Back to Search Start Over

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 :
Jan Hauke
Judit Horvath
Eva Groß
Andrea Gehrig
Ellen Honisch
Karl Hackmann
Gunnar Schmidt
Norbert Arnold
Ulrike Faust
Christian Sutter
Julia Hentschel
Shan Wang‐Gohrke
Mateja Smogavec
Bernhard H. F. Weber
Nana Weber‐Lassalle
Konstantin Weber‐Lassalle
Julika Borde
Corinna Ernst
Janine Altmüller
Alexander E. Volk
Holger Thiele
Verena Hübbel
Peter Nürnberg
Katharina Keupp
Beatrix Versmold
Esther Pohl
Christian Kubisch
Sabine Grill
Victoria Paul
Natalie Herold
Nadine Lichey
Kerstin Rhiem
Nina Ditsch
Christian Ruckert
Barbara Wappenschmidt
Bernd Auber
Andreas Rump
Dieter Niederacher
Thomas Haaf
Juliane Ramser
Bernd Dworniczak
Christoph Engel
Alfons Meindl
Rita K. Schmutzler
Eric Hahnen
Source :
Cancer Medicine, Vol 7, Iss 4, Pp 1349-1358 (2018)
Publication Year :
2018
Publisher :
Wiley, 2018.

Abstract

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

Language :
English
ISSN :
20457634
Volume :
7
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Cancer Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.f20fad57668492e8e5c076a0c75dc32
Document Type :
article
Full Text :
https://doi.org/10.1002/cam4.1376