Original ArticleClinicopathologic characteristics of colorectal cancer with microsatellite instability
Introduction
Colorectal cancers (CRC) are considered to belong to the most common cancers in industrialized countries. They are the third most common cancer in men after lung and prostate cancers and come second in women after breast cancer. In Tunisia, CRC have an annual incidence of 10.3/100,000 individuals. However, a significant proportion (9%) of these cancers occurs before age 40 years, suggesting genetic susceptibility [13].
The deficiency of the DNA mismatch repair (MMR) system is a major mechanism for carcinogenesis. It is involved in the development of hereditary non-polyposis colorectal cancers (HNPCC, also called Lynch syndrome) and in nearly 20% of sporadic CRC [3]. This deficiency is responsible for microsatellite instability (MSI), resulting from the accumulation of small insertions or deletions that frequently arise during replication of these short repeated sequences [25].
Dysfunction of MMR proteins may be related either to an alteration of a gene at the constitutional level, which is the case with Lynch syndrome mutations constitutional MMR genes (hMLH1, hMSH2, hPMS1, hPMS2 and hMSH6), or to altered gene in somatic tumor. In the latter case, it is often a loss of function of hMLH1 most often involved is its epigenetic repression by methylation of its promoter [34].
Determining the MSI phenotype by molecular biology techniques has been standardized by the international conference organized by the National Institute of Health in 1998 [3], which recommends the genotyping of five markers: three dinucleotide repeat markers (D2S123, D5S346, D17S250) and two mononucleotide repeat markers (BAT25 and BAT26) [3]. The realization of this phenotype, which compares the constitutional and tumor genome of a patient, assumes control of the histological quality of the tumor sample.
Besides a fundamental interest because of the original transformation mechanism, the study of tumors with MSI instability is of great clinical interest. It has indeed been shown in several studies that tumors with MSI had several epidemiological, anatomical, histological and prognostic features [1], [14], [39].
The aim of the present study was to analyze in a series of CRC from Tunisia the clinico-pathological characteristics of colorectal cancers with microsatellite instability.
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Patients and tumor samples
Patients who had undergone resection of CRC between January and December 2007 were identified from the files of the Department of Pathology, CHU Farhat-Hached of Sousse, Tunisia. Patients with history of familial adenomatous polyposis or preoperative anticancer therapy were excluded from the study. Fifty patients were retained for this study. For all of these cases, matched pairs of colorectal tumor and normal adjacent tissues were obtained as formalin-fixed, paraffin-embedded specimens.
MSI detection
The quality of DNA samples was checked by PCR amplification of a 268-pb fragment within the human β-globin gene. The integrity of DNA samples was validated in 44 of the 50 CRC cases tested. MSI analyses were then performed for these 44 CRC cases. Of these, 24 patients (54.5%) were found to have MSS tumors, 14 patients (31.8%) had instability at one marker (MSI-L), and six patients (13.6%) had instability at two or more markers (MSI-H). Fig. 1 illustrates representative examples for MSI analysis.
Discussion
Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent cause of inherited colorectal cancer. It is an autosomal dominantly inherited syndrome characterized by the occurrence of early onset CRC, an excess of synchronous and metachronous CRC, as well as a defined spectrum of extracolonic tumors, particularly cancers of the endometrium, small intestine, hepato-biliary tract, upper urinary tract and stomach [23]. Most of these cases remain unknown for lack of a suitable diagnostic
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by the “Ministère de l’Enseignement Supérieur, de la Recherche Scientifique et Technologie” and the “Ministère de la Santé” of Tunisia.
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