title: Patterns of somatic mutations in VH genes reveal pathways of clonal transformation from MGUS to multiple myeloma.
abstract: Monoclonal gammopathy of undetermined significance (MGUS) can transform to multiple myeloma (MM). In myeloma, mutated V(H) genes with sequence homogeneity reveal a postfollicular origin. Previously, some MGUS cases showed mutated V(H) genes with intraclonal variation, indicating an earlier stage of arrest. We investigated progression from 2 of 2 MGUS to MM, in which V(H) genes confirmed clonal evolution. In one MGUS case, intraclonal heterogeneity was evident, and transformation to myeloma occurred rapidly with apparent homogeneity in the emergent clone. However, residual MGUS-derived sequences were detectable at this time. Heterogeneity in MGUS does not associate with benign disease, but it indicates an origin from a tumorigenic cell, most likely surface immunoglobulin(+), undergoing somatic mutation. The remaining case displayed intraclonal homogeneity at the MGUS stage, conceivably resulting from a self-cloning outgrowth from MGUS with heterogeneity. Transformation can occur at either MGUS stage, but it involves a single cell in which somatic mutation is then silent.
authors.affiliation: Molecular Immunology Group, Tenovus Laboratory, Cancer Sciences Division, Southampton University Hospitals, Southampton, United Kingdom.
authors.forename: Niklas
authors.initials: N
authors.lastname: Zojer
authors.forename: Heinz
authors.initials: H
authors.lastname: Ludwig
authors.forename: Michael
authors.initials: M
authors.lastname: Fiegl
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.forename: Surinder S
authors.initials: SS
authors.lastname: Sahota
mesh_terms: D001854:Bone Marrow Cells / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018450:Disease Progression; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology*; D009154:Mutation; D010265:Paraproteinemias / Q000235:genetics* / Q000276:immunology
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region