Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women
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
Affiliations
Ilnaz Sepahi
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Ulrike Faust
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Marc Sturm
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Kristin Bosse
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Martin Kehrer
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Tilman Heinrich
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Kathrin Grundman-Hauser
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Peter Bauer
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Stephan Ossowski
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Hana Susak
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
Raymonda Varon
Institute of Medical and Human Genetics, Charité Universitätsmedizin Berlin
Evelin Schröck
Institute for Clinical Genetics
Dieter Niederacher
Department of Obstetrics and Gynaecology, Düsseldorf University Hospital
Bernd Auber
Department of Human Genetics, Hannover Medical School
Christian Sutter
Institute of Human Genetics, University Hospital Heidelberg
Norbert Arnold
Department of Gynaecology and Obstetrics and Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Christian-Albrechts-University of Kiel
Eric Hahnen
Centre for Hereditary Breast and Ovarian Cancer, University of Cologne and University Hospital Cologne
Bernd Dworniczak
Institute of Human Genetics, University Hospital Münster
Shan Wang-Gorke
Department of Gynaecology and Obstetrics, University Hospital Ulm
Andrea Gehrig
Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg
Bernhard H. F. Weber
Institute of Human Genetics, University of Regensburg
Christoph Engel
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig
Johannes R. Lemke
Institute of Human Genetics, University of Leipzig Hospitals and Clinics
Andreas Hartkopf
Department of Obstetrics and Gynecology, University of Tuebingen
Huu Phuc Nguyen
Department of Human Genetics, Ruhr-University Bochum
Olaf Riess
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Christopher Schroeder
Institute of Medical Genetics and Applied Genomics, University of Tübingen
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.
