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Microsatellite Instability in Colorectal Cancer: Considerations for Molecular Diagnosis and High-Throughput Screening of Archival Tissues

¹ Department of Pathology, National University of Singapore;² Molecular Diagnosis Centre, Department of Laboratory Medicine, and³ Department of Hemato-Oncology, National University Hospital, Singapore

^aaddress correspondence to this author at: Department of Pathology, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074; fax 65-67751757, e-mail patkoaye@nus.edu.sg

The first 300 words of the full text of this article appear below.

Microsatellite instability (MSI) (1) is the consequence of a failure in the DNA replication proofreading mechanism. In two-thirds of colorectal cancer (CRC) patients with high-frequency MSI (H-MSI), the cause is an epigenetic hypermethylation of one of the mismatch repair (MMR) genes; in the remaining 30% [the hereditary non-polyposis colorectal cancer (HNPCC) subgroup], the cause is inherited mutations in these genes. Distinction between H-MSI and microsatellite-stable (MSS) CRC may also have prognostic and therapeutic implications (2)(3).

The MSI test should be complemented with morphologic (4) and clinicopathologic evaluation, immunohistochemical (IHC) staining (5) (as manifested by absence of hMLH1 and/or hMSH2 antibody reactivity), and when indicated, screening and confirmation of MMR gene mutations. Direct sequencing, another viable diagnostic approach, is limited by the complex nature of the genes, the broad mutational spectrum, and the cost (6).

In the present study, we reviewed the MSI testing performed in our routine molecular diagnostic laboratory and correlated the findings with mutation analysis and IHC studies; we also propose the most cost-effective manner of diagnosing CRC and report the fidelity of tissue microarrays (TMAs) for high-throughput analysis of large tissue archives.

Approximately 20% (29 tumors from 27 patients) of the 131 MSI cases we analyzed underwent surgery in our hospital; thus, samples for IHC studies and sequencing were available. CRC tissue and noncancerous colonic mucosa were manually microdissected, and DNA was extracted with the DNeasy^TM Tissue Kit (Qiagen GmbH). The microsatellite repeat sequences analyzed were Bat-25 (4q12/c-kit), Bat-26 (2p16.3/hMSH2), D2S123 (2p16/hMSH2), D5S346 (5q21/APC), and D17S250 (17q11.2/BRCA1). The method (7) was modified from that of Berg et al. (8) and based on international recommendations (9)(10). Individual PCR . . . [Full Text of this Article]

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