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Effect of Arg399Gln single-nucleotide polymorphism in XRCC1 gene on survival rate of Indian squamous cell head-and-neck cancer patients


1 Department of Radiation Oncology, Amrita Institute of Medical Science, Kochi; School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
2 School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
3 Department of Head and Neck Surgery, Apollo Cancer Hospital, Chennai, India

Correspondence Address:
Moorthy Anbalagan,
School of Biosciences and Technology, Vellore Institute of Technology, Vellore - 632 014, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_476_18

 > Abstract 


Background: Head-and-neck squamous cell carcinoma (HNSCC) is one of the most common cancers that contribute to 20%–40% of all cancer incidences in India. Indian patients with HNSCC are mostly associated with tobacco usage and may have different genetic alterations compared with Western patients who are mostly associated with human papillomavirus infection. Polymorphisms in DNA repair genes are correlated to individuals' susceptibility and progression of cancer. XRCC1 is a DNA repair enzyme.
Materials and Methods: In the present prospective study, Indian population of HNSCC patients (n = 45) were screened for Arg399Gln variant of XRCC1 using polymerase chain reaction-restriction fragment length polymorphism technique, prospective evaluation of the patients was done after treatment, and the single-nucleotide polymorphism results were correlated to survival functions.
Results: Out of 45 patients, 28 patients were Arg/Arg, 12 patients were Arg/Gln, and 5 patients were Gln/Gln. Overall survival for the entire cohort and Arg/Arg, Arg/Gln, and Gln/Gln cohort was 36.3 (95% confidence interval [CI]: 33–39.5), 38.6 (95% CI: 35.3–41.9), 35.8 (95% CI: 28.6–42.9), and 26.4 (95% CI: 13.7–39.1) months (P = 0.097), respectively. Progression-free survival (PFS) of the entire patient cohort and Arg/Arg, Arg/Gln, and Gln/Gln cohort was 35.2 (95% CI: 31.4–39.1), 38.2 (95% CI: 34.3–42.1), 32.7 (95% CI: 26.2–39.1), and 22.3 (95% CI: 9.4–35.3) (P = 0.061), respectively.
Conclusions: This study suggests that HNSCC patients with Gln substitution in place of Arg at position 399 (both homozygous and heterozygous) in XRCC1 protein have significantly inferior survival functions, higher recurrence rate, and events after radical treatment.

Keywords: Arg399Gln, head-and-neck squamous cell carcinoma, Indian patients, survival correlation, XRCC1



How to cite this URL:
Dutta D, Abarna R, Shubham M, Subbiah K, Duraisamy S, Chinnusamy R, Anbalagan M. Effect of Arg399Gln single-nucleotide polymorphism in XRCC1 gene on survival rate of Indian squamous cell head-and-neck cancer patients. J Can Res Ther [Epub ahead of print] [cited 2019 Sep 15]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=264698




 > Introduction Top


Cancer is one of the most common causes of death in developing countries.[1] Based on GLOBOCAN 2012 analysis, there is a prediction that about 57% of people are diagnosed with cancer, 65% of the patients had cancer-related death, and 48% of the cancer patients for the past 5 years were diagnosed in less-developed region.[2] Survival rates are poorer in economically challenged population as the patients in advanced stage do not receive adequate treatment.[3] Head-and-neck squamous cell carcinoma (HNSCC) is the sixth common cancer in the world [4] and seen commonly in Indian male tobacco users. HNSCC is mostly caused due to tobacco usage in Indian population, whereas in the Western population, human papillomavirus (HPV) infection is the major cause of HNC.[5] Prolonged tobacco usage leads to somatic mutations in the genome which is considered to be one of the main causes of cancer.

