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Year : 2014  |  Volume : 5  |  Issue : 4  |  Page : 269-273

An insight of genetic polymorphism and the commonly studied polymorphisms associated with oral cancer

Department of Oral Pathology, SRM Dental College, Ramapuram, Chennai, Tamil Nadu, India

Date of Web Publication20-Nov-2014

Correspondence Address:
Jeevankumar Sangeetha
Department of Oral Pathology, SRM Dental College, Ramapuram, Chennai - 600 089, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0976-433X.145154

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Oral and pharyngeal cancers are some of the most common cancers worldwide. The risk of developing oral cancer is modified by environment, lifestyle, genetics, and a combination of these factors. Both environmental carcinogens and polymorphisms together or individually play an important role in the pathogenesis of oral and pharyngeal cancer. Various genes show polymorphisms, which are thought to play a major role in interindividual variability in drug response, and in susceptibility to chemical induced diseases, like several types of cancers. The objective of this review is to discuss in detail about the various polymorphism, molecular functions and the polymorphic association of various genes.

Keywords: Microsatellite, minisatellite, polymorphism, tandem repeats, xenobiotics

How to cite this article:
Sangeetha J, Rameshkumar A, Ramya R, Rajashree P, Rajkumar K. An insight of genetic polymorphism and the commonly studied polymorphisms associated with oral cancer. SRM J Res Dent Sci 2014;5:269-73

How to cite this URL:
Sangeetha J, Rameshkumar A, Ramya R, Rajashree P, Rajkumar K. An insight of genetic polymorphism and the commonly studied polymorphisms associated with oral cancer. SRM J Res Dent Sci [serial online] 2014 [cited 2023 Jan 28];5:269-73. Available from:

  Introduction Top

Oral cancer is a significant public health problem in many parts of the world, and particularly in South-East Asia. In India, it is the common form of cancer prevalent among the males. [1] Oral cancer is ranked among the first three types of cancer in the Indian subcontinent posing a major problem in the country. [2] Oral squamous cell carcinoma (SCC) and other premalignant conditions are largely carcinogen induced, as major risk factors include tobacco, smoking and alcohol consumption. An individual's physiological responses to environmental stimuli can be modulated by genetic variations. [3] Among tobacco users, differential susceptibility may be due to polymorphism in genes encoding the biotransformation enzymes, which are involved in the metabolism of tobacco and transforming it into either a carcinogen or a relatively harmless compound. [4] The altered function or activity of gene products along with exposure of carcinogenic agents leads to increase in individual's risk of cancer. [3] Little progress has been made in improving overall survival from SCC during the past 30 years, in part because of a limited understanding of the molecular pathobiology of this disease. [5]

Each individual is unique, though the comparison of the genomes of any two individuals shows a 0.1% difference. The nucleotide variation in the form of polymorphism of the genes may influence the rate of transcription of the gene, the enzyme genes, whose functions are modified, the stability of messenger RNA, and quality of resulting protein. Variations may be a single base pair substitution for one base pair to another or variable number of tandem repeats (VNTRs) in the coding and the noncoding region of the specific gene. It is clear from various DNA sequencing studies that many genes are polymorphic. In this article, we describe the various types of polymorphisms in detail and some of the commonly studied polymorphism in oral cancer.

  Polymorphism Top

Population genetics deals mostly with variation within a species. The differences in DNA sequences are called polymorphisms that occur either in coding and noncoding regions of genes. [6] Polymorphism appears to be widespread among genes of the immune system possibly resulting from an evolutionary adaptation of the organism facing an ever evolving environment through mutations. Some polymorphisms may have direct functional significance by altering directly or indirectly the level of genes expression or its function, others may only be useful for the determination of genetic linkage to a particular haplotype associated in turn with a given clinical condition. [7] Common polymorphisms include small segmental deletions/insertions duplications, and single nucleotide polymorphisms (SNPs) and tandem repeat segments like minisatellite, and microsatellite. [3]

