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

TY - JOUR

T1 - 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

AU - Hauke, Jan

AU - Horvath, Judit

AU - Groß, Eva

AU - Gehrig, Andrea

AU - Honisch, Ellen

AU - Hackmann, Karl

AU - Schmidt, Gunnar

AU - Arnold, Norbert

AU - Faust, Ulrike

AU - Sutter, Christian

AU - Hentschel, Julia

AU - Wang-Gohrke, Shan

AU - Smogavec, Mateja

AU - Weber, Bernhard H F

AU - Weber-Lassalle, Nana

AU - Weber-Lassalle, Konstantin

AU - Borde, Julika

AU - Ernst, Corinna

AU - Altmüller, Janine

AU - Volk, Alexander E

AU - Thiele, Holger

AU - Hübbel, Verena

AU - Nürnberg, Peter

AU - Keupp, Katharina

AU - Versmold, Beatrix

AU - Pohl, Esther

AU - Kubisch, Christian

AU - Grill, Sabine

AU - Paul, Victoria

AU - Herold, Natalie

AU - Lichey, Nadine

AU - Rhiem, Kerstin

AU - Ditsch, Nina

AU - Ruckert, Christian

AU - Wappenschmidt, Barbara

AU - Auber, Bernd

AU - Rump, Andreas

AU - Niederacher, Dieter

AU - Haaf, Thomas

AU - Ramser, Juliane

AU - Dworniczak, Bernd

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Schmutzler, Rita K

AU - Hahnen, Eric

N1 - © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

PY - 2018/4

Y1 - 2018/4

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1002/cam4.1376

DO - 10.1002/cam4.1376

M3 - SCORING: Journal article

C2 - 29522266

VL - 7

SP - 1349

EP - 1358

JO - CANCER MED-US

JF - CANCER MED-US

SN - 2045-7634

IS - 4

ER -