BRAF mutation testing of MSI CRCs in Lynch syndrome diagnostics: performance and efficiency according to patient`s age

Hendrik Bläker1, Saskia Haupt2, Monika Morak3,4, Elke Holinski-Feder3,4, Alexander Arnold5, David Horst5, Julia Sieber-Frank6, Florian Seidler6, Elizabeth Alwers7, Jenny Chang-Claude8, Hermann Brenner7,9,10, Wilfried Roth11, Christoph Engel12, Markus Löffler12, Gabriela Möslein13, Hans-Konrad Schackert14, Jürgen Weitz14, Claudia Perne15,16, Stefan Aretz15,16, Robert Hüneburg16, Wolff Schmiegel17, Deepak Vangala17, Nils Rahner18, Verena Steinke-Lange3,4, Moritz von Winterfeld19, Vincent Heuveline2, Magnus von Knebel Doeberitz6, Aysel Ahadova6, Michael Hoffmeister7, Matthias Kloor6

1Institute of Pathology, University Hospital Leipzig, Leipzig, Germany. 2Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany. 3Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany. 4Medical Genetics Center, Munich, Germany. 5Institute of Pathology, Charite Berlin, Berlin, Germany. 6Department of Applied Tumor Biology, University Hospital Heidelberg and Cooperation Unit Applied Tumor Biology, German Cancer research Center (DKFZ), , Heidelberg, Germany. 7Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ) , Heidelberg, Germany. 8Division of Cancer Epidemiology, Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ) , Heidelberg, Germany. 9Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) , Heidelberg, Germany. 10German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 11Institute of Pathology, University Hospital Mainz, Mainz, Germany. 12Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 13Center for Hereditary Tumors, Helios University Hospital Wuppertal, University of Witten/Herdecke, Wuppertal, Germany. 14Department of Surgery, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany. 15Institute of Human Genetics, University of Bonn, Bonn, Germany. 16Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany. 17Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany. 18Medical Faculty, Institute of Human Genetics, Heinrich-Heine University, Düsseldorf, Germany. 19Department of General Pathology, Insititute of PAthology, University Hospital Heidelberg, Heidelberg, Germany

Abstract

Objective

Microsatellite instability (MSI) can occur sporadically or in the context of Lynch syndrome (LS). Due to the association of BRAF mutations with sporadic MSI colorectal cancer (CRC), international diagnostic guidelines recommend somatic BRAF mutation testing in MSI CRC patients to exclude LS. Sporadic MSI CRC occur at older age, whereas LS-associated CRC is related to young age of onset. We asked whether the efficacy of BRAF mutation testing in LS diagnostics may be age-dependent.

Methods                                                            

Using population-based cohorts from published studies and databases, systematic comparison of the prevalence of BRAF V600E mutations in LS-associated CRCs and MSI CRCs was performed. Costs and sensitivity of the BRAF mutation testing for exclusion of LS were analyzed.

Results

BRAF mutations were found in 15 among 969 (1.6%, 95% CI: 0.9-2.6%) MSI CRCs from LS mutation carriers from the literature and German HNPCC Consortium. 6/7 LS patients with BRAF-mutant CRC and reported age were <50 years. Among unselected MSI CRCs BRAF mutations were found in 44.8% (339/756), 92.3% (313/339) of which were detected in patients >60 years. In MSI CRC patients <50, BRAF mutations were detected only in 0.6% (2/339). Here, inclusion of BRAF mutation testing led to increased costs and to higher risk of missing LS patients (1.2%) compared to other age groups.

Conclusions

BRAF testing in patients <50 years is cost-inefficient and carries the highest risk of missing LS patients among different age groups. We suggest to perform germline analysis without prior BRAF testing in MSI CRC patients <50 years.

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