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
page: 25

DISCUSSION

The MS-MLPA method for the analysis of the genes study, the tumor tissues isolated from patients with colon cancer genomic DNA. The MMR genes (PMS2, MSH6, MLH1, MSH2, MGMT, MSH3,MLH3) in terms of percentage of methylation and the frequency of methylation in a test of specific molecular investigated by MS-MLPA management. The data obtained was presented according to the criteria evaluated for sex, age and type of case. According to the relative proportions of defective MMR genes, MLH1, MSH2 and MSH6 are “major” and the remaining MMR genes are “minor” susceptibility genes. MLH1 and MSH2 account for nearly 90% of all mutations, whereas MHS6 mutations occur in 7% of HNPCC families, and the remaining genes are together responsible for under 5% of HNPCC families. In Finland, the MLH1 accounts for more than 90% of Finnish HNPCC families with a known predisposing mutation [24]. This may be explained by the predominance of two common founding mutations of MLH1 (a 3.5k b genomic deletion of exon 16 and a splice acceptor site mutation of exon 6), which account for 63% of all mutations detected in Finnish HNPCC kindreds [25,26]. In general, MMR gene mutations are spread equally over the coding sequences of the three major susceptibility genes and their exon-intron boundaries. Of these, five mutation hot-spots were detected in MLH1 exons 1 and 16, MSH2 exons 3 and 12, and MSH6 exon 4 [12]. The majority (81%) of inherited MLH3 mutations are clustered in exon 1 [27]. Most MLH1 and MSH2 mutations are nonsense (11 and 49%) and frameshift mutations (44 and 19%) that cause the truncation and loss-of-function of the respective protein product. Missense mutations account for 32% of MLH1 and 18% of MSH6 mutations. Often, these mutations, especially missense mutations of MSH6, are associated with small or atypical HNPCC families, sometimes with milder phenotypes, thus their pathogenicity is more difficult to determine [28,29]. Due to the rarity of mutations in the remaining genes, the analysis of mutation distribution and frequency of different types of mutations remains unknown. We have considered adenoma and adenocarcinoma in patients with colon cancer in two different groups. A nearly 61.63% rate of methylation of MMR genes is seen to occur in patients with adenocarcinomas and 49.91% in patients with adenomas. Epigenetics provide a new perspective for the early diagnosis, treatment and prognosis of these tumors. Studies indicate that CpG island methylation in the MMR genes are also a mechanism underlying gene inactivation and tumorigenesis [30,31]. With the development of epigenetics in recent years, DNA methylation has gradually become a new research focus. In the human genome, 5’ promoters of 50% of genes contain a CpG region, also known as a CpG island, with a length of >197 bp. The CpG island is in a non methylation state under normal circumstances. The CpG island methylation may lead to the loss of gene expression and replication errors [32,33]. The promoter methylation of the hMLH1 gene is the most common in known MMRs genes. The detection rate of the hMLH1 gene promoter methylation in our study was very similar to the reported data [34]. Increasing knowledge on the properties of the MMR system and its connections to other biological pathways is essential to better understand the fundamental mechanisms of cancer development and to identify targets for preventive and therapeutic interventions. We think our analyses revealed novel and non random epigenetic patterns that contribute to the understanding of the developmental mechanisms of colon cancers, which is in agreement with what has been previously reported by others [1].

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