Team 1: Genetic Predisposition to cancer

Team leader : Pr. Claude Houdayer

Research Activities

The Genetic Predisposition to Cancer team is addressing three main challenges: i) reducing missing heritability, as currently only 10 to 30% of familial cancer aggregations are explained; ii) understanding genotype-phenotype correlations and identifying modifier factors, due to the significant variability in penetrance and expressivity observed within the same family and between cancer-predisposed families; and iii) biological and clinical interpretation of genetic variations, with implications for diagnosis, prognosis, prevention, and therapeutic choices. The team also explores the medico-economic aspect through participation in the European H2022-2025 study Preventable. Finally, the team is active in supporting patient associations in oncogenetics.

Three model pathologies and genes are studied through constitutional and tumor approaches: breast cancer predisposition (BRCA1, BRCA2, and other homologous recombination genes), colon cancer predisposition (MMR genes and other genes involved in digestive carcinogenesis with or without polyposis), and Li-Fraumeni syndrome (TP53 gene). The team is thus clinical-biological and multidisciplinary.

The team relies on:

• Extensive recruitment of perfectly phenotyped patients and associated biological collections (DNA, RNA extracted from blood, tissues, tumors, etc.) thanks to close ties with clinical genetics, Pathology, and the deployment of clinical research projects (DOCC collection for digestive cancer, STRATEGIC project for digestive and breast/ovarian cancer, for example).
• Curiosity and technological innovation in service of the scientific questions. The team is resolutely technophile in the development of i) wet lab analyses, particularly on RNA, including qualitative and quantitative analysis of splicing defects and their functional consequences (minigene tests, patient RNA analysis, RT-ddPCR, SEALigHTS, cell models), development of 3rd generation RNA sequencing (PromethION2-Oxford Nanopore Technologies and Revio-PacBio), study of circular RNAs and reverse splicing, ii) but also functional studies on patient cells, CRISPR/Cas9-edited cells, and homologous recombination tests (GIScar signature of homologous recombination deficiency). This wet lab activity is accompanied by the development and implementation of dedicated bioinformatics tools such as LORID, SOSTAR, MAGIC SpliceLauncher, SPiP, CircNet for RNA studies, and DIVA for the search for deep intronic variants.
• Local, national (National Association of Molecular Genetics Practitioners (ANPGM), Cancer and Genetics Group (GGC), etc.), and international collaborations (European Reference Network Genturis, ENIGMA, etc.).
• Databases: the team develops and manages the reference oncogenetics database FroG (French Oncogenetics Database) with the Institut Curie, participates in PredCAP (Observatory of Genetic Predisposition Syndromes to Cancer in Children and Adolescents), and the OFELy database, which gathers clinical data from 2,259 families with Lynch syndrome.

Flagship publications

Leman R, Muller E, Legros A, Goardon N, Chentli I, Atkinson A, et al. GIScar, an Academic-developed Genomic Instability Score Predicting Sensitivity to Maintenance Olaparib for Ovarian Cancer. Clin Cancer Res. 2023 ;29(21):4419-4429

Levacher C, Viennot M, Drouet A, Beaussire L, Coutant S, Théry JC, Baert-Desurmont S, Laé M, Ruminy P, Houdayer C. Disequilibrium between BRCA1 and BRCA2 Circular and Messenger RNAs Plays a Role in Breast Cancer. Cancers (Basel). 2023 ;15(7):2176

Meulemans L, Baert Desurmont S, Waill MC, Castelain G, Killian A, Hauchard J, Frebourg T, Coulet F, Martins A, Muleris M, Gaildrat P. Comprehensive RNA and protein functional assessments contribute to the clinical interpretation of MSH2 variants causing in-frame splicing alterations. Journal of Medical Genetics 2023 ;60(5):450-459

Raad S, Rolain M, Coutant S, Derambure C, Lanos R, Charbonnier F, Bou J, Bouvignies E, Lienard G, Vasseur S, Farrell M, Ingster O, Baert Desurmont S, Kasper E, Bougeard G, Frébourg T, Tournier I. Blood functional assay for rapid clinical interpretation of germline TP53 variants. J Med Genet 2021 ; 58(12):796-805

Meulemans L, Mesman RLS, Caputo SM, Krieger S, Guillaud-Bataille M, Caux-Moncoutier V, Léone M, Boutry-Kryza N, Sokolowska J, Révillion F, Delnatte C, Tubeuf H, Soukarieh O, Bonnet-Dorion F, Guibert V, Bronner M, Bourdon V, Lizard S, Vilquin P, Privat M, Drouet A, Grout C, Calléja FMGR, Golmard L, Vrieling H, Stoppa-Lyonnet D, Houdayer C, Frebourg T, Vreeswijk MPG, Martins A, Gaildrat P. Skipping Nonsense to Maintain Function: The Paradigm of BRCA2 Exon 12. Cancer Res 2020 ;80(7):1374-1386

Tubeuf H, Caputo SM, Sullivan T, Rondeaux J, Krieger S, Caux-Moncoutier V, Hauchard J, Castelain G, Fiévet A, Meulemans L, Révillion F, Léoné M, Boutry-Kryza N, Delnatte C, Guillaud-Bataille M, Cleveland L, Reid S, Southon E, Soukarieh O, Drouet A, Di Giacomo D, Vezain M, Bonnet-Dorion F, Bourdon V, Larbre H, Muller D, Pujol P, Vaz F, Audebert-Bellanger S, Colas C, Venat-Bouvet L, Solano AR, Stoppa-Lyonnet D, Houdayer C, Frebourg T, Gaildrat P, Sharan SK, Martins A. Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using BRCA2 Exon 3 as a Model System. Cancer Res 2020 ;80(17):3593-3605

Leman R, Harter V, Atkinson A, Davy G, Rousselin A, Muller E, et al. SpliceLauncher: a tool for detection, annotation and relative quantification of alternative junctions from RNAseq data. Bioinformatics. 2020 ;36(5):1634–6

Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, Gauthier-Villars M, Stoppa-Lyonnet D, Consolino E, Brugières L, Caron O, Benusiglio PR, Bressac-de Paillerets B, Bonadona V, Bonaïti-Pellié C, Tinat J, Baert-Desurmont S, Frébourg T. Revisiting the Li-Fraumeni syndrome from 415 TP53 mutation carriers. J Clin Oncol 2015 ;33(21):2345-52

Members

Contact

Claude Houdayer, Professeur des Universités – Praticien Hospitalier
UFR Santé
22, boulevard Gambetta
76183 ROUEN
France

claude.houdayer@chu-rouen.fr

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