DNA Repair and Uveal Melanoma (D.R.U.M.)

Marc-Henri Stern

Marc-Henri Stern Chef d'équipe Tél :

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.

Publications clés

Année de publication : 2018

Manuel Rodrigues, Lenha Mobuchon, Alexandre Houy, Alice Fiévet, Sophie Gardrat, Raymond L Barnhill, Tatiana Popova, Vincent Servois, Aurore Rampanou, Aurore Mouton, Stéphane Dayot, Virginie Raynal, Michèle Galut, Marc Putterman, Sarah Tick, Nathalie Cassoux, Sergio Roman-Roman, François-Clément Bidard, Olivier Lantz, Pascale Mariani, Sophie Piperno-Neumann, Marc-Henri Stern (2018 May 16)

Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors.

Nature communications : 1866 : DOI : 10.1038/s41467-018-04322-5

Année de publication : 2016

Marie Schoumacher, Stéphanie Le Corre, Alexandre Houy, Eskeatnaf Mulugeta, Marc-Henri Stern, Sergio Roman-Roman, Raphaël Margueron (2016 Jun 9)

Uveal melanoma cells are resistant to EZH2 inhibition regardless of BAP1 status.

Nature medicine : 577-8 : DOI : 10.1038/nm.4098

Année de publication : 2014

Ronald Lebofsky, Charles Decraene, Virginie Bernard, Maud Kamal, Anthony Blin, Quentin Leroy, Thomas Rio Frio, Gaëlle Pierron, Céline Callens, Ivan Bieche, Adrien Saliou, Jordan Madic, Etienne Rouleau, François-Clément Bidard, Olivier Lantz, Marc-Henri Stern, Christophe Le Tourneau, Jean-Yves Pierga (2014 Aug 14)

Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types.

Molecular oncology : 783-90 : DOI : 10.1016/j.molonc.2014.12.003