Lozynska M. The role of genetic factors in the diseases of intestine with high risk of colorectal cancer occurrence

The thesis presents a theoretical synthesis and a new solution of the problem of genetic diagnostics in the diseases of intestine with high risk of colorectal cancer occurrence for the inhabitants of the west regions of Ukraine. Four main genetic forms of the multiply adenomatous polyposis were revealed. The mutations of APC gene were determined in 28.0% of probands with multiple adenomatous polyposis confirming the diagnosis of familial adenomatous polyposis.The hereditary predisposition was confirmed in 31.3% patients with colorectal cancer. The monogenic diseases contribute to 9.7% of colorectal cancer. The majority of the patients with cancer were diagnosed in the families with Lynch syndrome II. The phenomenon of anticipation is found in probands. It is proved that the disease begins earlier for offspring than for parents. Mutations of MYH gene were determined in 8% of probands with multiple adenomatous polyposis.The frequency of T allele of polymorphic variant C677T of MTHFR gene (pт=0.40) for females with colorectal cancer is higher comparing with males (pт=0.189). The CT genotype was found more frequently for females, than in males with colorectal (60.0% і 32.4%, accordingly) and for patients without hereditary predisposition to cancer (in 61.8%), than for persons with hereditary aggravation on this disease (in 27.3%). The aneuploidy and the ploidy abnormalities initiated "cancer" phenotype on the chromosome level. The additional copies of the chromosomes 2, 3, 5, 7 and 20, the monosomy of the chromosomes 8, 17, 18 and rearrangements of the chromosome 1 were found to be the most significant in tumor progression.Colorectal cancer was developed on the ground of inflammatory bowel disease in 5.9% of probands. At least one of three common variants (1007fs, R702W, G908R) of CARD15/NOD2 gene mutations was confirmed in 41.4% patients with Crohn's disease. In all unrelated affected probands with inflammatory bowel disease included to the study the allele frequencies of 1007fs, R702W and G908R were 0.16, 0.07 and 0.05 respectively for the Crohn's disease, and 0.13, 0.05 and 0 for the ulcerative colitis. The 3.8-fold increased risk for the development of Crohn's disease was observed in patients were identified as 1007fs carriers in heterozygous state. The algorithm of the genetic diagnostics of the intestine diseases with high risk of colorectal cancer development was proposed.