**6. XRCC3**

528 DNA Repair

SNPs in low penetrance genes whose protein products would affect a pathway involved in carcinogenesis have been documented as cancer predisposition or susceptibility risk factors. Low penetrance candidates are found in a wide variety of pathways ranging from

The recognition that carcinogens can also be mutagens that change the DNA sequence gave impetus to the relevance of DNA damage and repair to carcinogenesis. All the effects of exogenous factors and endogenous factors on tumor production could be accounted for by the DNA damage that they cause and by the errors introduced into DNA during the cell's efforts to repair this damage. According to the mutator phenotype hypothesis, cancer phenotypes result from mutations in genes that maintain genetic stability in normal cells. Mutations in genetic stability genes can cause mutations in other genes that govern genetic stability, initiating a cascade of mutations throughout the genome. So, the prompt response of the cells to repair genetic injury and its ability to maintain genomic stability by means of a variety of DNA repair mechanisms are therefore essential in preventing tumor initiation and

Genetic variants or mutations in high penetrance genes are disease causing whereas genetic variations in low penetrance genes are insufficient to cause cancer, but may influence cancer risk. So genetic variants in low penetrance genes are disease risk associated. Individual low penetrance risk alleles are insufficient to cause cancer, but influence cancer risk. Low penetrance genes, with an attendant increased risk of causing cancer, albeit, less likely than high penetrance genes (Ponder, 2001; Shields & Harris, 2000) predispose individuals to

DNA repair mechanisms are controlled by specific set of genes encoding the enzymes that catalyze cellular response to DNA damage. It is well documented that loss of repair function, or alteration of the control of repair process, can have very serious consequences for cells and individuals and can lead to development of cancer. Several genes involved in DNA repair pathways are considered to be low penetrance genes. A link between failure of DNA repair and carcinogens was suggested when individuals with chromosome breakage syndrome such as Xeroderma Pigmentosum, Fanconi Anemia, Bloom Syndrome, Ataxia telangiectasia who have inherited genetic defects in certain DNA repair systems were

Because DNA damage is associated with cancer development, it was hypothesized that genes involved in DNA damage repair may influence cancer susceptibility. Polymorphisms in DNA repair genes may be associated with differences in the DRC of DNA damage and may influence an individual's risk for cancer, because the variant genotype in those polymorphisms might destroy or alter repair function. A large number of SNPs have been determined among individuals in DNA repair genes. It has been documented that genetic variations in DNA damage repair genes could result in variations in efficacy and accuracy of DNA repair enzymes and could have effect on the sensitivity of the organism to

Genetic variation in DNA repair genes in each of the five DNA repair pathways has been implicated in cancer susceptibility (Berwick & Vineis 2000; Goode et al., 2002). Genetic variations such as SNPs in DNA repair genes are associated with reduced function of their encoded proteins, rather than absence of function and may alter an individual's capability to

recognized to be at an increased susceptibility to development of certain cancers.

metabolism and detoxification or environmental carcinogens to DNA damage repair.

progression.

cancer upon interacting with environmental factors.

**5. SNPs in DNA damage repair genes** 

environmental genotoxins.

The X-ray repair cross-complementing group 3 (XRCC3), the DNA repair gene which codes for a protein participating in homologous recombination repair (HRR) of double strand breaks (DSB), has been of considerable interest as a candidate gene for cancer susceptibility. The variant allele of the Thr241Met had been reported to have relatively high DNA adduct levels in lymphocyte DNA and hence with relatively low DNA repair capacity (Matullo et al., 2001). Several molecular epidemiologic studies have been performed to evaluate the role of XRCC3 polymorphisms such as XRCC3 4541 A>G, XRCC3 17893 A>G, XRCC3 Thr 241 Met on various neoplasms, such as cancer of breast, lung, bladder, colorectal, head and neck, skin etc (Han et al., 2004; Shen et al., 2004; Ritchey et al., 2005; Jin et al., 2005; Matullo et al.,2005; Garcia-Closas et al., 2006; Zienoldding et al., 2006; Yi et al., 2006). But rather than conclusive, the results from these studies remain fairly conflicting. Ahmd Aizat (2011) reported lack of association of XRCC3 Thr 241 Met with sporadic colorectal cancer susceptibility in Malaysian population. (Han et al., 2006) performed a meta –analysis on XRCC3 polymorphism and cancer risk involving 48 case-control studies including 24,975 cancer patients and 34,209 controls. From the analysis results, (Han et al., 2006) reported that

**9. P53** 

in susceptibility.

