|Year : 2018 | Volume
| Issue : 3 | Page : 651-657
Modulation of risk of squamous cell carcinoma head and neck in North Indian population with polymorphisms in xeroderma pigmentosum complementation Group C gene
Suresh Kumar Yadav1, Sudhir Singh2, Shalini Gupta3, Madan Lal Brahma Bhatt2, Durga P Mishra4, D Roy5, Somali Sanyal1
1 Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Lucknow, Uttar Pradesh, India
2 Department of Radiotherapy, King George's Medical University, Lucknow, Uttar Pradesh, India
3 Department of Oral Pathology and Microbiology, King George's Medical University, Lucknow, Uttar Pradesh, India
4 Division of Endocrinology, Central Drug Research Institute, Lucknow, Uttar Pradesh, India
5 Department of Zoology, Shri Murli Manohar Town Post Graduate College, Ballia, Uttar Pradesh, India
|Date of Web Publication||12-Jun-2018|
Dr. Somali Sanyal
Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Lucknow - 226 028, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: Genetic variations in nucleotide excision repair genes can alter the risk of squamous cell carcinoma of head and neck (SCCHN).
Materials and Methods: The present study has genotyped 334 subjects from North Indian population for xeroderma pigmentosum complementation Group C (XPC) rs2228001A>C, XPC rs77907221 polyadenylate (PAT) deletion/insertion (D/I), xeroderma pigmentosum complementation Group D - rs13181A>C, and xeroderma pigmentosum complementation Type G rs17655 G>C polymorphisms with polymerase chain reaction (PCR)-restriction-fragment length polymorphism or allele-specific PCR methods.
Results: Compared to D allele, I allele for XPC PAT D/I polymorphism was associated with significantly decreased the risk of SCCHN (odds ratios = 0.67, 95% confidence interval [CI] =0.48–0.94, P = 0.03). Haplotype CI constituted from XPC polymorphisms was also associated with decreased risk of SCCHN (P = 0.004). In contrast, haplotype Crohn's disease significantly increased the risk for SCCHN (P < 0.00). A significant early onset of SCCHN was observed in individuals with CC genotype for XPC A>C polymorphism (P = 0.004).
Conclusion: Our results suggest a possible risk modulation for SCCHN with XPC polymorphisms in North Indian population.
Keywords: Polymorphisms, squamous cell carcinoma of head and neck, xeroderma pigmentosum complementation Group C, xeroderma pigmentosum complementation Group D, xeroderma pigmentosum complementation Group G
|How to cite this article:|
Yadav SK, Singh S, Gupta S, Brahma Bhatt ML, Mishra DP, Roy D, Sanyal S. Modulation of risk of squamous cell carcinoma head and neck in North Indian population with polymorphisms in xeroderma pigmentosum complementation Group C gene. J Can Res Ther 2018;14:651-7
|How to cite this URL:|
Yadav SK, Singh S, Gupta S, Brahma Bhatt ML, Mishra DP, Roy D, Sanyal S. Modulation of risk of squamous cell carcinoma head and neck in North Indian population with polymorphisms in xeroderma pigmentosum complementation Group C gene. J Can Res Ther [serial online] 2018 [cited 2020 Jul 8];14:651-7. Available from: http://www.cancerjournal.net/text.asp?2018/14/3/651/228637
| > Introduction|| |
Squamous cell carcinoma of head and neck (SCCHN) constitutes a major burden of cancer among North Indian subset of population. It develops from epithelial cells called squamous cells, found in outer layer of the skin and mucous membrane. SCCHN can take origin from various sites such as oral cavity, oropharynx, nasal cavity, paranasal sinuses, nasopharynx, larynx, and hypopharynx. It is the 7th most common cancer worldwide, with incidence >30/100,000 population in India. It commonly affects male in their fifth and sixth decade. Cigarette smoking, alcohol consumption, and nonbalanced diet are important risk factors in the Western countries while bidi smoking, chewing betel or areca nuts, and snuff are major risk factors in the Indian subcontinent. However, only a few smokers and alcoholics develop SCCHN, this may be due to differential susceptibility to disease in overall population. Smoking-induced DNA damages are repaired by DNA repair system, any error in repairing system can lead to carcinogenesis. Polymorphisms in DNA repair gene can alter the DNA repair efficiency, so that cells become more prone to develop cancer.
