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Journal Article Ppublish 3 citations

PubMed: 35017683 DOI: 10.1038/s10038-022-01014-3

Increased incidence of pathogenic variants in ATM in the context of testing for breast and ovarian cancer predisposition.

J Hum Genet 67(6):339-345

Authors: P Macquere, S Orazio, F Bonnet, N Jones, V Bubien, J Chiron, D Lafon, E Barouk-Simonet, J Tinat, L Venat-Bouvet, P Gesta, M Longy, N Sevenet

Affiliations

  • Unité d'oncogénétique, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux Cedex, France.
  • INSERM U1218, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux Cedex, France.
  • Registre des Hémopathies Malignes de la Gironde, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux Cedex, France.
  • University of Bordeaux, Inserm, Bordeaux Population Health Research Centre, Epicene team, UMR 1219, 33000, Bordeaux, France.
  • Consultations d'oncogénétique, Centre Hospitalier de la Côte Basque, Bayonne, France.
  • Consultations d'oncogénétique, CHU de Bordeaux, 1, place Amélie Raba-Léon, 33076, Bordeaux Cedex, France.
  • Consultations d'oncogénétique, CHU de Limoges, Limoges, France.
  • Service d'oncogénétique régional Poitou-Charentes, CH Niort, Niort, France.
  • Unité d'oncogénétique, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux Cedex, France.
  • INSERM U1218, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux Cedex, France.
  • UFR de Pharmacie, Univ. Bordeaux, 146 rue Léo Saignat, 33076, Bordeaux Cedex, France.

Abstract

Pathogenic Variants (PV) in major cancer predisposition genes are only identified in approximately 10% of patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Next Generation Sequencing (NGS) leads to the characterization of incidental variants in genes other than those known to be associated with HBOC syndrome. The aim of this study was to determine if such incidental PV were specific to a phenotype. The detection rates of HBOC-associated and incidental PV in 1812 patients who underwent genetic testing were compared with rates in control groups FLOSSIES and ExAC. The rates of incidental PV in the PALB2, ATM and CHEK2 genes were significantly increased in the HBOC group compared to controls with, respective odds ratios of 15.2 (95% CI = 5.6-47.6), 9.6 (95% CI = 4.8-19.6) and 2.7 (95% CI = 1.3-5.5). Unsupervised Hierarchical Clustering on Principle Components characterized 3 clusters: by HBOC (P = 0.01); by ExAC and FLOSSIES (P = 0.01 and 0.02 respectively); and by HBOC, ExAC and FLOSSIES (P = 0.01, 0.04 and 0.04 respectively). Interestingly, PALB2 and ATM were grouped in the same statistical cluster defined by the HBOC group, whereas CHEK2 was in a different cluster. We identified co-occurrences of PV in ATM and BRCA genes and confirmed the Manchester Scoring System as a reliable PV predictor tool for BRCA genes but not for ATM or PALB2. This study demonstrates that ATM PV, and to a lesser extent CHEK2 PV, are associated with HBOC syndrome. The co-occurrence of ATM PV with BRCA PV suggests that such ATM variants are not sufficient alone to induce cancer, supporting a multigenism hypothesis.

MeSH

Incidence, Research Design, Genetic Testing, Ovarian Neoplasms, Genes, Hereditary Breast And Ovarian Cancer Syndrome, High-Throughput Nucleotide Sequencing

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