title: Mutational landscape reflects the biological continuum of plasma cell dyscrasias.
abstract: We subjected 90 patients covering a biological spectrum of plasma cell dyscrasias (monoclonal gammopathy of undetermined significance (MGUS), amyloid light-chain (AL) amyloidosis and multiple myeloma) to next-generation sequencing (NGS) gene panel analysis on unsorted bone marrow. A total of 64 different mutations in 8 genes were identified in this cohort. NRAS (28.1%), KRAS (21.3%), TP53 (19.5%), BRAF (19.1%) and CCND1 (8.9%) were the most commonly mutated genes in all patients. Patients with non-myeloma plasma cell dyscrasias showed a significantly lower mutational load than myeloma patients (0.91±0.30 vs 2.07±0.29 mutations per case, P=0.008). KRAS and NRAS exon 3 mutations were significantly associated with the myeloma cohort compared with non-myeloma plasma cell dyscrasias (odds ratio (OR) 9.87, 95% confidence interval (CI) 1.07-90.72, P=0.043 and OR 7.03, 95% CI 1.49-33.26, P=0.014). NRAS exon 3 and TP53 exon 6 mutations were significantly associated with del17p cytogenetics (OR 0.12, 95% CI 0.02-0.87, P=0.036 and OR 0.05, 95% CI 0.01-0.54, P=0.013). Our data show that the mutational landscape reflects the biological continuum of plasma cell dyscrasias from a low-complexity mutational pattern in MGUS and AL amyloidosis to a high-complexity pattern in multiple myeloma. Our targeted NGS approach allows resource-efficient, sensitive and scalable mutation analysis for prognostic, predictive or therapeutic purposes.
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Voigtlaender
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Janjetovic
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Thiele
authors.affiliation: Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Alawi
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: März
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Brandt
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Radloff
authors.affiliation: Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schön
authors.affiliation: Amyloidosis Center, Department of Internal Medicine, Division of Hematology/Oncology/Rheumatology, University of Heidelberg, Heidelberg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Hegenbart
authors.affiliation: Amyloidosis Center, Department of Internal Medicine, Division of Hematology/Oncology/Rheumatology, University of Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schönland
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Langer
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Binder
mesh_terms: D000368:Aged; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010265:Paraproteinemias / Q000235:genetics* / Q000473:pathology; D011379:Prognosis