High-precision radiation therapy with intensity-modulated radiation therapy (IMRT) has shown to reduce toxicity vis-a-vis three-dimensional conventional radiation therapy (3DCRT) but has not shown to improve survival functions. A prospective randomized study in Indian patient population comparing 3DCRT and IMRT in locally advanced head-and-neck cancer has not shown any difference in survival outcome. Even after treatment with IMRT, only 60%–70% of the patients had long-term control (5-year survival).[6] However, conventional RT causes more toxicity, mostly in mucosal- and dysphagia-related parameters.[7],[8] Outcome after treatment not only depends on the stage of the disease and treatment received but also on various other relatively nonspecific parameters such as “depth of invasion,” thickness of the tumor, age of the patient, tobacco usage history, duration of disease, and many other similar factors. There is a need to identify specific prognostic molecular markers that will predict survival outcome in a given stage of disease.

Single-nucleotide polymorphisms (SNPs) in the human genome form the basis for differences in cause, susceptibility/resistance to diseases, response to treatment among individuals, and many more.[9] Single-nucleotide changes in the coding region of a gene produce a variant form of protein which may function in a different way compared to its wild-type counterpart. Thus, SNPs in DNA repair enzyme-encoding genes and cancer are highly related, and several studies are carried out in relating SNPs of various DNA repair enzymes to cause, response to treatment, and disease progression of cancer. Out of five different DNA repair pathways that exist in a cell, base excision repair (BER) pathway repairs the small base lesions that are caused due to deamination, methylation, and oxidation. The main genes involved in these pathways are Ape1, XRCC1, and OGG1. This pathway repairs the single-strand breaks (SSBs) in DNA that were caused by either alkylating agents or ROS exposure, and also, it includes base oxidation repair. The first step of the BER pathway is to discharge the damaged base with the help of DNA glycosylases, then the sugar-phosphate chains are cleaved by apurinic/apyrimidinic endonuclease (APE1), and the AP site is formed, followed by synthesis of DNA (by DNA polβ/XRCC1) with appropriate nucleotide, and finally comes the process of ligation.[10]

XRCC1 acts as a scaffolding protein with multiple DNA repair enzymes, which allows these enzymes to carry out the enzymatic steps in repairing the damaged DNA. XRCC1 gene is located on the 19th chromosome (19q13.2), and it consists of 17 exons, which encodes 633 amino acid protein and has molecular weight of 70 kDa.[11] The three common SNPs reported in XRCC1 are present at amino acid 194 (Arg > Trp), 280 (Arg > His), and 399 (Arg > Gln). Codon 194 and 280 are situated in the first linker between polβ-binding N-terminal domain and BRCT, and the codon 399 is present in PAR-binding motif on the BRCT surface; hence, role of XRCC1 with Arg399Gln SNP is of interest. HNSCC patients of Indian origin were screened for Arg399Gln SNP in XRCC1 gene by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

To establish a link between Arg399Gln variants of XRCC1 with HNSCC patient survival, patients' SNP status of XRCC1 was correlated to their disease progression, response to treatment, and survival rate.


 > Materials and Methods Top


Fresh tumor samples were collected from 45 head-and-neck cancer patients (n = 45), treated with curative intent during the period of April 2014 to October 2016. The study was conducted after obtaining the Institutional Human Ethical Committee (IECH No: IECH/2013/Dec 18-006) approvals and informed consent from patients. The objective of the study was to screen for SNPs for various genes of which results pertaining to Arg399Gln variant of XRCC1 gene are reported here. Using the genomic DNA isolated from patients, specific primers were used to PCR amplification of exon 10 of XRCC1 where codon 399 is present. Arg399Gln variant was screened by PCR-based RFLP in order to correlate these SNPs with disease progression, response to treatment, and survival functions (prognostication).

Inclusion criteria were nonnasopharyngeal head-and-neck cancer (oral cavity, oropharyngeal, and laryngeal cancers), biopsy-proven squamous cell carcinoma, and patients undergoing radical-intent treatment with either surgery or radical radiation therapy; patients with potentially curable disease (Stage I–IVA) were also included in the study. Patients with thyroid cancer or nasopharyngeal cancer, metastatic disease, history of previous malignancies, or pretreated with radiation or chemotherapy, patients with poor performance status (KPS <70), and individuals who not willing for radical treatment or follow-up were excluded in this study.

