Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma

Abstract

Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.

Genetic variations in the Hippo signaling pathway and breast cancer risk in African American women in the AMBER Consortium

“…We and other have previously demonstrated that PTPN14 negatively regulated YAP oncogenic function through direct interaction with YAP (52) and activation of LATS1/2 proteins (53). Interestingly, PTPN14 loss-of-function and deleterious missense mutations were found in skin cancer (54). To our knowledge, there is no published study of germline variants in PTPN14 with cancer risk.…”

Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer

“…In addition to copy number-altered genes, the presence of cancer-relevant mutant genes, such as Ptch1 gene (in two of the three tumors), in the Aurora-A transgenic mouse mammary tumors implicate the cognate pathways, for example, Hedgehog pathway involving PTCH1, in Aurora-A gain-of-function-associated breast cancers. PTCH1 gene alterations have been reported in human breast cancer (30,54,55). Thus, although the findings from our BLG-Aurora-A transgenic mouse model of mammary adenocarcinoma reveal the identity of a set of genes contributing to Aurora-A-driven mammary tumorigenesis shared with humans, more in-depth functional genomic analyses are warranted to elucidate the significance of these genes in the Aurora-A overexpressing subset of human breast cancer.…”

Histologic Mimics of Basal Cell Carcinoma

“…19,21,22 DIFFERENTIAL DIAGNOSIS There are multiple benign and malignant dermatologic entities that may mimic BCC histologically, and misdiagnosis may lead to unnecessary excision or delayed workup of metastatic disease. Histologic mimics of BCC may include nonneoplastic processes (such as follicular induction over dermatofibromas), benign adnexal tumors (especially follicular tumors), or cutaneous carcinomas with basaloid or blue-cell features.…”