title: Rare SNPs in receptor tyrosine kinases are negative outcome predictors in multiple myeloma.
abstract: 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.
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken (CCC MF), University Hospital Würzburg, Würzburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Keppler
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken (CCC MF), University Hospital Würzburg, Würzburg, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Weiβbach
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Langer
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knop
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken (CCC MF), University Hospital Würzburg, Würzburg, Germany.
authors.forename: Jordan
authors.initials: J
authors.lastname: Pischimarov
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kull
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Stühmer
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinbrunn
authors.affiliation: Comprehensive Cancer Center Mainfranken (CCC MF), University Hospital Würzburg, Würzburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bargou
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken (CCC MF), University Hospital Würzburg, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken (CCC MF), University Hospital Würzburg, Würzburg, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Leich
mesh_terms: D018572:Disease-Free Survival; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008024:Ligands; D009101:Multiple Myeloma / Q000235:genetics* / Q000628:therapy; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D000072417:Protein Domains; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D008024:Ligands; D020794:Receptor Protein-Tyrosine Kinases
keywords: amplicon sequencing; multiple myeloma; rare SNP; receptor tyrosine kinases