Universität zu Köln

Sepahi, Ilnaz, Faust, Ulrike, Sturm, Marc ORCID: 0000-0002-6552-8362, Bosse, Kristin, Kehrer, Martin, Heinrich, Tilman, Grundman-Hauser, Kathrin, Bauer, Peter, Ossowski, Stephan, Susak, Hana ORCID: 0000-0002-7965-7675, Varon, Raymonda, Schroeck, Evelin, Niederacher, Dieter, Auber, Bernd, Sutter, Christian, Arnold, Norbert ORCID: 0000-0003-4523-8808, Hahnen, Eric, Dworniczak, Bernd, Wang-Gorke, Shan, Gehrig, Andrea, Weber, Bernhard H. F., Engel, Christoph ORCID: 0000-0002-7247-282X, Lemke, Johannes R., Hartkopf, Andreas, Riess, Olaf and Schroeder, Christopher (2019). Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women. BMC Cancer, 19 (1). LONDON: BMC. ISSN 1471-2407

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sepahi, Ilnaz UNSPECIFIED UNSPECIFIED UNSPECIFIED Faust, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Sturm, Marc UNSPECIFIED orcid.org/0000-0002-6552-8362 UNSPECIFIED Bosse, Kristin UNSPECIFIED UNSPECIFIED UNSPECIFIED Kehrer, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinrich, Tilman UNSPECIFIED UNSPECIFIED UNSPECIFIED Grundman-Hauser, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Bauer, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Ossowski, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Susak, Hana UNSPECIFIED orcid.org/0000-0002-7965-7675 UNSPECIFIED Varon, Raymonda UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeck, Evelin UNSPECIFIED UNSPECIFIED UNSPECIFIED Niederacher, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Auber, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Sutter, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Arnold, Norbert UNSPECIFIED orcid.org/0000-0003-4523-8808 UNSPECIFIED Hahnen, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED Dworniczak, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang-Gorke, Shan UNSPECIFIED UNSPECIFIED UNSPECIFIED Gehrig, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Bernhard H. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Engel, Christoph UNSPECIFIED orcid.org/0000-0002-7247-282X UNSPECIFIED Lemke, Johannes R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartkopf, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Riess, Olaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Christopher UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-144609
DOI:	10.1186/s12885-019-5946-0
Journal or Publication Title:	BMC Cancer
Volume:	19
Number:	1
Date:	2019
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1471-2407
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BRCA1 MUTATION CARRIERS; HEREDITARY BREAST; OVARIAN-CANCER; SUSCEPTIBILITY GENE; GERMLINE MUTATIONS; FAMILY-HISTORY; MRE11; ASSOCIATION; MODIFIERS; AGE Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14460