Abstract P3-08-01: TruRisk® based next-generation sequencing in <i>BRCA1/2</i>-negative breast and ovarian cancer families reveal high mutation prevalence in additional risk genes
Authors: K Keupp, L Richters, L Bülow, S Kröber, C Ernst, B Blümcke, B Versmold, A Waha, J Driesen, A Baasner, J Altmüller, H Thiele, P Nuernberg, B Wappenschmidt, G Neidhardt, K Rhiem, R Schmutzler, E Hahnen, J Hauke
Journal: Cancer Research (2017)

Abstract Background: 24% of familial breast cancer (BC) and/or ovarian cancer (OC) cases analyzed within the framework of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) are due to pathogenic BRCA1/2 mutations. However, the mutation prevalence of non-BRCA1/2 genes associated with familial BC and/or BC/OC is largely unknown. Methods: Here, we present the first NGS data generated using the GC-HBOC-designed TruRisk® gene panel. In this study a cohort of 2028 BRCA1/2 and CHEK2 c.1100delC negative index cases was analyzed which comprises consecutive patients from BC families and BC/OC families complying the inclusion criteria of the GC-HBOC. Sequencing was performed on MiSeq, NextSeq, or HiSeq devices (Illumina) using customized SureSelect XT enrichment (Agilent). Data analysis was carried out using the SeqPilot software (version 4.2.2), SophiaDDM (Version 3.5.0.12-p5.0.0) as well as an in house bioinformatics pipeline (Cologne Center for Genomics, varpipe_v2.X). The analysis of copy number variations (CNV) based on NGS-data is currently in process and not yet included in the present mutation prevalence. Results: By focusing on 22 BC/OC associated genes (ATM, BARD1, BRIP1, CDH1, CHEK2, FAM175A, FANCM, MLH1, MRE11A, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RINT1, STK11, TP53, XRCC2), we identified 71 different deleterious variants in 104 unrelated mutation carriers derived from 2028 BC and BC/OC families (8%). Interestingly, we identified a high prevalence of ATM mutations (n=29, 1.4%) in the familial cases. Additionally mutations in PALB2 (n=27), NBN (n=9), CHEK2 (n=14), BARD1 (n=9), BRIP1 (n=10), RAD51C (n=11) were frequently observed and we confirmed FANCM (n=17) as a novel BC predisposing gene. No mutations in MLH1, MRE11A, PTEN, RAD51D, STK11 and XRCC2 were identified in our collective. Conclusions: Due to the unexpectedly high mutation prevalence in familial cases, our study highlights the importance of these genes to be included in BC/OC routine diagnostics. In contrast we found low occurrence or absence of mutations for a subset of our gene selection which requires further investigation to optimize the gene panel for diagnostic purposes. Nevertheless this approach confirms the TruRisk® gene panel as a reliable tool for this comprehensive analysis. Citation Format: Keupp K, Richters L, Bülow L, Kröber S, Ernst C, Blümcke B, Versmold B, Waha A, Driesen J, Baasner A, Altmüller J, Thiele H, Nuernberg P, Wappenschmidt B, Neidhardt G, Rhiem K, Schmutzler R, Hahnen E, Hauke J. TruRisk® based next-generation sequencing in BRCA1/2-negative breast and ovarian cancer families reveal high mutation prevalence in additional risk genes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-08-01.