부산대학교 도서관

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, ATMand CHEK2genes 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, PALB2and ATMwere grouped in the same statistical cluster defined by the HBOC group, whereas CHEK2was in a different cluster. We identified co-occurrences of PV in ATMand BRCAgenes and confirmed the Manchester Scoring System as a reliable PV predictor tool for BRCAgenes but not for ATMor PALB2. This study demonstrates that ATMPV, and to a lesser extent CHEK2PV, are associated with HBOC syndrome. The co-occurrence of ATMPV with BRCAPV suggests that such ATMvariants are not sufficient alone to induce cancer, supporting a multigenism hypothesis.