Nucleotide excision repair (NER) is one of the major DNA repair pathways, in repairing damage, induced by tobacco carcinogens. It eliminates various structurally unrelated DNA lesions by a stepwise “cut and patch”-type reaction. Variation in DNA repair capacity (DRC) has been reported in general population that have resulted from variation in NER gene. Several genes such as xeroderma pigmentosum complementation Group C (XPC), XPD, and XPG play central and critical role in NER and help to maintain genomic integrity.
The DNA binding domains of XPC interact with HR23B to form a complex that recognizes and binds to the sites of DNA damage. More than 100 polymorphic variants in the XPC gene have been reported. Two most common polymorphisms are Lys939Gln (XPC A>C, rs2228001) and a polyadenylate (PAT) deletion/insertion polymorphism (XPC PAT deletion/insertion [D/I], rs77907221) in intron 9. These have shown association with many human malignancies, including cancers of lung, bladder, breast, esophagus, skin, and head and neck.
The xeroderma pigmentosum complementation Group D (XPD) protein is a DNA helicase and is an essential part of the transcription factor II H (TFIIH) complex. Some studies have suggested that XPD polymorphisms may be associated with reduced DNA repair because of a possible reduction in helicase activity. A number of single nucleotide polymorphisms (SNPs) are reported in the XPD gene. However, only four SNPs, rs13181, rs1799793, rs238406, and rs1052555 with high heterozygosity frequency have been subjects of association. Among these, XPD A>C (rs13181) considered as “tagging SNP,” is mostly described till date. XPD A>C (rs13181) is predicted to result in a lysine-to-glutamine transition at position 751. This polymorphism may affect its interactions with different protein, diminish the activity of TFIIH complexes, and alter the genetic susceptibility for cancer.
The xeroderma pigmentosum Group G (XPG), one important component of the NER pathway, encodes a structure-specific endonuclease catalyzing 3' incision and involves the subsequent 5' incision by ERCC1-XPF heterodimer., Several SNPs in XPG gene have been identified and have been studied for their association with cancer risk.,,, Of these, the rs17655 G>C (Asp1104His) polymorphism is common and regarded as a tagger, which was most frequently investigated for its association with cancer risk.
Several studies have examined the individual association of XPC rs2228001A>C, XPC rs77907221 PAT D/I, XPD rs13181A>C, and XPG rs17655 G>C polymorphisms with different cancer risk. However, a comprehensive study on all the aforesaid polymorphisms with risk of SCCHN, especially on Indian population is lacking. In the present study, we hypothesized that these polymorphisms individually or in combination can modulate the risk of SCCHN in North Indian population.
| > Materials and Methods|| |
The subjects in this study belonged to North Indian population. The cases (167) were registered in tertiary care centers at Lucknow for the treatment of SCCHN. The mean age of patients in was 52.13 (range 28–92 years). Cancer-free healthy controls (167) were also selected from the same geographical area, ethnic background and approximately from similar age group as the cases. Other demographic and clinical data from cancer cases and controls are detailed in [Table 1]. The studies have been approved by the appropriate institutional and/or national research ethics committees and have been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants, included in this study.
The blood samples of healthy controls and clinically and histologically confirmed SCCHN patients were collected after taking their consent. The venous blood was drawn in ethylenediaminetetraacetic acid vials thoroughly mixed and kept at −20°C.
Genomic DNA isolation and its quantification
Genomic DNA was isolated from collected blood samples using GenElute Blood Genomic DNA Miniprep kit (Sigma Aldrich, USA) as per manufacturer's protocol. The isolated DNA was quantified using QUBIT 2.0 Fluorometer (Invitrogen, USA). The quality of DNA was further visualized on 0.8% agarose gel having 0.5 μg/ml ethidium bromide.
