic BCCs, BCNS-BCCs have a significantly lower mutational load, lower proportion of UV mutagenesis, increased genomic stability, and harbor fewer functionally resistant SMO mutations at baseline, explaining why BCNS-BCCs lack intrinsic resistance to SMO inhibitors. BCNS-BCCs appear to have reduced mutator phenotype compared with sporadic BCCs, which may contribute to their relatively more indolent clinical course and responsiveness to therapy.

Loss of Primary Cilia Drives Switching from Hedgehog to Ras/MAPK Pathway in Resistant Basal Cell Carcinoma

“…The study on human paraffin samples was performed with approval from the Stanford University institutional review board, protocol 18325 (Stanford, CA), with a waiver of written, informed consent from participants for the paraffin blocks. Histological diagnoses of Gorlin syndrome patients and sporadic naive and resistant BCC samples used in this study were previously confirmed in Chiang et al, (2018) and Atwood et al (2015). Histological diagnoses of BCC and SCC samples used for Gli1 and p-MEK immunostainings were confirmed by an independent dermatopathologist.…”

Keratinocyte Carcinomas: Current Concepts and Future Research Priorities

“…Their clinical utility is, limited by their side-effect profile, which includes muscle spasms, alopecia, taste loss, weight loss, precluding their long-term use (121)(122)(123). Inhibition of DNA repair pathways, including PARP inhibition, is a promising future therapeutic direction for SHH pathway-resistant BCCs (124). Immune checkpoint blockade has successfully treated hypermutated cancers, including SCC, enabling heightened sensitivity to effector T cells.…”

The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview

“…Although BCCs from syndromic individuals are histopathologically indistinguishable from sporadic BCCs [17,23], the corresponding molecular phenotypes do not fully overlap. NBCCS-BCCs present lower mutation load and UV-induced mutagenesis compared with sporadic BCCs, suggesting that strict sun protection is effective in this genetically predisposed population [24]. Reduced mutational load could explain the relatively indolent clinical course NBCCS-BCCs and the responsiveness to target therapy.…”