Predispositions and Origins of Waldenstrom Macroglobulinemia: Implications from Genetic Analysis

  • Linda M. Pilarski
  • Jitra Kriangkum
  • Sophia Adamia
  • Helga M. Ogmundsdottir
  • Andrew R. Belch
Chapter

Abstract

Waldenstrom macroglobulinemia (WM) is a complex malignancy harboring both intra-clonal and inter-clonal diversity as defined phenotypically or by IgH gene rearrangements. Splicing defects play a key role in cancer and promote aberrant splicing that leads to malignant transformation. WM provides an example of a cancer where genetic changes in splicing sites contribute to aberrant splicing events leading to oncogenesis. Inherited polymorphisms in the hyaluronan synthase 1 gene (HAS1) appear to predispose individuals to WM, as well as to multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). Together with acquired mutations, they promote aberrant splicing events. In addition, recurrent HAS1 splicing mutations are shared by WM and MM patients. A close relationship between WM, MM, and CLL suggests that these systemic B cell malignancies may share at least some genetic predispositions and a common first progenitor. Subsequent oncogenic events may generate the cancer stem cells from which each malignancy arises in any given patient. We speculate that the expression of HAS1 splice variants leads to multiple transformation events from which the primary WM clone ultimately emerges. Such transformation events may occur on a continuous basis throughout the course of WM. The properties of aberrant HAS1 splice variants may explain the observed risk of WM conferred by intronic HAS1 polymorphisms. There is thus a high probability that HAS1 is clinically important as a predisposing gene imposing risk for WM as well as being a contributor to oncogenesis and to progression of WM.

Keywords

Waldenstrom macroglobulinemia Cancer stem cells Cancer progenitors Hyaluronan synthase 1 Cancer predispositions Systemic B cell malignancies Aberrant splicing Clonal dominance 

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Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Linda M. Pilarski
    • 1
  • Jitra Kriangkum
    • 1
  • Sophia Adamia
    • 2
  • Helga M. Ogmundsdottir
    • 3
  • Andrew R. Belch
    • 1
  1. 1.University of Alberta and Cross Cancer InstituteEdmontonCanada
  2. 2.Medical OncologyDana-Farber Cancer Institute, Harvard Medical SchoolBostonUSA
  3. 3.University of IcelandReykjavikIceland

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