The BER glycosylase NEIL1 is a risk gene for familial breast cancer. M. R. Dufault1, E. Hahnen*2,3, H. Hellebrand1, J. Hauke2,3, G. Neidhardt2,3, S. Engert1, S. Preissler-Adams5, N. Arnold6, T. M. Strom7, K. Rhiem2,3, B. Wappenschmidt2,3, N. Ditsch4, R. K. Schmutzler#2,3, A. Meindl#1 1) Department of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Technical University, Munich, Germany; 2) Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany; 3) Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; 4) Klinikum Grohadern, Ludwig-Maximilians-Universität, Munich, Germany; 5) Institut of Human Genetics at the University of Münster, Germany; 6) Department of Obstetrics and Gynaecology at the University of Kiel, Germany; 7) Institute of Human Genetics, Klinikum rechts der Isar, Technical University, Munich, Germany.

   * contributed equally as first author; # contributed equally as corresponding authors
    Introduction: Approximately 70% of familial breast cancer susceptibility remains unexplained. Over the past decade, several genes apart from BRCA1 & BRCA2 have been identified as breast cancer susceptibility genes including the genes RAD51C, BRIP1, PALB2, ATM, CHEK2. While these genes were identified using a candidate gene approach, more recently, XRCC2, FANCC & BLM have all been identified using an exome sequencing approach. A common characteristic of all of these genes is their involvement in the Homologous Recombination (HR) DNA repair pathway. Methods and Results: We performed exome sequencing of families with a strong history of breast cancer in at least two affected family members and identified a deleterious frameshift mutation in the NEIL1 gene (c.572insC; p.P192Afs*51). By screening familial cases & population matched controls we identified three distinct frameshift mutations in 10 out of 950 families compared with eight out of 3165 controls (OR = 4.16, 95%1 CI = 1.47 - 12.17, P = 0.0030). Furthermore, we found five putative pathogenic variants in 13 out of 950 families which were only present in eight out of 3165 controls (OR = 5.41, 95%1 CI = 2.07 - 15.11, P = 0.0002). Overall, we identified NEIL1 mutations in 23 out of 950 families (2.42 %) compared to sixteen out of 3165 controls (0.51 %). This 4.79 -fold increase in risk clearly points to NEIL1 being a novel moderately penetrant gene for familial breast cancer. Segregation analysis was performed for the truncating mutations and in most instances, the mutation tracked with the phenotype. Similarly, segregation could be shown for the missense mutation G326A. Discussion: NEIL1 is a Base Excision Repair (BER) protein that responds early to DNA damage caused by oxidative stress. In addition, it also responds quickly to interstrand crosslinks (ICL). Inactivating mutations in the NEIL1 gene have been linked to human gastric and colorectal cancer and promoter methylation in head and neck squamous cell carcinoma. Consistent with its role in colorectal cancer, two cases of colon cancer were present in pedigrees that harbored NEIL1 mutations. In other families, pancreatic cancer was present. Our data identified NEIL1 as the first gene of the BER pathway associated with a risk of familial breast cancer.

You may contact the first author (during and after the meeting) at