MICROSATELLITE INSTABILITY OF COLORECTAL CANCERS IN PATIENTS FROM THE REPUBLIC OF MACEDONIA
Stefanovska A-M1,*, Jasar D2,*, Zografski G2, Josifovski T3, Panovski M3, Efremov GD1, Dimovski AJ1
*Corresponding Author: Dr. Aleksandar J. Dimovski, Macedonian Academy of Sciences and Arts, Research Center for Genetic Engineering and Biotechnology, Aven Krste Misirkov 2, POB 428, 1000 Skopje, Republic of Macedonia; Tel: +3892-120253; Fax: +3892-115434; E-mail: aleks@manu.edu.mk
page: 11

INTRODUCTION

Microsatellite instability (MSI) is a form of genomic instability caused by defective DNA mismatch repair that occurs during DNA replication. MSI is manifested by accumulation of mutations in the repetitive microsatellite  sequences scattered throughout the genome [1,2]. Most hereditary nonpolyposis colorectal cancer (HNPCC) tumors (85-90%) [3] and a smaller proportion of sporadic, nonhereditary colorectal tumors show MSI [4]. HNPCC is the most frequent hereditary form of colorectal cancer, caused by highly penetrant germline mutations in one of the six mismatch repair (MMR) genes (MSH2, MLH1, PMS1, PMS2, MSH6, MLH3) [5-7]. Fifteen to 20% of sporadic colorectal tumors that are associated with MSI have similar clinical and histopathological characteristics as HNPCC tumors, such as early age at diagnosis, proximal localization, mucinous histology and lymphocytic infiltration [4]. The molecular mechanism for MSI in these tumors is not mutational inactivation of any of the MMR genes but, in most patients, it is inactivation of the MLH1 gene by somatic hypermetilation of its promoter [8,9]. Generations of MMR defects and consequent MSI phenotypes are considered to be an early event in tumorigenesis, occurring as early as the aberrant crypt focus stage [10].

Molecular testing for MSI is the most reliable labora­tory method for the identification of HNPCC carriers, especially those who do not meet the so-called Amsterdam clinical criteria [11,12]. In addition, it has been suggested that patients with MSI tumors have improved survival and favorable prognosis [13,14], and that they have a different response to particular chemotherapy regimens in compari­son with patients with microsatellite stable (MSS) tumors [15].

In 1997, the National Cancer Institute (NCI) of the USA recommended a reference panel of five microsatellite  markers for the identification of MSI in tumors. The results of the MSI testing should be interpreted as MSI-high (MSI-H) if two or more of the five microsatellites exhibit instability (30-40% or more of markers if more than five are tested), MSI-low (MSI-L) if only one microsatellite is unstable (less than 30-40% of markers if more than five markers are tested), and MSS if none of the microsatellites used exhibit instability [16]. A recent study suggested that a low level of MSI can be detected in most colorectal carcinomas and that MSI-L and MSS tumors have similar features, possibly because of a common molecular background [17].

The aim of this study was, firstly, to evaluate a panel of microsatellites, following NCI recommendations, and to establish a simple and fast assay for MSI assessment. Secondly, we conducted a retrospective study for evaluation of the frequency of MSI tumors among the colorectal cancer patients from the Republic of Macedonia during a period of 5 years, and compared the MSI status with the histopathological features of the tumors and the clinical course of the disease.




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