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Carcinogenesis Advance Access published online on May 13, 2004
Carcinogenesis, doi:10.1093/carcin/bgh187
© 2004 by Oxford University Press
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Received July 11, 2003
Revised April 6, 2004
Accepted May 9, 2004

CANCER BIOLOGY

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

Mark R. Velangi 1*, Elizabeth C. Matheson 1, Gareth J. Morgan 2, Graham H. Jackson 3, Penelope R. Taylor 3, Andrew G. Hall 1, Julie A. E. Irving 1

1 Northern Institute for Cancer Research, University of Newcastle Upon Tyne, UK
2 Department of Haematology, Leeds General Infirmary, Newcastle Upon Tyne, UK
3 Department of Haematology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

* To whom correspondence should be addressed. E-mail: ms.velangi{at}btinternet.com.


  Abstract

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 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 9 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 2 cell lines, JIM1 and JIM3 and in 2 of 4 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 disease suggests a contributory role in disease progression.


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