Aberrations of DNA repair pathways play a major role in oncogenesis, since hereditary DNA repair defects lead to cancer predispositions. Our goal is to clarify the relationship between DNA repair defects in response to double-strand breaks and the emergence of specific malignancies. Breast and ovary cancer predispositions are of particular interest as they are often associated with BRCA1 or BRCA2 mutations, key actors of the homologous recombination pathway.
We aim to:
- characterize the genomic alterations in hereditary breast cancers to understand the mechanisms of malignant transformation;
- identify genetic signatures of interest for clinical management of the patients;
- identify new causes of cancer predisposition.
– DNA repair defects in hereditary breast cancers
We set up a global characterization of BRCA1 and BRCA2 mutated tumors, including genomic, epigenetic and gene expression analyses in order to understand the mechanisms of malignant transformation and deliver diagnostic markers. We identified tumor signatures indicative of the genetic conditions responsible for the cancer, potentially of clinical interest for the management of the patients, such as status of specific genes or chromosomes (i.e. TP53 and inactive chromosome X) or overall genomic profiles using novel bioinformatics approaches. In this regard, we showed that measure of genomic structural instability consistently identifies BRCA1/2 defects in breast cancer (Fig. 1). The underlying mechanism leading to such pattern and its potential stability are currently under investigation.
Many cancer-prone families remain without defined genetic cause. Using a “one family at a time” approach and whole genome analyses, we identified BAP1 germline mutation as a new kidney cancer predisposition gene (Fig. 2).
– Characterization of atypical genetic defects in DNA repair
In close relationship with the Genetic department of Institut Curie hospital, our team participates in diagnosis of patients addressed for suspicion of DNA repair defects. We aim to improve diagnosis of atypical cases and to identify new repair defects and thus new putative predispositions to cancers. For example, we identified frequent low expression of a mis-localized ATM product in AT patients with missense mutations.
– Genomics and genetics of uveal melanoma
The identification of BAP1 as a strong cancer susceptibility gene led to a new project aiming to unravel the genetic and genomic bases of uveal melanoma, a rare but dismal cancer for which Institut Curie is a recognized leader in clinical care.