Disruption of DNA damage response pathways in tumorigenesis: investigating the role of ATM and BAP1 in hereditary cancers.

The use of massive parallel sequencing techniques for genetic testing of hereditary cancer syndromes provides the possibility of analyzing multiple genes at the same time with limited costs. However, novel genes are being found in melanoma-prone families, but in many cases a causal relation has not been yet established. Moreover, the same gene is often found associated with multiple tumors, suggesting that spectrum of non-melanoma cancers in melanoma tumor syndromes could be broader than that currently known. This thesis describes the effort to tackle these issues, with a particular focus on two genes involved in DNA damage repair: the Ataxia-Telangiectasia Mutated (ATM) and BRCA1-associated protein 1 (BAP1) genes. During the last year of my PhD I completed the first and carried out the second of the following two studies: “Germline ATM variants predispose to cutaneous melanoma: a joint analysis across the genomel and melanostrum consortia”, and “BAP1-tumor predisposition syndrome and susceptibility to breast cancer”.