Genotyping for xeroderma pigmentosum complementation Group C rs77907221 polyadenylate deletion/insertion polymorphism
Genotyping for XPC rs77907221 PAT D/I polymorphism was performed by direct resolution of polymerase chain reaction (PCR) fragments on 2% agarose gel. PCR was carried out in 10 μl volume reactions containing 20 ng DNA, 20 mMTris-Hcl, 50 mM KCL, 2 mM MgCl2, 0.11 mM each DNTP, 0.3 μM each primer, and 0.5 U taq polymerase (Sigma Aldrich, USA). PCR primers used for genotyping are listed in [Table 2]. The lengths of PCR product for D and I allele were 249 and 327 bp, respectively [Figure 1]a.
|Table 2: Primers and restriction enzymes used for genotyping xeroderma pigmentosum complementation Group C, xeroderma pigmentosum complementation Group D and xeroderma pigmentosum Type G polymorphisms in squamous cell carcinoma of head and neck cases and controls|
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|Figure 1: Showing different genotypes of XPC rs77907221 PAT D/I (A), XPC rs 2228001 A>C (B), XPD rs13181 A>C (C.) and XPG rs17655 G>C (D) polymorphisms on 2% agarose gel. (a) Lane 1, 2, 4 represent I/I (327 bp), D/I (327 and 249 bp) and D/D (249 bp) genotypes respectively for XPC rs77907221 PAT D/I polymorphism. (b) Lane 3, 4, 5 represent AC (244 and 189 bp), CC (189bp) and AA (244bp) genotypes respectively for XPC rs 2228001 A>C polymorphism. (c) Lane 1, 2, 6 represent the CC (182), AC (182 and 245 bp bp)and AA (245 bp) genotypes respectively for XPD rs13181 A>C polymorphism. (d) Lane 1, 2, 3 represent GC (158, 99, 59 bp), CC (99, 59 bp) and GG (158 bp) genotypes respectively for XPG rs17655 G>C polymorphisms|
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Genotyping for xeroderma pigmentosum complementation Group C rs2228001A>C, xeroderma pigmentosum complementation Group D rs13181A>C, and XPG rs17655 G>C polymorphisms
PCR-restriction-fragment length polymorphism method was used for the determination of genotypes of XPC rs2228001A>C, XPD rs13181A>C, and XPG rs17655 G>C polymorphisms. PCR was carried out with similar reaction conditions as XPC PAT D/I polymorphism. PCR primers used are listed in [Table 2]. PCR products were digested for 5 h with appropriate restriction endonucleases from NEB, USA [Table 2] that recognize and cut either wild type or variant sequences at 37°C and analyzed on 2% agarose gel against 50 bp ladder [Figure 1]b, [Figure 1]c, [Figure 1]d. Most of the genotyping assays were carried out with samples of known genotype as a positive control. The genotype results were regularly checked and confirmed by direct DNA sequencing.
The statistical significance for deviations from Hardy–Weinberg Equilibrium was calculated using the Pearson Chi-square test. To determine the difference between the SCCHN cases and controls with respect to genotype distributions and allele frequencies Chi-square test (yates corrected) was used. It was also used to find out the difference in the distribution of genotype combinations between the cases and controls. Odds ratios (OR), 95% confidence interval (CI) and P values for the assessment of associated risk due to genotypes and variant allele of studied polymorphisms were calculated by Epi-Info programme (http://wwwn.cdc.gov/epiinfo/). The median, 5th and 95th percentiles were used to summarize the age at onset of SCCHN according to genotypes. Kruskal–Wallis tests were used to compare the genotype-specific distributions of age at onset. SNPStats (http://bioinfo.iconcologia.net/SNPstats) was employed to construct haplotypes. The extent of linkage disequilibrium (LD) was expressed in the maximum likelihood estimate of LD, D'.
