**4. Single Nucleotide Polymorohisms (SNPs) in low penetrance genes**

Genetic variations seen in human genome includes insertion/deletion of one or more nucleotides (indels) the copy number variations (CNNs) that can involve DNA sequences of a few kilobases up to millions of bases and single nucleotide polymorphisms (SNPs) which are the substitution of a single nucleotide along the DNA. With an estimated number of more than 10 million to be present in the human genome, SNPs are the most common form of genetic variation (Miller et al., 2005).

Variations in several classes of low penetrance genes known as Single nucleotide polymorphism (SNPs) are very common in the population. SNPs are DNA sequence variations that occur when a single nucleotide (A, T, C, or G) in the genome sequence is altered. For a variation to be considered as SNP, it must be present in at least 1% of the population. SNPs are relatively common in the population and as such may be associated with a much higher attributable risk in the population as a whole than the rare high penetrance genes. Therefore, variants in low penetrance genes could explain a greater proportion of sporadic cancers than the high penetrance genes. SNPs acting together with environmental factors are well documented candidates for cancer susceptibility. Even though, SNPs in these low penetrance genes have only small effect when considered singly, they may produce a high risk profile when acting together with other shared genetic variants and environmental factors (Gary et al., 1999). On the basis of biological plausibility,

Low Penetrance Genetic Variations in DNA Repair Genes and Cancer Susceptibility 529

repair damaged DNA. This may result in gene product (protein) not being formed, or that the protein is less active, or that it is formed in an uncontrolled fashion, may be at the wrong time, or in the wrong amount. Some minor genetic alterations may not affect protein activity, or interactions, whereas others may significantly disrupt cellular function. It is also possible that since certain proteins work in a number of different processes or complexes, the loss or impairment of one type of protein can affect several different functions of the cell and organism. Deficiency or impairment in DNA repair genes which results in alteration of the key gene expression may have an influence on DNA repairs functions and could lead to altered cancer risk. The importance of these mechanisms in cancer prevention is evident from the increased cancer risk associated with disruption of these pathways (Digweed, 2003). So studies on DNA repair as a susceptibility factor for cancer are increasing exponentially. Majority of cancer susceptibility studies have focused on the identification of low-penetrance disease susceptibility alleles applying candidate gene pathway studies and genome wide association studies. Genetic association studies and genome wide association scans have identified a number of polymorphisms in several low penetrance genes and their role in etiology of several cancers, through risk

DNA double strand breaks (DSBs) which can result from a variety of factors including ionizing radiation, free radicals, replication errors, telomere dysfunction are one of the most severe types of DNA damage (Khanna & Jackson, 2001). Unpaired or misrepaired DSBs can lead to cell death, genomic instability and oncogenic transformation (Jeggo & Jackson, 2001). Homologous recombination (HR) and nonhomologous enjoining (NHEJ) are the two major DSB repair pathways in mammalian cells. Reports are available suggesting that several Single Nucleotide Polymorphisms in the NHEJ genes may be relevant to modify the risk of multiple myloma (Roddam et al., 2002), glioma (Liu et al., 2008) and, breast cancer (Garcia-Closas et al., 2006). Another study by (Tseng et al., 2009), showed significant association between the XRCC4 and LIGH genotypes with non-small cell lung cancer (NSCLC) risk in an analysis of individual polymorphism associations, and the risk of NSCLC increased

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

modification (Tomlinson et al., 2008).

**6. XRCC3** 

further in a combined analysis of multiple polymorphisms.

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 metabolism and detoxification or environmental carcinogens to DNA damage repair.

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 progression.

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 cancer upon interacting with environmental factors.

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

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

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 environmental genotoxins.

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 repair damaged DNA. This may result in gene product (protein) not being formed, or that the protein is less active, or that it is formed in an uncontrolled fashion, may be at the wrong time, or in the wrong amount. Some minor genetic alterations may not affect protein activity, or interactions, whereas others may significantly disrupt cellular function. It is also possible that since certain proteins work in a number of different processes or complexes, the loss or impairment of one type of protein can affect several different functions of the cell and organism. Deficiency or impairment in DNA repair genes which results in alteration of the key gene expression may have an influence on DNA repairs functions and could lead to altered cancer risk. The importance of these mechanisms in cancer prevention is evident from the increased cancer risk associated with disruption of these pathways (Digweed, 2003). So studies on DNA repair as a susceptibility factor for cancer are increasing exponentially. Majority of cancer susceptibility studies have focused on the identification of low-penetrance disease susceptibility alleles applying candidate gene pathway studies and genome wide association studies. Genetic association studies and genome wide association scans have identified a number of polymorphisms in several low penetrance genes and their role in etiology of several cancers, through risk modification (Tomlinson et al., 2008).

DNA double strand breaks (DSBs) which can result from a variety of factors including ionizing radiation, free radicals, replication errors, telomere dysfunction are one of the most severe types of DNA damage (Khanna & Jackson, 2001). Unpaired or misrepaired DSBs can lead to cell death, genomic instability and oncogenic transformation (Jeggo & Jackson, 2001). Homologous recombination (HR) and nonhomologous enjoining (NHEJ) are the two major DSB repair pathways in mammalian cells. Reports are available suggesting that several Single Nucleotide Polymorphisms in the NHEJ genes may be relevant to modify the risk of multiple myloma (Roddam et al., 2002), glioma (Liu et al., 2008) and, breast cancer (Garcia-Closas et al., 2006). Another study by (Tseng et al., 2009), showed significant association between the XRCC4 and LIGH genotypes with non-small cell lung cancer (NSCLC) risk in an analysis of individual polymorphism associations, and the risk of NSCLC increased further in a combined analysis of multiple polymorphisms.
