The search result changed since you submitted your search request. Documents might be displayed in a different sort order.
  • search hit 2 of 2
Back to Result List

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

Please always quote using this URN: urn:nbn:de:bvb:20-opus-237676
  • 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 missenseBackground 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.show moreshow less

Download full text files

Export metadata

Additional Services

Share in Twitter Search Google Scholar Statistics
Metadaten
Author: 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, Nguyen Huu Phuc, Olaf Riess, Christopher Schroeder
URN:urn:nbn:de:bvb:20-opus-237676
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Humangenetik
Language:English
Parent Title (English):BMC Cancer
Year of Completion:2019
Volume:19
Article Number:787
Source:BMC Cancer (2019) 19:787. https://doi.org/10.1186/s12885-019-5946-0
DOI:https://doi.org/10.1186/s12885-019-5946-0
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:BRCA1; DNA-repair; DNA-repair genes; age at onset; breast cancer; extreme phenotypes; hereditary breast and ovarian cancer; next-generation-sequencing; panel sequencing
Release Date:2023/03/13
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International