| > Results|| |
Genotypes for nucleotide excision repair polymorphisms and the risk of cancer
Among the polymorphisms studied in three different genes of NER only the XPC rs77907221 PAT D/I polymorphism showed direct association with the risk of SCCHN. The frequency of I/I genotype was marginally higher in control than in SCCHN cases [Table 3]. The difference was even significant after adjustment of OR with age and sex (OR = 0.37, 95% CI = 0.15–0.930. Similarly, the frequency of I allele for XPC rs77907221 PAT D/I polymorphism was significantly higher in the control than in cases [Table 3]. The XPC rs2228001A>C polymorphism and polymorphisms of XPD and XPG did not show any individual association with the risk of SCCHN.
|Table 3: Distribution of genotypes and allele frequencies for different nucleotide excision repair gene polymorphisms in squamous cell carcinoma of head and neck cases and controls|
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Number of variant allele from studied nucleotide excision repair polymorphisms and risk of squamous cell carcinoma of head and neck
To check the effect of variant alleles from studied XPC, XPD, and XPG polymorphisms at different dose on the risk of SCCHN the study population was stratified as in [Table 4]. The risk of disease did not show any significant alterations with the decrease or increase of variant alleles in the genotypes. However, as we further dichotomized the population as carrier of 0–2 variant alleles and 3–6 variant alleles, individuals with higher number of variant allele (3–6) showed significant protection from SCCHN compared to individuals who were not carrying or carrying lesser number of variant alleles (0–2) [Table 4].
|Table 4: Number of variant allele in the combined genotypes from studied nucleotide excision repair polymorphisms and risk of squamous cell carcinoma of head and neck|
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Haplotypes of xeroderma pigmentosum complementation Group C rs2228001A>C and rs77907221 polyadenylate deletion/insertion polymorphism and the risk of squamous cell carcinoma of head and neck
Haplotyping of XPC rs2228001A>C and rs77907221 PAT D/I polymorphisms generated 4 different haplotypes as detailed in [Table 5]. The frequency of haplotype Crohn's disease (CD) was significantly higher in SCCHN cases (21.1%) compared to healthy controls (8.2%). This indicates a high risk of SCCHN with haplotype CD. In contrast, a significantly reduced risk of SCCHN was observed with haplotype CI which was more frequent in control (27.7%) than in cases (14.4%). The frequencies of other haplotypes were almost similar between cases and controls. Further, the above polymorphisms of XPC were not in significant LD (D' =0.587, r = 0.502).
|Table 5: Distribution of different haplotypes of xeroderma pigmentosum complementation Group C rs2228001A>C and xeroderma pigmentosum complementation Group C rs77907221 PAT deletion/insertion polymorphisms in squamous cell carcinoma of head and neck cases and controls|
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Age at onset with different genotypes of xeroderma pigmentosum complementation Group C, xeroderma pigmentosum complementation Group D, and xeroderma pigmentosum complementation Group G polymorphisms
SCCHN patients with CC genotype for XPC rs2228001A>C polymorphism showed early onset of disease than patients with AA genotypes. The difference in the age distribution was statistically significant (P = 0.004). No statistically significant difference in the age at onset was observed with the genotypes from XPC rs77907221 PAT D/I, XPD rs13181A>C, or XPG rs17655G>C polymorphisms [Table 6].
|Table 6: Effect of studied nucleotide excision repair polymorphisms on age of onset of squamous cell carcinoma of head and neck|
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Nucleotide excision repair gene polymorphisms in relation to different clinical parameters of squamous cell carcinoma of head and neck
Clinically, cancer patients were subdivided in high-risk and low-risk groups. The high-risk group has disease with III and IV stage, Grade >1, lymph node and metastasis positive and tumor T status >T3. Whereas, the low-risk group has disease with Stage I and II, Grade 1, they were lymph node and metastasis negative and tumor T status >T1 but < T3. Compared to the noncarrier individuals who were carrier of I allele for XPC rs77907221 PAT D/I polymorphisms were at a higher risk to develop tumors of large size. Similarly, they were also at a higher risk to develop metastatic disease compared to individuals who were not carrying I allele [Table 7].
|Table 7: Effect of studied NER polymorphisms on clinical parameters of SCCHN|
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| > Discussion|| |
Our results suggest that genotypes and haplotypes of XPC gene polymorphisms modulate the risk for development as well as clinical outcome of SCCHN in North Indian population. Individually studied polymorphisms in XPD and XPG did not show any association with the risk of SCCHN. However, in a combined analysis, we observed a reduced risk of SCCHN in individuals who were carrying high number of variant allele from the studied XPC, XPD, and XPG polymorphisms.
