GENESIS: a French national resource to study the missing heritability of breast cancer

Olga M. Sinilnikova, Marie-Gabrielle Dondon, Séverine Eon-Marchais, Francesca Damiola, Laure Barjhoux, Morgane Marcou, Carole Verny-Pierre, Valérie Sornin, Lucie Toulemonde, Juana Beauvallet, Dorothée Le Gal, Noura Mebirouk, Muriel Belotti, Olivier Caron, Marion Gauthier-Villars, Isabelle Coupier, Bruno Buecher, Alain Lortholary, Catherine Dugast, Paul Gesta, Jean-Pierre Fricker, Catherine Noguès, Laurence Faivre, Elisabeth Luporsi, Pascaline Berthet, Capucine Delnatte, Valérie Bonadona, Christine M. Maugard, Pascal Pujol, Christine Lasset, Michel Longy, Yves-Jean Bignon, Claude Adenis, Laurence Venat-Bouvet, Liliane Demange, Hélène Dreyfus, Marc Frenay, Laurence Gladieff, Isabelle Mortemousque, Séverine Audebert-Bellanger, Florent Soubrier, Sophie Giraud, Sophie Lejeune-Dumoulin, Annie Chevrier, Jean-Marc Limacher, Jean Chiesa, Anne Fajac, Anne Floquet, François Eisinger, Julie Tinat, Chrystelle Colas, Sandra Fert-Ferrer, Clotilde Penet, Thierry Frebourg, Marie-Agnès Collonge-Rame, Emmanuelle Barouk-Simonet, Valérie Layet, Dominique Leroux, Odile Cohen-Haguenauer, Fabienne Prieur, Emmanuelle Mouret-Fourme, François Cornélis, Philippe Jonveaux, Odile Bera, Eve Cavaciuti, Anne Tardivon, Fabienne Lesueur, Sylvie Mazoyer, Dominique Stoppa-Lyonnet, Nadine Andrieu

Less than 20 % of familial breast cancer patients who undergo genetic testing for BRCA1 and BRCA2 carry a pathogenic mutation in one of these two genes. The GENESIS (GENE SISter) study was designed to identify new breast cancer susceptibility genes in women attending cancer genetics clinics and with no BRCA1/2 mutation. The study involved the French national network of family cancer clinics. It was based on enrichment in genetic factors of the recruited population through case selection relying on familial criteria, but also on the consideration of environmental factors and endophenotypes like mammary density or tumor characteristics to assess potential genetic heterogeneity. One of the initial aims of GENESIS was to recruit affected sibpairs. Siblings were eligible when index cases and at least one affected sister were diagnosed with infiltrating mammary or ductal adenocarcinoma, with no BRCA1/2 mutation. In addition, unrelated controls and unaffected sisters were recruited. The enrolment of patients, their relatives and their controls, the collection of the clinical, epidemiological, familial and biological data were centralized by a coordinating center. Inclusion of participants started in February 2007 and ended in December 2013. A total of 1721 index cases, 826 affected sisters, 599 unaffected sisters and 1419 controls were included. 98 % of participants completed the epidemiological questionnaire, 97 % provided a blood sample, and 76 % were able to provide mammograms. Index cases were on average 59 years old at inclusion, were born in 1950, and were 49.7 years of age at breast cancer diagnosis. The mean age at diagnosis of affected sisters was slightly higher (51.4 years). The representativeness of the control group was verified. The size of the study, the availability of biological specimens and the clinical data collection together with the detailed and complete epidemiological questionnaire make this a unique national resource for investigation of the missing heritability of breast cancer, by taking into account environmental and life style factors and stratifying data on endophenotypes to decrease genetic heterogeneity.