PP44. LOW PENETRANCE ALLELS PREDISPOSING TO COLORECTAL CANCER IN MACEDONIAN PATIENTS
Z. STERJEV1, Z. Serafimovska1, A. Kapedanovska1, M. Hiljadnikova-Bajro1, T. Josifovski2, M. Panovski2, L. Suturkova1, A. J. Dimovski1 1. Faculty of Pharmacy, University "Sts.Cyril and Methodius", Skopje, R. Macedonia 2. Clinic for Abdominal Surgery, Faculty of Medicine, University "Sts.Cyril and Methodius", Skopje, R. Macedonia e-mail: adimovski@ff.ukim.edu.mk
*Corresponding Author:
page: 67

Abstract

Colorectal cancer is a disease of the genome, which is altered at multiple sites in cancer cells by cumulative epigenetic and genetic changes. Genetic syndromes predisposing to colorectal cancer include two autosomal dominant syndromes, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), as well as influence of low-penetrance gene variants involved in metabolic pathways, DNA methylation, modification of colonic microenvironment, immune response, oncogenes and tumor suppressor genes.

We examined the influence of polymorphisms in 5 different genes (TGFbRI6A, CCND1 G870A, SULT1A1 Arg213His, MTHFR C677T and TS promoter VNTR variant) in a case-control study involving 186 patients with colorectal cancer and 186 controls (94 newborns and 92 aged individuals without a history of a malignant disease) from the Republic of Macedonia. Genotypes were obtained by PCR-RFLP and allele discrimination - real time PCR analysis on DNA samples isolated from peripheral blood. The influence of each polymorphism on major clinicopathological characteristic of patients [age at diagnosis, sex, localization, TNM stadium, chromosomal (CIN) or microsatellite (MSI) instability of tumors] was also evaluated. Statistical analyses were done by conditional and unconditional logistic regression.

Only MTHFR 677 T-allele showed statistically significant difference in allele frequency between patients above 60 years of age (0.71) and controls (0.59) (p=0.001, RR 1.45 95% CI 1.1481-1.8213). The difference in genotype distribution between this subgroup of patients and controls [TT/TC+CC  and TT+CT/CC, RR 1.38 and 1.15, respectively] suggested a gene dosage effect of the variant in our population.

MTHFR plays a central role in folate metabolism, irreversibly converting 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, which is a vital source of methyl groups for DNA methylation. Previous studies have demonstrated that MTHFR 677 T allele has reduced activity of 30% in heterozygotes and up to 70% in homozygotes. Whether this variant acts through reduced methylation of critical genes involved in colorectal cancerogenesis or through reduced inactivation of xenobiotics present in the diet of our population will be evaluated in the follow-up study.




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