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BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Breast Cancer | Research article

Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women

Authors: Ilnaz Sepahi, Ulrike Faust, Marc Sturm, Kristin Bosse, Martin Kehrer, Tilman Heinrich, Kathrin Grundman-Hauser, Peter Bauer, Stephan Ossowski, Hana Susak, Raymonda Varon, Evelin Schröck, Dieter Niederacher, Bernd Auber, Christian Sutter, Norbert Arnold, Eric Hahnen, Bernd Dworniczak, Shan Wang-Gorke, Andrea Gehrig, Bernhard H. F. Weber, Christoph Engel, Johannes R. Lemke, Andreas Hartkopf, Huu Phuc Nguyen, Olaf Riess, Christopher Schroeder

Published in: BMC Cancer | Issue 1/2019

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Abstract

Background

Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon.

Methods

We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways.

Results

Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00–27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05.

Conclusions

To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results.
Appendix
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Metadata
Title
Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women
Authors
Ilnaz Sepahi
Ulrike Faust
Marc Sturm
Kristin Bosse
Martin Kehrer
Tilman Heinrich
Kathrin Grundman-Hauser
Peter Bauer
Stephan Ossowski
Hana Susak
Raymonda Varon
Evelin Schröck
Dieter Niederacher
Bernd Auber
Christian Sutter
Norbert Arnold
Eric Hahnen
Bernd Dworniczak
Shan Wang-Gorke
Andrea Gehrig
Bernhard H. F. Weber
Christoph Engel
Johannes R. Lemke
Andreas Hartkopf
Huu Phuc Nguyen
Olaf Riess
Christopher Schroeder
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-5946-0

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