title: Mechanisms and clinical applications of chromosomal instability in lymphoid malignancy.
abstract: Lymphocytes are unique among cells in that they undergo programmed DNA breaks and translocations, but that special property predisposes them to chromosomal instability (CIN), a cardinal feature of neoplastic lymphoid cells that manifests as whole chromosome- or translocation-based aneuploidy. In several lymphoid malignancies translocations may be the defining or diagnostic markers of the diseases. CIN is a cornerstone of the mutational architecture supporting lymphoid neoplasia, though it is perhaps one of the least understood components of malignant transformation in terms of its molecular mechanisms. CIN is associated with prognosis and response to treatment, making it a key area for impacting treatment outcomes and predicting prognoses. Here we will review the types and mechanisms of CIN found in Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma and the lymphoid leukaemias, with emphasis placed on pathogenic mutations affecting DNA recombination, replication and repair; telomere function; and mitotic regulation of spindle attachment, centrosome function, and chromosomal segregation. We will discuss the means by which chromosome-level genetic aberrations may give rise to multiple pathogenic mutations required for carcinogenesis and conclude with a discussion of the clinical applications of CIN and aneuploidy to diagnosis, prognosis and therapy.
authors.affiliation: Department of Medicine and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.|Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Maxwell M
authors.initials: MM
authors.lastname: Krem
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
authors.affiliation: Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Horwitz
authors.affiliation: Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Tidwell
mesh_terms: D043171:Chromosomal Instability; D053960:DNA Breaks; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D006801:Humans; D011995:Recombination, Genetic
chemical_list: D004273:DNA, Neoplasm
keywords: aneuploidy; chromosomal instability; leukaemia; lymphoma; translocations