1. 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
- Author
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Dieter Niederacher, Mateja Smogavec, Konstantin Weber-Lassalle, Ellen Honisch, Judit Horvath, Victoria G. Paul, Christian Ruckert, Thomas Haaf, Norbert Arnold, N Herold, Katharina Keupp, Bernhard H. F. Weber, Julika Borde, Beatrix Versmold, Janine Altmüller, Alfons Meindl, Andreas Rump, Sabine Grill, Verena Hübbel, Christoph Engel, Shan Wang-Gohrke, Juliane Ramser, Holger Thiele, Christian Kubisch, Bernd Dworniczak, Alexander E Volk, Nana Weber-Lassalle, Jan Hauke, Kerstin Rhiem, Corinna Ernst, Gunnar Schmidt, Nadine Lichey, Peter Nürnberg, Christian Sutter, Barbara Wappenschmidt, Julia Hentschel, Nina Ditsch, Rita K. Schmutzler, Andrea Gehrig, Bernd Auber, Karl Hackmann, Eva Groß, Esther Pohl, Eric Hahnen, and Ulrike Faust
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,Genes, BRCA2 ,Genes, BRCA1 ,Estrogen receptor ,0302 clinical medicine ,Odds Ratio ,Prevalence ,Missense mutation ,10. No inequality ,skin and connective tissue diseases ,Exome ,Original Research ,Cancer Biology ,Aged, 80 and over ,medicine.diagnostic_test ,hereditary breast cancer ,Middle Aged ,3. Good health ,030220 oncology & carcinogenesis ,Hereditary Breast and Ovarian Cancer Syndrome ,Female ,Adult ,medicine.medical_specialty ,PALB2 ,03 medical and health sciences ,Young Adult ,Breast cancer ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Radiology, Nuclear Medicine and imaging ,Genetic Predisposition to Disease ,Genetic Testing ,ddc:610 ,CHEK2 ,Genetic Association Studies ,Genetic testing ,Aged ,business.industry ,Genetic Variation ,medicine.disease ,030104 developmental biology ,Breast cancer predisposition ,Case-Control Studies ,business ,Ovarian cancer - 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.
- Published
- 2018