Integration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing.
Using the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population.
Odds ratio conferred by PVs within BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, BRIP1, CHEK2, and MSH6 were estimated at 13.22 [10.01–17.22], 8.61 [6.78–10.82], 8.22 [4.91–13.05], 4.54 [2.55–7.48], 5.23 [1.46–13.17], 3.20 [2.14–4.53], 2.49 [1.42–3.97], 1.67 [1.18–2.27], and 2.50 [1.12–4.67], respectively. PVs within RAD51C, RAD51D, and BRIP1 were associated with ovarian cancer family history (OR = 11.36 [5.78–19.59], 12.44 [2.94–33.30] and 3.82 [1.66–7.11]). PALB2 PVs were associated with bilateral breast cancer (OR = 16.17 [5.48–34.10]) and BARD1 PVs with triple-negative breast cancer (OR = 11.27 [3.37–25.01]). Burden tests performed in both patients and the French Exome Project population confirmed the association of PVs of BRCA1, BRCA2, PALB2, and RAD51C with HBOC.
Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism.
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We thank the Cancéropole Nord-Ouest and the Institut National du Cancer (INCa) for funding. The FREX Consortium was supported by France Génomique National infrastructure, funded as part of the “Investissement d’Avenir” program managed by Agence Nationale pour la Recherche (contrat ANR-10-INBS-09). The French National League Against Cancer (LNC) and the French National Cancer Institute (INCa) provided grants to the Northwest Data Center (CTD-CNO). We also thank the high-throughput sequencing platform of Basse-Normandie SéSAME (Sequencing for Health, Agronomy, the Sea and the Environment) for technological support. We are grateful to Camille Charbonnier-Le Clezio for critical review of the manuscript.
Principal coinvestigators of the French Exome Project consortium
Emmanuelle Génin, Richard Redon, Jean-François Deleuze, Dominique Campion, Jean-Charles Lambert, and Jean-François Dartiques.
The authors declare no conflict of interest.
Member's of the French Exome Project Consortium are listed below Acknowledgement.
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