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| Item Type: | Article |
|---|---|
| Title: | Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer |
| Creators Name: | Hauke, J. and Horvath, J. and Groß, E. and Gehrig, A. and Honisch, E. and Hackmann, K. and Schmidt, G. and Arnold, N. and Faust, U. and Sutter, C. and Hentschel, J. and Wang-Gohrke, S. and Smogavec, M. and Weber, B.H.F. and Weber-Lassalle, N. and Weber-Lassalle, K. and Borde, J. and Ernst, C. and Altmüller, J. and Volk, A.E. and Thiele, H. and Hübbel, V. and Nürnberg, P. and Keupp, K. and Versmold, B. and Pohl, E. and Kubisch, C. and Grill, S. and Paul, V. and Herold, N. and Lichey, N. and Rhiem, K. and Ditsch, N. and Ruckert, C. and Wappenschmidt, B. and Auber, B. and Rump, A. and Niederacher, D. and Haaf, T. and Ramser, J. and Dworniczak, B. and Engel, C. and Meindl, A. and Schmutzler, R.K. and Hahnen, E. |
| Abstract: | The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67-4.94), CDH1 (OR: 17.04, 95%CI: 3.54-82), CHEK2 (OR: 2.93, 95%CI: 2.29-3.75), PALB2 (OR: 9.53, 95%CI: 6.25-14.51), and TP53 (OR: 7.30, 95%CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73-2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors. |
| Keywords: | Breast Cancer Predisposition, Hereditary Breast Cancer |
| Source: | Cancer Medicine |
| ISSN: | 2045-7634 |
| Publisher: | Wiley |
| Volume: | 7 |
| Number: | 4 |
| Page Range: | 1349-1358 |
| Date: | April 2018 |
| Official Publication: | https://doi.org/10.1002/cam4.1376 |
| PubMed: | View item in PubMed |
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