Balkan Journal of Medical Genetics

ALTERATIONS OF COPY NUMBER OF METHYLATION PATTERN IN MISMATCH REPAIR GENES BY METHYLATION SPECIFIC-MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION IN CASES OF COLON CANCER
Onrat ST1*, Çeken I2, Ellidokuz E3, Kupelioğlu A4
*Corresponding Author: Serap Tutgun Onrat, Department of Medical Genetics, Afyon Kocatepe University Medical Faculty, ANS Arastırma Uygulama Hastanesi, Morfoloji Binası, Ozdilek yolu, Afyonkarahisar, 03200, Turkey; Tel.: +90-272-246-3301, Fax: +90-272-246-3300, E-mail: tutgunonrat@ yahoo.com, sonrat@aku.edu.tr
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INTRODUCTION

At least six different mismatch repair (MMR) genes [MLH1 (MutL homolog 1, 19 exons), MSH2 (MutS homolog 2, 16 exons), MSH6 (MutS homolog 6), MLH3 (MutL homolog 3), PMS2 (postmeiotic segregation increased 2) and MSH3 (MutS homolog 3)] have been identifed. Their protein products interact to form protein complexes that mediate distinct functions in the repair of insertion/deletion and single-base substitution mismatches [1]. The product of MLH1 and PMS2 direct the mismatch recognition complex to repair insertion/deletion loops (IDLs), whereas those of MSH2, MSH6 are directed to single-base mismatches [1-3]. The mismatch repair (MMR) system is critical for the maintenance of genomic stability and increase the fidelity of DNA replication by identifying and excising single-base mismatches and IDLs that may arise during DNA replication. Cells that have MMR deficiency may lead to the accumulation of mutations that initiate cancer. The MMR genes are involved in one of the most prevalent cancer syndromes in humans known as hereditary non polyposis colon cancer (HNPCC). Mutations in MLH1 and MSH2 have been found in about 90% of HNPCC cases. Mutations in other MMR genes have been less frequent in HNPCC patients. In many sporadic colon cancers, hypermethylation of the MLH1 gene promoter that results in silencing of its transcription has been observed more frequently than mutations [4]. DNA MMR is an evolutionarily conserved postreplicative repair mechanism, which eliminates mistakes in the newly synthesized DNA strand during DNA replication [5]. Such biosynthetic mistakes include base/base mismatches and IDLs. The latter mistakes arise during the slippage of the primer against the template strand, especially in repeated sequence motifs like microsatellites. A model for the eukaryotic MMR mechanism is provided by Saccharomyces cerevisiae [6] where mutations in three genes lead to 100- to 700-fold increases in mutation levels at poly (GT) sequences. The discovery of defects in MMR that co-segregate with certain cancer predisposition syndromes (for example, HNPCC) highlights the essential role of MMR in mutation avoidance. Mismatch repair consists of five major steps: 1) mismatch recognition, 2) assembly of the repair complex, 3) strand discrimination, 4) degradation of the mismatch-containing strand, and 5) resynthesis of the excised strand [5]. Depending on the type of mismatch on the newly synthesized DNA strand, either an MSH2-MSH6 (MutSα) or MSH2-MSH3 (MutSβ) dimer recognizes the mismatch. The MSH2-MSH6 complex is involved in the repair of single base pair mismatches, whereas the MSH2-MSH3 complex preferentially targets mismatches from two up to 13 nucleotides [7]. The first HNPCC-associated DNA MMR gene, MSH2, was identified by genetic linkage analysis [8]. To date, six human MutS homologues and four MutL homologues are known to participate in DNA MMR, but not all are associated with HNPCC predisposition [9]. According to recent knowledge, HNPCC predisposition is a consequence of an inherited mutation in one of four MMR genes (MLH1, MSH2, MSH6 and PMS2) resulting in defective DNA MMR. The roles of MLH3, MSH3 and PMS1 in HNPCC predisposition is less clear [10- 12]. Estimates of the relative proportions of mutations in the different MMR genes vary depending on the country and population [13-16]. DNA changes are crucial steps in tumor initiation and progression [17]. Next to mutations in oncogenes and tumor suppressor genes, alterations in DNA copy numbers and DNA methylation patterns have been observed as common changes in colorectal and gastric cancer. Copy number changes can lead to increased or decreased gene expression, whereas mutations can have an activating or inactivating effect. Besides these genetic changes, epigenetic changes, such as DNA methylation, may result in altered gene expression levels. Usually, aberrant methylation of normally unmethylated CpG-rich areas, also known as CpG islands, which are located in the promoter regions of genes, have been associated with transcriptional inactivation of important tumor suppressor genes, DNA repair genes or metastasis inhibitor genes [18,19].

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