Welcome to the UPF Digital Repository

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

Show simple item record

dc.contributor.author Sepahi, Ilnaz
dc.contributor.author Ossowski, Stephan
dc.contributor.author Susak, Hana
dc.contributor.author Schroeder, Christopher
dc.date.accessioned 2019-10-23T08:06:56Z
dc.date.available 2019-10-23T08:06:56Z
dc.date.issued 2019
dc.identifier.citation Sepahi I, Faust U, Sturm M, Bosse K, Kehrer M, Heinrich T et al. Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women. BMC Cancer. 2019;19(1):787. DOI: 10.1186/s12885-019-5946-0
dc.identifier.issn 1471-2407
dc.identifier.uri http://hdl.handle.net/10230/42490
dc.description.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.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof BMC Cancer. 2019;19(1):787
dc.rights © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1186/s12885-019-5946-0
dc.subject.keyword Breast cancer
dc.subject.keyword Age at onset
dc.subject.keyword DNA-repair genes
dc.subject.keyword Next-generation-sequencing
dc.subject.keyword Panel sequencing
dc.subject.keyword Extreme phenotypes
dc.subject.keyword Hereditary breast and ovarian cancer
dc.subject.keyword BRCA1
dc.subject.keyword DNA-repair
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

This item appears in the following Collection(s)

Show simple item record

Search DSpace

Advanced Search


My Account


Compliant to Partaking