**10. MMR genes** 

Low Penetrance Genetic Variations in DNA Repair Genes and Cancer Susceptibility 531

The P53 gene plays a critical role in cell cycle control, the initiation of apoptosis, and maintenance of genomic stability and in DNA repair (Levine, 1997). TP53 is highly polymorphic in coding and non coding regions and some of these polymorphisms have been shown to increase cancer susceptibility and modify cancer phenotypes in TP53 mutation carriers (Whibley et al., 2009). Over 80 TP53 polymorphisms have been identified and validated in human populations. (IARC TP53 Database, R13). Nearly 90% are located in introns, outside splice sites, or in non coding exons. Among the P53 polymorphism, the codon 72 polymorphism (Arg72 Pro) in exon 4 of TP53 is the most extensively studied, both in experimental and population studies. Codon 72 is located within a proline rich region and Arg72 has been reported to be more effective in inducing apoptosis than Pro72. The Arg/Pro polymorphism at codon 72 of the P53 gene alters the ability of the P53 protein to induce apoptosis, influences the behaviour of mutant P53, decreases the DNA repair capacity and has been linked to with an increased risk of cancer, especially lung cancer. Several studies have examined the associations between P53 codon 72 (Arg72Pro) polymorphism and risk of different cancers, but with in consistent results. Few studies reported higher risk for lung cancer in individuals with the Arg/Pro or Pro/Pro genotype and especially Pro/Pro genotype with smoking induced lung cancer (Weston et al., 1992; Jin et al., 1995 ; Fan et al., 2000; Zhou et al., 2001). In a Chilean population, Fan et al., (2000) investigated the influence of polymorphic genotype TP53 on lung cancer susceptibility and the Pro/Pro genotype of TP53 was found to contribute significantly to lung cancer susceptibility risk [ OR 3.88 (95% CI 1.16 – 13.39) ]. The study by Alexandrov et al (2002) were consistent with the hypothesis that Benzo(a)pyrene (Polycyclic aromatic hydrocarbon, PAH) induce G : C to T : A transverse mutations in the hotspot codons of TP53 and are hence involved in the malignant transformation of the lung tissue of smokers. In an Indian case – control study involving 211 lung cancer cases and 211 controls, Sreeja et al (2007) reported an OR of 2.5 (95% CI 1.470 4.302 , p= 0.001) for the TP53 Pro/Pro variant genotype for lung cancer susceptibility and the risk tended to be higher for women [ OR =2.4 , p=0.003 ] . Recently, Ahmd Aizat (2011) reported a significant association of Pro/Pro homozygous variant of p53 with sporadic colorectal cancer susceptibility (OR = 1.886, CI: 1,046 – 3.399 , p= 0,035) and suggested that p53 Pro72Pro genotype carriers might be having a higher risk for Colorectal cancer susceptibility in Malaysian population (personal communication, unpublished data) However, meta-analysis on the risk association of TP53 Arg72Pro polymorphism with lung cancer (Matakidou et al., 2003) and breast cancer (Schmidt et al., 2007) do not support a significant role for this polymorphism

In the maintenance of genomic stability, the DNA mismatch repair (MMR) systems comprising of various MMR genes play a key role. MMR genes mediate DNA repair through removal of mismatched nucleotide pairs and insertion/ deletion heterologies generated during DNA replication. Germ line mutations as well as hypermethylation in MMR genes have been reported in familial/hereditary forms of colorectal cancer. So, it was hypothesized that common variants in relevant genes encoding DNA MMR enzymes might impact the risk of sporadic form of CRC and studies have been carried out to explore this possibility. Even though the functional relevance of majority of polymorphisms in the genes

individuals carrying the XRCC3 Met/Met genotype showed a. small cancer risk under a recessive genetic model. Specifically, the XRCC3 Met/Met genotype showed significantly increased risk of breast cancer, but not significant risk of cancer for head and neck, bladder, and non-melanoma skin cancer. This meta analysis results support that the XRCC3 might represent a low penetrance susceptible gene especially for cancer of breast, bladder, head and neck, and non-melanoma skin cancer.
