GENETIC POLYMORPHISMS OF DNA DAMAGE REPAIR GENES ON COLORECTAL CANCER’S RISK
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Date
2012
Authors
AHMAD AIZAT, ABDUL AZIZ
Journal Title
Journal ISSN
Volume Title
Publisher
Pusat Pengajian Sains Perubatan Universiti Sains Malaysia
Abstract
The incidence of sporadic colorectal cancer (CRC) is increasing in Asian
countries, including Malaysia. Although several factors have been implicated in CRC
etiology, CRC develops as a result of interaction between environmental factors and
genetic predisposition. However, the genetic predisposition factors associated with CRC
development remains still undetermined. In humans, there are a number of DNA repair
pathways, each responsible for repairing different types of DNA damages inflicted by
environmental factors. It was hypothesized that genetic variations such as single
nucleotide polymorphisms (SNPs) in DNA damage repair genes could have effects on
the sensitivity of the organism to environmental genotoxins and may influence CRC
susceptibility. In order to test this hypothesis, a case-control study was designed and
undertaken at Human Genome Centre (HGC), USM during 2010-2012. The aim was to
investigate the genotype and allele frequencies of 8 SNPs of 6 genes, namely XRCC1
Arg399Gln, XPD/ERCC2 Lys751Gln, XRCC3 Thr241Met, XPC Lys939Gln, P53
Arg72Pro as well as MLH1 Asp132His, Ile219Val and Val384Asp polymorphisms in
Malaysian CRC patients and healthy normal controls, and to determine whether these
SNPs contribute to CRC susceptibility risk in Malaysian population. This study
involved 510 study subjects, comprising of 255 histopatologically confirmed sporadic
CRC patients as cases and 255 healthy normal individuals as controls. After getting
informed consents from study subjects, peripheral blood samples were collected, DNA
was extracted and all the above 8 polymorphisms were genotyped employing PCRRFLP
method. The genotypes were categorized into homozygous wildtype,
heterozygous variant and homozygous variant. On comparing the genotype frequencies
of all SNPs between cases and controls, the homozygous variant genotypes P53
Pro72Pro and XPC Gln939Gln were significantly higher in cases. The risk association
of all the 8 SNPs either singly and/or in combination with CRC predisposition risk was
examined by using binary logistic regression and deriving odds ratios (OR) and 95%
CIs. On evaluating risk associated with variant genotypes singly, homozygous variant
P53 Pro72Pro and XPC Gln939Gln showed significantly higher risk association with
CRC susceptibility. When analyzed in 2 way combinations, the genotype combinations
of XPD/ERCC2 Ly/Lys+XPC Gln/Gln; XRCC3 Thr/Thr+P53 Pro/Pro; XPC Gln/Gln+
MLH1 Asp/Asp; XPC Gln/Gln+ MLH1 Ile/Ile; P53 Arg/Arg+ XPC Gln/Gln; P53
Pro/Pro+ MLH1 Asp/Asp; P53 Pro/Pro+ MLH1 Ile/Ile and P53 Pro/Pro+ MLH1
Val/Val emerged as high risk combination genotypes associated with CRC
susceptibility. Finally, in 3 way genotype combinations, the genotype combinations of
P53 Pro/Pro+XPC Lys/Lys+XRCC3 Thr/Thr; P53 Pro/Pro+XPC Lys/Gln+XRCC3
Thr/Thr; P53 Arg/Arg+XPC Gln/Gln+MLH1 Asp/Asp; P53 Arg/Arg+XPC
Gln/Gln+MLH1 Ile/Ile and P53 Pro/Pro+XPC Lys/Lys+MLH1 Val/Val, were found to
be associated with higher CRC susceptibility risk. Furthermore, several genotypes such
as XRCC1 Arg/Gln genotype singly and combination genotypes such as XRCC1
Arg/Arg+XPD Lys/Gln, XRCC1 Arg/Gln+XPC Gln/Gln, XRCC1 Arg/Arg+XRCC3
Thr/Thr, XRCC1 Arg/Arg+P53 Arg/Pro, XRCC1 Arg/Gln+P53 Arg/Arg, XRCC1
Gln/Gln+P53 Arg/Pro, XRCC1 Arg/Gln+MLH1 Asp/Asp, XRCC1 Arg/Pro+MLH1
Ile/Val, XRCC1 Gln/Gln+MLH1 Ile/Ile, XRCC1 Arg/Gln+MLH1 Val/Val and XPD
Lys/Lys+ XRCC3 Thr/Met were observed to show low risk association. From the
present study results it is suggested that variant genotypes of P53 (P53 Pro/Pro) and
XPC (XPC Gln/Gln) either singly and/or in combination, may be considered as high risk
genotypes associated with CRC susceptibility.
Description
Keywords
Human Genome