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  • br XPC gene polymorphisms in relation to different

    2020-07-08


    3.5. XPC gene polymorphisms in relation to different clinical parameters of patients with oral cancer
    Distribution of genotypes for different XPC polymorphisms among different disease categories are listed in Table 7. Frequency of patients with variant allele genotypes (D/I + I/I) for XPC intron 9 PAT poly-morphism were higher (63%) among high stage (stage III + IV) diseases compared to low stage disease (sate I + II; 16%). Similarly, risk of being diagnosed with larger size tumor were significantly higher (OR = 3.5; Table 7) with D/I + I/I genotypes than D/D genotypes. Compared to D/ D genotypes, patients with D/I + I/I genotypes were also found to harbour metastatic disease at the time of diagnosis. Rest of the
    Table 5
    Frequency distribution of different genotypes and Elafibranor (GFT505) of XPC PAT D > I, XPC C > T, XPC A > C polymorphisms among cases of Oral submucous fibrosis, Lichenplanus, Leukoplakia and healthy controls.
    Genotypes Oral submucous fibrosis P- value Lichenplanus P- value Leucoplakia P- value Controls
    XPC PAT D/IGenotypes Ref 34 Ref 42 Ref 138
    Significant association.
    Table 6
    Distribution of different haplotypes of XPC A > C, C > T & PAT D > I polymorphism in Oral diseases and controls.
    SNP1 SNP2 SNP3 Cases Controls p- value Odds ratio 95% CI
    Significant association.
    genotypes for XPC A > C and C > T polymorphisms did not show any association with any clinical parameters of oral cancer (Table 7).
    4. Discussion
    Premalignant oral lesions often lead to the development of oral cancer and prevention of oral lesion could therefore reduce the in-cidence of oral cancer. This indicates that identification of susceptibility markers such as SNP for pre malignant as well as malignant oral lesion will be helpful in proper management of oral diseases. SNPs of DNA repair genes, particularly of XPC have been previously reported to alter the risk of many different cancers. However, the association of XPC polymorphisms with oral cancer and especially with pre malignant oral lesions are not well explored. In the present study we analysed the association of XPC A > C (Lys939Gln, rs2228001), C > T (Ala499Val, rs2228000) and intron 9 PAT (D > I) polymorphisms with the risk for development of pre malignant oral lesions as well as oral cancer. 
    Compared to the D/D genotype, the PAT I/I homozygous subjects of intron 9 PAT (D > I) polymorphisms showed lower DNA Repair Capacity (DRC) and hence this polymorphism may modulate DRC and could be a useful biomarker for identifying individuals at risk of de-veloping cancer (Qiao et al., 2002a; Qiao et al., 2002b). This XPC-PAT polymorphism has also been reported to be in linkage disequilibrium with another single nucleotide polymorphism C > A located at the −5 position of the XPC intron 11 splice acceptor site (intron 11C/A poly-morphism) which has been reported to be associated with increased skipping of exon 12. The abnormally spliced XPC mRNA isoform has diminished DNA repair activity and may contribute to cancer suscept-ibility (Khan et al., 2002). The present study reports an association of XPC intron 9 PAT (D > I) polymorphism with the susceptibility of OSMF, Leukoplakia as well as oral cancer. In particular the hetero-zygote, i.e. the D/I genotype was found to lower the risk of above mentioned oral diseases. We have already reported similar association of D/I genotype with the risk of oral pre malignant lesions in a study
    Table 7
    Distribution of different genotypes of XPC A > C, C > T & PAT D > I polymorphism among different disease categories.
    XPC A>C, C>T & D/IGenotypes/Alleles
    P-value
    Odds
    Ratio
    XPC PAT D/I
    Ref 1
    XPC C>T
    Ref 1
    XPC A>C
    Ref 1
    Lymph Node
    XPC PAT D/Ins
    DD
    Ref
    DI+II
    XPC C>T
    CC
    Ref
    CT+TT
    XPC A>C
    AA
    AC+CC
    Metastasis
    XPC PAT D/Ins
    DD
    Ref
    DI+II
    XPC C>T
    CC
    Ref
    CT+TT
    XPC A>C
    AA
    AC+CC
    Tumor stage
    I+II
    XPC PAT D/I
    DD
    Ref
    DI+II
    6 (continued on next page)
    Table 7 (continued)
    XPC C>T
    XPC A>C
    Cell differentiated >Grade 1 Grade 1
    grade
    XPC PAT D/I
    XPC C>T
    XPC A>C
    Significant association.
    with smaller sample size (Tripathi et al., 2017) as well as with squa-mous cell carcinoma of head and neck (Yadav et al., 2018).The I allele of this XPC polymorphism is associated with reduced DNA repair ca-pacity and hence accumulation of DNA damage (Qiao et al., 2002c). It is possible that too much DNA damage induces the otherwise healthy cells to undergo apoptosis and hence prevents the development or oral diseases. However, once disease has been established, the same variant allele genotypes i.e. D/I + I/I of PAT (D > I) polymorphism are found to be associated with higher stage and metastatic oral cancer. Which probably might occur due to contribution of those damaged cells which have evaded apoptosis to the development of aggressive disease in a person where cancer has already initiated or established.