  Single Nucleotide Polymorphism Top

The different types of polymorphisms are named after the type of mutation that created them. There is a difference between "polymorphism and mutation." If the frequency of a particular allele (genetic sequence) is more than 1% in a particular population, it is called polymorphism, and if it is <1% it is known as mutation. About 90% of sequence variants in humans are differences in single bases of DNA called SNP. [8] SNP is a single base substitution in DNA and is one of the common form of substitutions. It forms 90% of DNA polymorphism being the most simple and common source of genetic polymorphism. The two types of SNP being transition, in which substitution occurs between purines (A, G) or between pyrimidines (C, T) forming two third of all SNP. [Table 1] The other type being transversion substitution between purine, and pyrimidine. SNP occurring in the coding single nucleotide polymorphisms and regulatory region of the gene can cause functional differences. [8] SNP in the coding region may have two different effects on the resulting protein namely synonymous and nonsynonymous. Substitution causing no amino acid change to the protein produced is synonymous. Change in the encoded amino acid that results in altered protein is nonsynonymous leading to protein misfolding, polarity shift, improper phosphorylation and other functional consequences. [3]
Table 1: Commonly studied gene polymorphisms

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  Tandem Repeats Top

A number of recombination events are responsible for the evolution and plasticity of genomes, and also of many pathologies. These include general (homologous) recombination, translocation, gene conversion, sister chromatid exchange, insertion of transposable elements and variation in tandemly repeated DNA sequences that are not yet part of genes, but might be at the origin of new coding sequences. [9] In the human genome, the sites that have the properties most favorable to such extensive variation include a repetition of the same short DNA sequence a variable number of times. Such sequences are called tandem-repeat sequences

  Short Tandem Repeats/(Simple Sequence Repeat) Top

A microsatellite is a short stretch of DNA that is repeated several times. It makes ~3% of the human genome and as an uneven distribution. It consists of two, three or four nucleotides repeated some variable number of times. A DNA sequence with such variation may be as short as two base pairs or as long as several hundred base pairs. It is otherwise known as "STR." The repeat region is variable (polymorphic), each variant is referred to as an allele. The alleles are distinguished by their length. Based on number of base pairs it can be Mononucleotide (e.g., CCCCCCCC or AAAAAA), Dinucleotide (e.g., CACACACACA), Trinucleotide (e.g., CCA CCA CCA CCA), (e.g., GATA GATA GATA GATA GATA GATA GATA). The number of repetitive sequences varies among individuals, and hence microsatellites can be used as informative polymorphic markers for genetic mapping and for disease susceptibility analysis. [10]

  Variable Number of Tandem Repeats Top

When tandemly repeated sequences are replicated during cell division, the number of repeats can change. That is the reason, why they are also called VNTRs. Minisatellites are formed with repeated bases of 10-60. [6] In humans, microsatellites are spread all over the genome, [8] whereas minisatellites appear to cluster towards telomeres. [11] In spite of their similar structure, minisatellites and microsatellites appear to be strikingly different in many respects. The pattern of allele interruption leads to significant inter individual variations that makes some human population predisposed to allele expansion of pathological length. [12] The natural instability of tandem repeats makes them interesting structures to reveal and analyze some of the mechanisms underlying genome evolution in higher eukaryotes.

  Commonly Studied Polymorphisms in Oral Cancer Top

The various DNA variants lead to the great variety of enzymes. [13] These variants are thought to arise from different DNA sequences. [9] This leads to the diversity in the physical and physiological characteristics in the human population. Some of the polymorphism studies carried out extensively involved single nucleotide studies of xenobiotic, DNA repair genes and various cytokines. SNP being the most common form of genetic variation can affect the way an individual responds to the environment and modify disease risk. [3] SNP(s) account for >90% of the variations in the human genome, and the remaining 10% of these variations include chromosomal aberrations, DNA copy number and microsatellites. [14]

Xenobiotics have been defined as chemicals, to which an organism is exposed that are extrinsic to the normal metabolism of that organism. If not metabolized, these chemicals would accumulate and lead to toxic concentrations. [15] The enzymes that metabolize these chemicals are classified into phase I (activation) and phase II (neutralisation) and transporter enzymes.

