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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

Authors :
Hauke, Jan
Horvath, Judit
Gross, Eva
Gehrig, Andrea
Honisch, Ellen
Hackmann, Karl
Schmidt, Gunnar
Arnold, Norbert
Faust, Ulrike
Sutter, Christian
Hentschel, Julia
Wang-Gohrke, Shan
Smogavec, Mateja
Weber, Bernhard H. F.
Weber-Lassalle, Nana
Weber-Lassalle, Konstantin
Borde, Julika
Ernst, Corinna
Altmueller, Janine
Volk, Alexander E.
Thiele, Holger
Huebbel, Verena
Nuernberg, Peter
Keupp, Katharina
Versmold, Beatrix
Pohl, Esther
Kubisch, Christian
Grill, Sabine
Paul, Victoria
Herold, Natalie
Lichey, Nadine
Rhiem, Kerstin
Ditsch, Nina
Ruckert, Christian
Wappenschmidt, Barbara
Auber, Bernd
Rump, Andreas
Niederacher, Dieter
Haaf, Thomas
Ramser, Juliane
Dworniczak, Bernd
Engel, Christoph
Meindl, Alfons
Schmutzler, Rita K.
Hahnen, Eric
Hauke, Jan
Horvath, Judit
Gross, Eva
Gehrig, Andrea
Honisch, Ellen
Hackmann, Karl
Schmidt, Gunnar
Arnold, Norbert
Faust, Ulrike
Sutter, Christian
Hentschel, Julia
Wang-Gohrke, Shan
Smogavec, Mateja
Weber, Bernhard H. F.
Weber-Lassalle, Nana
Weber-Lassalle, Konstantin
Borde, Julika
Ernst, Corinna
Altmueller, Janine
Volk, Alexander E.
Thiele, Holger
Huebbel, Verena
Nuernberg, Peter
Keupp, Katharina
Versmold, Beatrix
Pohl, Esther
Kubisch, Christian
Grill, Sabine
Paul, Victoria
Herold, Natalie
Lichey, Nadine
Rhiem, Kerstin
Ditsch, Nina
Ruckert, Christian
Wappenschmidt, Barbara
Auber, Bernd
Rump, Andreas
Niederacher, Dieter
Haaf, Thomas
Ramser, Juliane
Dworniczak, Bernd
Engel, Christoph
Meindl, Alfons
Schmutzler, Rita K.
Hahnen, Eric
Publication Year :
2018

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.

Details

Database :
OAIster
Notes :
English
Publication Type :
Electronic Resource
Accession number :
edsoai.on1201319430
Document Type :
Electronic Resource