ANALYSIS OF CRITICAL REGIONS OF CANDIDATE GENES FOR
FAMILIAL AND SPORADIC COLORECTAL CANCER CASES
Djansugurova L., Zhunussova G., Perfilyeva A., Zhunusbekova B., Iksan O.,
Abdikerim S., Skvortsova L., Khussainova E.
Institute of General Genetics and Cytology, SC MES RK, Almaty, Kazakhstan
In recent years there has been considerable worldwide increase in colorectal
cancer (CRC) morbidity and a significant rejuvenation of this type of cancer. Despite
the fact that the majority of colorectal cancers cases are sporadic, about 20-30% of
patients present with familial history of CRC. Identification of association between key
candidate genes and risk of CRC is intensively studied on different populations. Here
we present the results of molecular-epidemiological study of different types of
colorectal cancer in population from Kazakhstan.
Blood samples were collected from patients diagnosed with rectal or colon cancer
(249 individuals) as well as a matched control cohort of healthy volunteers (245
individuals). Among CRC patients there were 32 patients with early onset CRC (28-50
yrs), including 10 patients with a family history of cancer. The candidate
polymorphisms of DСС, TP53, hMLH1, GSTT1 and GSTM1 genes were genotyped for
sporadic CRC cases. The mutation hot spots regions of genes APC, KRAS, MLH1, and
TP53 associated with famous familial syndromes were studied for the suspected familial
cases.
Our results showed a significant association with increased CRC risk in the
following genotypes: DCC (32008376 G/G and G/A vs. A/A; OR=3.45, p<0.0002),
MLH1 (-93G/G vs. G/A and A/A, OR=1.45, p<0.04), TP53 (Pro72Pro; OR=3.80,
p<0.0001), and GSTM1 deletions (OR=1.83, p<0.001). Analysis for ethnicity and
smoking for each of the investigated polymorphisms showed that some genotypes can
have a predictive value for susceptibility to CRC, at least those that demonstrate
statistically significant ORs either for the combined mixed population of Kazakhstan or
for both main ethnic groups separately (Kazakhs and Russians): TP53 Pro72Pro
homozygous (for Kazakh - OR=3.40, p<0.003; for Russian - OR=4.69, p<0.0001) and
GSTM1 deletions (for Kazakh - OR=2.30, p<0.01; for Russian - OR=1.64, p<0.02).
The spectrum of mutations (8 mutations) in “hotspots” regions of genes (APC,
TP53, MLH1, MSH2) associated with early CRC development and possible family
inheritance were defined. In a cohort of patients with early CRC onset 3 new previously
non-described mutations were identified (mutation in intron 15 of MLH1 gene (c.173290C>A), mutation in intron 4 (c.376-19C>T) and intron 9 (c .993 + 12T>C) of TP53
gene). Well known coding polymorphisms were observed in exon 8 of MLH1
(rs1799977 - A655G/Ile219Val), in exon 7 of MSH2 (rs5028341 - C1168T/Leu390Phe),
in exon 15 of APC (rs1801166 - G3949C/p.Glu1317Gln and rs41115 – 4479G>A).
The single deletion, c.3613delA (p.Ser1205fs), located in exon 15 of APC gene, was
found in the heterozygous state in two patients with a family history of adenomatous
polyposis.
The results of the research will significantly enhance the ability of the national
screening program for colon and rectum neoplasms and increase the efficiency of
measures for the prevention of this disease in Kazakhstan.