Genomics of Non-Melanoma Skin Cancer
The team is supported by ARC foundation grant: "Emerging Leaders in Oncology".
This group belongs to the UMR 981:"Molecular predictors and new targets in oncology".
Cancer is a genetic disorder caused by DNA mutations. Keratinocyte skin cancers are the most frequent cancer types. They are predominantly caused by UV-radiation, which generates extremely high number of mutations. The interest of the laboratory is to understand the genetic mechanisms of keratinocyte cancers using multiomics approaches aiming to unravel the full catalogue of driver mutations and activated cancer pathways. Moreover, by dissecting the spectrums of somatic mutation we decipher the mechanism of acquisition of somatic mutations by UV-light.
Non-Melanoma Skin Cancers (NMSC) including cutaneous squamous cell carcinoma (CEC) and basal cell carcinoma (BCC) are the most common malignancies in Caucasians, with continuing increase in incidence worldwide. UV irradiation generates specific types of DNA lesions (mainly CPD and 6-4PP) which are usually repaired in an error free manner by global genome or transcription coupled Nucleotide Excision Repair (GG-NER or TC-NER). While when unrepaired UV lesions remain in the S-phase of the cell cycle, they interfere with the replication fork and can be bypassed by error-prone translesion synthesis polymerases (TLS), predominantly by Pol eta (POLH). This process results in high mutation rate leading to increased risk of cancer.
Xeroderma Pigmentosum (XP) is an autosomal recessive genetic disorder caused by inactivation of one of seven proteins or NER (XP-A,B,C,D,E,F,G) or of TLS Pol Eta (XPV) and is associated with 10’000 fold increase of NMSC.
We take advantage of Whole Genome Sequencing (WGS) of tumors from XP patients from different subgroups as well as of CRISPR/Cas9 modified cell lines irradiated with UVB in order to characterize UV-light induced mutagenesis and dissect its mechanism in skin cancers both sporadic and in the context of XP.
Currently the annotation of the non-coding part of human genome is rather poor. We propose to use somatic mutation and hyper-mutable skin cancer BCC (>60mut/Mb) in order to reveal certain types of functional elements in the genomes of skin cells. For that in addition to WGS of BCC (and blood) we perform RNA sequencing and methylation profiling of the same tumor and of the sample of adjacent skin. Skin is considered here as a tissue of origin for BCC and is used to approximate the effects of germline variation on expression and methylation. Such three ways comparison allows to reveal the effect of somatic mutations in regulatory regions of genes on Allele Specific Expression (ASE) in BCC.