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WGS of Basal Cell Carcinoma of skin reveals distinct mutational landscape and the role of HIPPO-YAP pathway in disease progression

Basal Cell Carcinoma (BCC) is the commonest type of skin cancer which has not been yet studied by whole genome sequencing (WGS). We have assembled the largest to date BCC cohort representing major histological subtypes for genetic analysis by WGS (89), WES (310) and RNAseq (360).
Mutational profile in BCC is due to UV-light exposure, however it differers from melanoma by high fraction of COSMIC signature SBS7b mutations. We explained it by high contribution to mutagenesis in BCC of GC-rich early replicating regions, which in BCC are characterized by more condensed and difficult to repair chromatin, than in melanoma. We report that loss of TP53 is the first event in BCC and precedes the loss of PTCH1. Moreover, we deduce from 17p copy neutral LOH regions that loss of TP53 results in a dramatic increase of mutation rates in BCC. In line with that BCC with TP53 mutations have 2.5-fold higher mutation burden than BCC with wt TP53. We discovered novel BCC driver genes outside the sonic Hedgehog pathway. 65% of BCC harbor mutations in HIPPO-YAP and Contact Inhibition of Proliferation pathways: (FAT1 (30%), NF2(9%), ARHGAP35 (18%), CREBBP (21%), PTPN14 (21%), LATS1 (9%)). We validated the role of these genes in BCC cell line by siRNA screening followed by migration and proliferation assays. Promoter mutations or amplifications of TERT were identified in 48% of BCC and resulted in overexpression of TERT. High-risk morpheaform BCCs were different from low-risk nodular BCCs by activation of HIPPO-YAP pathway and fibrotic types of tumor microenvironment.
This study provides new insights into the role of epigenetics in UV-induced mutational signatures, suggests that BCC might originate from preneoplastic skin lesions, and reports particular role of HIPPO-YAP pathway in BCC tumorigenesis and aggressiveness.

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