We observed that individuals carrying I allele for XPC rs77907221 PAT D/I polymorphism were at lower risk to develop SCCHN compared to individual with D allele. Similarly, individuals who were homozygotes for I allele were at lower risk to develop SCCHN compared to individuals who were homozygotes for D allele for the XPC rs77907221 PAT D/I polymorphism. A protective effect on the development of SCCHN was also observed with haplotype CI constituted from XPC rs2228001A>C and rs77907221PAT D/I polymorphisms. This protective effect with haplotype CI was possibly due to the presence of I allele from XPC rs77907221 PAT D/I polymorphisms. A similar protective association with I allele of XPC rs77907221 PAT D/I polymorphisms was also observed with nonmelanoma skin cancer. The PAT I allele is associated with reduced DRC  and therefore possibly responsible for accumulation of DNA damage in cells. It is plausible that individual with I allele has highly damaged cells which undergo damage-induced apoptosis which eventually prevent development of cancer in those individuals. Supporting our hypothesis Wang et al. showed an association of XPC with enhanced DNA damage-induced apoptosis in a p53 independent manner. Our hypothesis was further supported by our observation where we found a decrease in risk of SCCHN in individuals who were carrying high number (3–6) of variant alleles from XPC rs2228001A>C, XPC rs77907221 PAT D/I, XPD rs13181A>C, and XPG rs17655 G>C polymorphisms. In contrary, Shen et al. showed an increased risk for SCCHN with I allele for XPC rs77907221 PAT D/I polymorphism in non-Hispanic subjects. Similarly, I allele also showed association with high risk for prostate cancer  and lung cancer. Such contrast in finding could be due to difference in ethnicity and site of cancer.
Our results indicate that individuals who were homozygous for the C allele of XPC rs2228001A>C polymorphism develop SCCHN at an early age. Similarly, haplotype CD constructed from XPC rs2228001A>C and rs77907221PAT D/I polymorphisms showed association with high risk for the development of SCCHN. The XPC rs2228001A>C polymorphism has been previously reported to be associated with bladder cancer , and esophageal squamous cell carcinoma.
We have also demonstrated that although I allele for XPC rs2228001A>C polymorphism protect an individual to develop SCCHN but once contacted it pose a high threat to develop large-sized tumor and risk for metastasis.
Unlike previous reports,, we did not find any individual association of XPD rs13181A>C polymorphism with the risk of SCCHN. Similarly, we also noticed a lack of association of XPG rs17655 G>C polymorphism with the risk of SCCHN in North Indian population. A similar lack of association of XPG rs17655 G>C polymorphism with the risk of SCCHN been reported by Ma et al.
| > Conclusion|| |
This is the first study to report a risk modulation of SCCHN with XPC polymorphisms in the North Indian population. Carrier of variant allele for XPC rs77907221 PAT D/I polymorphism has decreased risk for developing SCCHN. Once disease onset, paradoxically, this same allele is associated with aggressive disease. Variant allele from XPC rs2228001A>C polymorphism enhanced the risk of development of SCCHN at an early age. XPD and XPG polymorphisms do not show any association with SCCHN. Although these findings need to be verified by other studies, it seems plausible that XPC polymorphisms can modulate the risk of SCCHN.
We are thankful to Prof. Rajesk K. Tiwari, Deputy Dean Academics, Amity University Uttar Pradesh, Lucknow Campus, Lucknow, Uttar Pradesh, India. We are also grateful to Dr. Sabyasachi Sanyal for helpful comments.
Financial support and sponsorship
The financial support for this work was provided by grant from SERB (SR/FT/LS-SC/2010).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]