Abstract LB-287: Identification of patients at risk for tumor predisposition syndromes based on the evaluation of sporadic cancer exome sequencing data: experiences from the NCT/DKTK MASTER program
Authors: Schrock Evelin , Hutter Barbara , Fröhlich Martina , Zakrzewski Falk , Uhrig Sebastian , Rump Andreas , Hackmann Karl , Porrmann Joseph , Gieldon Laura , Richter Daniela , Stenzinger Albrecht , Kindler Thomas , Weichert Wilko , Jost Philipp J. , Brandts Christian , Schulze-Osthoff Klaus , Falkenhorst Johanna , Bauer Sebastian , Klauschen Frederick , Klinghammer Konrad , Folprecht Gunnar , Wermke Martin , Spiekermann Karsten , Brors Benedikt , Gröschel Stefan , Heining Christoph , Horak Peter , Glimm Hanno , Fröhling Stefan , Klink Barbara 
Published: July 2017

Abstract
The MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Program of the NCT (National Center for Tumor Diseases) Heidelberg and the DKTK (German Cancer Consortium) is situated at the interface of cancer genomics and clinical oncology to provide whole exome/genome and transcriptome sequencing to selected patients with unmet medical need, and to evaluate the utility of such an approach regarding molecular stratification and individualized, biology-guided treatment. The program has enabled implementation of a shared, DKTK-wide workflow for rapid-turnaround clinical sequencing, comprising all steps from sample processing to reporting of results by a dedicated molecular tumor board. In clinical cancer genome sequencing programs, bioinformatics pipelines normally exclude germline variants detected in matched normal tissues to select for somatic mutations. However, in younger cancer patients (less than 51 years of age) and/or patients with rare cancer entities, which are eligible for analysis within MASTER, we anticipated an enrichment of patients with a possible hereditary background. If germline variants would be excluded in such cases a priori, relevant pathogenic mutations responsible for cancer development might be missed. Importantly, such mutations could also be therapeutically relevant. This applies in particular to tumors with mutations in genes involved in DNA damage response signaling, e.g. BRCA1/2, PALB2, ATM, and others, which respond to treatment with PARP inhibitors and platinum-based chemotherapy. Furthermore, germline mutations in these genes are responsible for hereditary breast and ovarian cancer and more than 120 tumor predisposition syndromes (TPS) known to date. Therefore analysis of germline variants of all known hereditary cancer genes was included as part of the NCT/DKTK MASTER workflow since 2015. A board-certified clinical geneticists experienced in evaluating rare private germline variants performed data interpretation. Recommendations were provided to the clinical oncologists for referral of patients to a TPS center for genetic counseling, further diagnostics, surveillance, and tumor prevention measures. We here present results from 321 NCT/DKTK MASTER patients analyzed thus far. Previously unknown pathogenic germline variants in 22 different tumor susceptibility genes, such as BRCA1/2, PALB2, ATM, NF1, MEN1, RB1, APC, SDHB, CDH1, and others, were detected in 36 patients (11%) with various cancers. We thus demonstrate the importance of evaluating germline variants obtained by “omics”-based molecular diagnostic approaches under clinical conditions. Furthermore, our results not only had implications for further surveillance of patients and their families, but also contributed to clinically “actionable” treatment recommendations.
Citation Format: Evelin Schrock, Barbara Hutter, Martina Fröhlich, Falk Zakrzewski, Sebastian Uhrig, Andreas Rump, Karl Hackmann, Joseph Porrmann, Laura Gieldon, Daniela Richter, Albrecht Stenzinger, Thomas Kindler, Wilko Weichert, Philipp J. Jost, Christian Brandts, Klaus Schulze-Osthoff, Johanna Falkenhorst, Sebastian Bauer, Frederick Klauschen, Konrad Klinghammer, Gunnar Folprecht, Martin Wermke, Karsten Spiekermann, Benedikt Brors, Stefan Gröschel, Christoph Heining, Peter Horak, Hanno Glimm, Stefan Fröhling, Barbara Klink. Identification of patients at risk for tumor predisposition syndromes based on the evaluation of sporadic cancer exome sequencing data: experiences from the NCT/DKTK MASTER program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-287. doi:10.1158/1538-7445.AM2017-LB-287