Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma
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Sarah Keppler1,2,*, Susann Weiβbach1,2,*, Christian Langer3, Stefan Knop4, Jordan Pischimarov1,2, Miriam Kull3, Thorsten Stühmer4, Torsten Steinbrunn4, Ralf Bargou2, Hermann Einsele4, Andreas Rosenwald1,2, Ellen Leich1,2
1Institute of Pathology, University of Würzburg, Würzburg, Germany
2Comprehensive Cancer Center Mainfranken (CCC MF), University Hospital Würzburg, Würzburg, Germany
3Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
4Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
*These authors have equally contributed to this work
Ellen Leich, email: [email protected]
Keywords: multiple myeloma, receptor tyrosine kinases, amplicon sequencing, rare SNP
Received: January 20, 2016 Accepted: May 04, 2016 Published: May 26, 2016
Multiple myeloma (MM) is a plasma cell disorder that is characterized by a great genetic heterogeneity. Recent next generation sequencing studies revealed an accumulation of tumor-associated mutations in receptor tyrosine kinases (RTKs) which may also contribute to the activation of survival pathways in MM. To investigate the clinical role of RTK-mutations in MM, we deep-sequenced the coding DNA-sequence of EGFR, EPHA2, ERBB3, IGF1R, NTRK1 and NTRK2 which were previously found to be mutated in MM, in 75 uniformly treated MM patients of the “Deutsche Studiengruppe Multiples Myelom”. Subsequently, we correlated the detected mutations with common cytogenetic alterations and clinical parameters. We identified 11 novel non-synonymous SNVs or rare patient-specific SNPs, not listed in the SNP databases 1000 genomes and dbSNP, in 10 primary MM cases. The mutations predominantly affected the tyrosine-kinase and ligand-binding domains and no correlation with cytogenetic parameters was found. Interestingly, however, patients with RTK-mutations, specifically those with rare patient-specific SNPs, showed a significantly lower overall, event-free and progression-free survival. This indicates that RTK SNVs and rare patient-specific RTK SNPs are of prognostic relevance and suggests that MM patients with RTK-mutations could potentially profit from treatment with RTK-inhibitors.
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