  Phase I Enzyme Top

Phase I enzymes make the lipophilic xenobiotic enzymes more polar, more reactive and provide sites for conjugation reactions to phase II enzymes. Phase I and phase II enzymes are commonly studied in polymorphism. Phase I xenobiotic metabolizing enzymes include members of cytochrome P450. [16] It plays an essential role in the metabolic activation of major classes of pro-carcinogens such as benzopyrene, a prototypic polycyclic aromatic hydrocarbon found in tobacco products. [17] Some of the reactions catalyzed lead to detoxification of carcinogens. Significant differences are known to exist in the distribution of the variant alleles of CYP1A1 in different population. CYP1A1 is the commonly studied variant in the pathogenesis of oral cancer. The other species of P-450 which includes CYP1A1, CYP1A2, CYP2E1, CYP3A are widely accepted variety of enzyme types that activate the carcinogens. [18] Some studies had shown positive and negative results for CYP1A1 exon 7 (ile/val) polymorphism to be a risk factor for oral cancer. While CYP2E1 RSa1 and Pst1 polymorphisms had been found to be associated with oral cancer. [19] In a meta-analysis study done recently indicated a marked association of CYP1A1*2A polymorphisms with oral cancer risk, particularly among Asians. [20]

  Phase II Enzymes Top

Phase-II enzymes include members of various transferases such as N-acetyl transferase, sulfo transferase, glucuronyl transferase and glutathione transferase. Glutathione transferase is the commonly studied phase II enzymes, (GSTT1, GSTP1, GSTM1, GSTM3). [4],[16],[22] GSTT1 and GSTM1 are involved in the elimination of carcinogens in the body, such as products of oxidative stress and polycyclic aromatic hydrocarbons from tobacco smoke. Deletion of the GSTT1 and GSTM1 gene results in a variant called GSTT1/GSTM1 null genotype and a complete loss of enzymatic activity. [5] An individual with the null variants is thus expected to have an impaired ability to detoxify carcinogens, and an increased risk of cancer, potentially affecting multiple cancer sites. This and the fact that GSTT1 and GSTM1 result in noteworthy associations with risk of various cancers lends support to the theory that these two variants, in particular GSTM1 are functional and truly impact cancer risk. [21] GSTP1 codon 105 was the commonly studied form of polymorphism. [22] Most of the studies had reported that GSTT1 null genotype to be commonly associated with oral cancer in India. [19]


N-acetyltransferases 1 and 2 (NAT1 and NAT2) are important enzymes for metabolism of tobacco carcinogens. The activity of the enzyme is affected due to the polymorphisms leading to DNA adduct formation leading to increased risk of precancer and cancer. [23] NAT1 and NAT2, are responsible for both O-acetylation (activation) and N-acetylation (usually detoxification) of aromatic and heterocyclic amine carcinogens in humans. In a study, it was stated that NAT2 acetylation status were not associated with increased risk of leukoplakia and cancer and that combination of NAT2 acetylation status and other genetic factors, such as DNA repair loci, may be involved in disease susceptibility. [14] The same author in another study stated that NAT1 and/or NAT2 phenotypes did not enhance the risk of oral cancer and leukoplakia either alone or in combination and concluded that sample size to be the limitation of their study. [23]

