Truncating variants in DNA-repair genes and their effect on AAO of hereditary breast cancer

I Sepahi; U Faust; M Sturm; K Bosse; M Kehrer; T Heinrich; K Grundman-Hauser; P Bauer; S Ossowski; H Susak; U Bick; E Schröck; D Niederacher; B Auber; C Sutter; N Arnold; E Hahnen; B Dworniczak; S Wang-Gorke; A Gehrig; BHF Weber; C Engel; J Lemke; H Huu Phuc Nguyen; O Riess; C Schroeder

doi:10.1055/s-0038-1651801

Senologie - Zeitschrift für Mammadiagnostik und -therapie, Table of Contents

Senologie - Zeitschrift für Mammadiagnostik und -therapie 2018; 15(02): e45-e46
DOI: 10.1055/s-0038-1651801

Abstracts

Georg Thieme Verlag KG Stuttgart · New York

Truncating variants in DNA-repair genes and their effect on AAO of hereditary breast cancer

Authors

I Sepahi

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland
U Faust

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland
M Sturm

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland
K Bosse

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland
M Kehrer

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland
T Heinrich

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland
K Grundman-Hauser

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland
P Bauer

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland

²CENTOGENE AG, Rostock, Deutschland
S Ossowski

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland

³Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spanien

⁴University Pompeu Fabra (UPF), Barcelona, Spanien
H Susak

³Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spanien

⁴University Pompeu Fabra (UPF), Barcelona, Spanien
U Bick

⁵Clinic of Radiology, Campus Virchow-Klinikum, Charité Universitätsmedizin Berlin, Berlin, Deutschland
E Schröck

⁶Institute for Clinical Genetics, Dresden, Deutschland
D Niederacher

⁷Department of Obstetrics and Gynaecology, Düsseldorf, Deutschland
B Auber

⁸Institute of Human Genetics, Hannover Medical School, Hannover, Deutschland
C Sutter

⁹Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Deutschland
N Arnold

¹⁰Department of Gynaecology and Obstetrics and Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Christian-Albrechts-University of Kiel, Kiel, Deutschland
E Hahnen

¹¹Centre for Hereditary Breast and Ovarian Cancer, University of Cologne and University Hospital Cologne, Cologne, Deutschland
B Dworniczak

¹²Institute of Human Genetics, Münster, Deutschland
S Wang-Gorke

¹³Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Deutschland
A Gehrig

¹⁴Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Deutschland
BHF Weber

¹⁵Institute of Human Genetics, University of Regensburg, Regensburg, Deutschland
C Engel

¹⁶Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Deutschland
J Lemke

¹⁷Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Deutschland
H Huu Phuc Nguyen

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland
O Riess

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland
C Schroeder

¹Institute of Medical Genetics and Applied Genomics, Tübingen, Deutschland

Abstract

Full Text

Inherited mutations in BRCA1 increase the risk of breast cancer up to 65% by age 70 in female carriers. There is a diversity in the lifetime risk of developing breast cancer among carriers of BRCA1 mutation. The cause of this variability is largely unknown but it is hypothesized that additional genetic factors contribute to the variable age at onset (AAO). Here we studied the role of mutations or rare variants in DNA repair genes in modifying the age of onset of hereditary breast cancer.

Next generation sequencing was used to screen 133 women positive for BRCA1 mutations and an AAO of breast cancer either below 35 (early AAO cohort) or above 60 years of age (Late AAO cohort) for mutations in 311 DNA-repair genes.

The patients in early AAO (73 women) manifested breast cancer at a mean age of 26.3 ± 2.1yrs while patients in the late AAO group (60 women) had developed breast cancer at a mean age of 68.8 ± 7.3yrs. 3703 variants were detected in all patients and 43 of those (1.1%) were presumed to be deleterious. Pathogenic variants were found in 36 genes other than BRCA1. 26 women in the early AAO group (35.6%; 95%-CI 24.7% to 47.7%) carried a germline DNA-repair mutation compared to 16 women of the late AAO cohort (26.7%; 95%-CI 16.1% to 39.7%). The incidence of germline mutations in DNA repair genes did not differ between both AAO cohorts (odds ratio: 1.5; 95%-CI 0.7 to 3.2; p-value = 0.35).