Journal Article

DNA mismatch repair pathway defects in the pathogenesis and evolution of myeloma

Mark R. Velangi, Elizabeth C. Matheson, Gareth J. Morgan, Graham H. Jackson, Penelope R. Taylor, Andrew G. Hall and Julie A.E. Irving

in Carcinogenesis

Volume 25, issue 10, pages 1795-1803
Published in print October 2004 | ISSN: 0143-3334
Published online October 2004 | e-ISSN: 1460-2180 | DOI:
DNA mismatch repair pathway defects in the pathogenesis and evolution of myeloma

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Genetic instability is a prominent feature in multiple myeloma and progression of this disease from monoclonal gammopathy of uncertain significance (MGUS) and smouldering myeloma (SMM) is associated with increasing molecular and chromosomal abnormalities. The DNA mismatch repair (MMR) pathway is a post-replicational DNA repair system that maintains genetic stability by repairing mismatched bases and insertion/deletion loops mistakenly incorporated during DNA replication. Deficiencies in proteins pivotal to this pathway result in a higher mutation rate, particularly at regions of microsatellite DNA. We have investigated the proficiency of the MMR pathway in clinical samples and myeloma cell lines. Microsatellite analysis showed instability at one or more of nine loci examined in 15 from 92 patients: 7.7% of MGUS/SMM, 20.7% of MM/plasma cell leukaemia (PCL) and 12.5% of relapsed MM/PCL. An in vitro heteroduplex G/T repair assay found reduced repair in two cell lines, JIM1 and JIM3, and in two of four PCL cases and was associated with aberrant expression of at least one mismatch repair protein. Thus we show that MMR defects are found in plasma cell dyscrasias and the increased frequency during more active stages of the disease suggests a contributory role in disease progression.

Keywords: LOH, loss of heterozygosity; MGUS, monoclonal gammopathy of uncertain significance; MM, multiple myeloma; MMR, DNA mismatch repair; MSI, microsatellite instability; PCL, plasma cell leukaemia

Journal Article.  6440 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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