title: Inherited and acquired variations in the hyaluronan synthase 1 (HAS1) gene may contribute to disease progression in multiple myeloma and Waldenstrom macroglobulinemia.
abstract: To characterize genetic contributions toward aberrant splicing of the hyaluronan synthase 1 (HAS1) gene in multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM), we sequenced 3616 bp in HAS1 exons and introns involved in aberrant splicing, from 17 patients. We identified a total of 197 HAS1 genetic variations (GVs), a range of 3 to 24 GVs/patient, including 87 somatic GVs acquired in splicing regions of HAS1. Nearly all newly identified inherited and somatic GVs in MM and/or WM were absent from B chronic lymphocytic leukemia, nonmalignant disease, and healthy donors. Somatic HAS1 GVs recurred in all hematopoietic cells tested, including normal CD34(+) hematopoietic progenitor cells and T cells, or as tumor-specific GVs restricted to malignant B and plasma cells. An in vitro splicing assay confirmed that HAS1 GVs direct aberrant HAS1 intronic splicing. Recurrent somatic GVs may be enriched by strong mutational selection leading to MM and/or WM.
authors.affiliation: Departments of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB.
authors.forename: Sophia
authors.initials: S
authors.lastname: Adamia
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Reichert
authors.forename: Hemalatha
authors.initials: H
authors.lastname: Kuppusamy
authors.forename: Jitra
authors.initials: J
authors.lastname: Kriangkum
authors.forename: Anirban
authors.initials: A
authors.lastname: Ghosh
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hodges
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Pilarski
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mant
authors.forename: Tony
authors.initials: T
authors.lastname: Reiman
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Belch
authors.forename: Linda M
authors.initials: LM
authors.lastname: Pilarski
mesh_terms: D001483:Base Sequence; D018450:Disease Progression; D005091:Exons; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics*; D006413:Hematopoietic System / Q000166:cytology / Q000473:pathology; D006801:Humans; D000076002:Hyaluronan Synthases; D007438:Introns; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D012326:RNA Splicing / Q000235:genetics; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics* / Q000473:pathology
chemical_list: D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases