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World J Gastroenterol. Oct 7, 2006; 12(37): 5932-5940
Published online Oct 7, 2006. doi: 10.3748/wjg.v12.i37.5932
Complementary analysis of microsatellite tumor profile and mismatch repair defects in colorectal carcinomas
Alfredo Blanes, Salvador J Diaz-Cano
Alfredo Blanes, Department of Pathology, University of Malaga School of Medicine, Malaga 29010, Spain
Salvador J Diaz-Cano, Department of Histopathology, King’s College Hospital and King’s College London School of Medicine, London SE5 9RS, United Kingdom
Correspondence to: Salvador J Diaz-Cano, MD, PhD, FRCPath King’s College Hospital, Department of Histopathology, Denmark Hill, London, SE5 9RS, United Kingdom.
Telephone: +44-20-73463041 Fax: +44-20-73463670
Received: July 4, 2005
Revised: July 17, 2005
Accepted: August 26, 2005
Published online: October 7, 2006

Microsatellite instability (MSI) is a prognostic factor and a marker of deficient mismatch repair (MMR) in colorectal adenocarcinomas (CRC). However, a proper application of this marker requires understanding the following: (1) The MSI concept: The PCR approach must amplify the correct locus and accurately identify the microsatellite pattern in the patient’s normal tissue. MSI is demonstrated when the length of DNA sequences in a tumor differs from that of nontumor tissue. Any anomalous expansion or reduction of tandem repeats results in extra-bands normally located in the expected size range (100 bp, above or below the expected product), differ from the germline pattern by some multiple of the repeating unit, and must show appropriate stutter. (2) MSI mechanisms: MMR gene inactivation (by either mutation or protein down-regulation as frequently present in deep CRC compartments) leads to mutation accumulation in a cell with every cellular division, resulting in malignant transformation. These mechanisms can express tumor progression and result in a decreased prevalence of aneuploid cells and loss of the physiologic cell kinetic correlations in the deep CRC compartments. MSI molecular mechanisms are not necessarily independent from chromosomal instability and may coexist in a given CRC. (3) Because of intratumoural heterogeneity, at least two samples from each CRC should be screened, preferably from the superficial (tumor cells above the muscularis propria) and deep (tumor cells infiltrating the muscularis propria) CRC compartments to cover the topographic tumor heterogeneity. (4) Pathologists play a critical role in identifying microsatellite-unstable CRC, such as occur in young patients with synchronous or metachronous tumors or with tumors showing classic histologic features. In these cases, MSI testing and/or MMR immunohistochemistry are advisable, along with gene sequencing and genetic counseling if appropriate. MSI is an excellent functional and prognostically useful marker, whereas MMR immunohistochemistry can guide gene sequencing.

Keywords: Colon carcinoma, Microsatellites, Mismatch Repair, Hereditary non-polyposis colon cancer