  Aldehyde Dehydrogenase 2 Top

Aldehyde dehydrogenase 2 (ALDH2) is a key gene in alcohol metabolism, and determines blood acetaldehyde concentrations after drinking. Ethanol is oxidized to acetaldehyde and then to acetate by alcohol dehydrogenase (ADH) and ALDH, both of which have genetic polymorphism. [24] Individuals with inactive ALDH2 are incapable of rapidly eliminating acetaldehyde after drinking ethanol, and the carcinogenicity of acetaldehyde. [25] Acetaldehyde has been found to interact covalently with DNA to form DNA adducts in humans, and DNA adduct levels have been reported to be much higher in alcoholics than in nonalcoholics. [26] One of the commonly studied gene, is the ADH1B Arg48 HIS gene, SNP rs. 3813867. [27]

  X-Ray Cross Complementing -1 Top

Genome integrity is maintained by an intricate network of DNA repair proteins. Organisms have developed several DNA-repair pathways as well as DNA-damage checkpoints. [28] Defects in this complex machinery are associated with genotoxic susceptibility and familial predispositions to cancer. [29] X-ray cross complementing-1 (XRCC1) participates in DNA single strand break and base excision repair (BER) to protect genome stability in mammalian cells. [30] One of the common polymorphisms of XRCC1 the Arg399Gln is located in the BRCT1 domain responsible for interacting with other repair components of BER. Protective effects of XRCC1 polymorphisms in cancer may also be observed by the enhanced efficiency of apoptosis at a cellular level as a result of diminished DNA repair capacity secondary to the genetic polymorphisms. [25],[29],[31]

[TAG:2]Tumor Necrosis Factor -α[/TAG:2]

Numerous studies have been conducted regarding association between tumor necrosis factor (TNF)-α and oral cancer risk, but the results remain controversial. A study showed that Allele G and the GG+GA genotype of TNF-α-308G>A may decrease the risk of oral cancer, while allele G and the GG genotype of TNF-α-238G>A may cause an increase. [32] Extensive research has indicated that functional polymorphisms affecting gene expression of TNF-α are strongly associated with increased risk for oral cancer. [33]

  Matrix Metalloproteinase Top

The matrix metalloproteinase (MMPs) group is represented by more than 20 human enzymes, which requires the presence of zinc to realize their functions. The main MMP classes are: Collagenases, gelatinases, stromelysins, and the membrane-type MMPs. The MMP-1 gene is located on chromosome 11q22 and the level of expression of this gene can be influenced by SNPs in the promoter region of their respective genes. In a study, it has been told that a SNP at −1607 bp in the MMP-1 promoter contributes to increased transcription and cells expressing the 2 G polymorphism may provide a mechanism for more aggressive matrix degradation, thereby facilitating cancer progression. [34] Genotyping MMPs as potential markers for susceptibility to oral cancer might allow a precise and early identification of individuals at high risk. In recent times, several DNA polymorphisms are found in the promoter region of various MMPs. [35]


The tumor suppressor gene p53 is crucial for host defense against genomic mutations that might cause many types of tumors. Cellular insults or DNA damage causes increased expression of p53 leading to cell cycle arrest. The function of p53 is disrupted in case of cancer. SNP at codon 72 in exon four of the p53 gene, which results in the substitution of arginine (Arg) by proline (Pro) in the transactivating domain is the commonly studied polymorphism in oral cancer. The structure and function of the p53 protein are altered because of these polymorphic variants. This cause lower apoptotic potential and increased susceptibility of cancer. [36]

  Conclusion Top

Our review supports the concept that the polymorphism of xenobiotic-metabolizing enzymes such as glutathione S-transferase of cytochrome P450 enzymes, DNA repair genes, inflammatory cytokines and their environmental interaction may be associated with oral and pharyngeal cancer. Thus by knowing the various genotypes and the haplotypes the individuals, who are more vulnerable to the disease can be grouped into respective haplogroups and specific treatment can be started or prevention measures can be taken at the earliest by referring to the data available in the genebanks.

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Single Nucleotid...
Tandem Repeats
Short Tandem Rep...
Variable Number ...
Commonly Studied...
Phase I Enzyme
Phase II Enzymes
Aldehyde Dehydro...
X-Ray Cross Comp...
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Matrix Metallopr...
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