Sample collection

Tumor samples were surgically removed from patients at Apollo Speciality Cancer Hospital, Chennai, India, and transferred to 1.5-ml microfuge tube containing 1 ml of TNES buffer (10-mM Tris, pH 7.5, 400-mM NaCl, 100-mM ethylenediaminetetraacetic acid, and 0.6% Sodium Dodecyl Sulfate (SDS) [600 μl]) and transported in dry ice container to Vellore Institute of Technology, Vellore, India.

DNA extraction

Genomic DNA was extracted from tumor samples by high salt method. The samples were incubated with proteinase K (20 mg/ml) in 1 ml of TNES buffer at 55°C overnight with shaking. At the end of incubation period, 166.7 μl of 6M NaCl was added, vortexed, and centrifuged at 12,000 RPM for 10 min at room temperature. The supernatant was transferred to a freshly labeled tube, and DNA was precipitated by adding an equal volume of ice-cold 100% ethanol. The DNA was pelleted by centrifugation at 12,000 RPM for 5 min at 4°C. The DNA pellet was washed with 70% ethanol and allowed to air dry, and the pellet was dissolved in TE buffer (200 μl). The integrity of genomic DNA was tested on a 0.8% agarose gel. The quantity of the DNA was calculated by measuring absorbance at 260 nm.

Genotyping

PCR-based RFLP was used to identify SNP in XRCC1 gene as reported earlier.[12] The primers used for amplification of XRCC1 to detect SNP at codon 399 are mentioned in [Table 1]. PCR was performed in a volume of 20 μl containing ×10 buffer, 10-mM dNTP, 10p mol of each primer, 1 U of Taq polymerase (TAKARA), and 50 ng of genomic DNA. The PCR conditions were as follows: initial denaturation at 95°C for 5 min followed by 30 cycles of denaturation at 95°C for 40 s, annealing at 56°C for 30 s and then extension at 72°C for 30 s, and final elongation at 72°C for 10 min. The PCR products were separated on 2% agarose gel. PCR product obtained using each patient's template DNA was digested at 37°C with restriction enzyme MspI (20 units) for 2 h to analyze SNPs in codon 399.
Table 1: Primers used for amplification of exon 10 in XRCC1 gene

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Statistical analysis

Patient demographics, follow-up, and mutation data were collected prospectively and analyzed using SPSS 20 statistical software. Survival analysis was done with Kaplan–Meier survival analysis, and patient-related factors were analyzed with nonparametric unpaired t-test, Wilcoxon rank – sum test, and ANOVA test.


 > Results Top


Using PCR primers, exon 10 of XRCC1 was amplified, and the DNA product was separated on a 2% agarose gel. A representative image with six of the samples' PCR products is shown in [Figure 1], where a 615-bp DNA can be seen. The PCR products were incubated with MspI restriction enzymes, and the restriction-digested products were separated on a 2% gel. As explained in [Figure 2], PCR product obtained from patients with Arg/Arg genotype will have a restriction site for Msp I enzyme, and hence, 615-bp DNA is cleaved by the enzyme to produce 375-bp and 240-bp products. PCR products obtained from patients with Gln/Gln genotype will not have restriction site for the enzyme thus the 615-bp product. PCR products obtained from patients with Arg/Gln genotype will have all three bands. Thus, the PCR-RFLP obtained from patients with three different genotypes was shown in [Figure 3]. Using this strategy, all the 45 samples were screened for XRCC1 Arg399Gln SNP, as shown in [Figure 4]. Out of 45 samples, 28 patients were Arg/Arg genotype, 12 patients were Arg/Gln genotype, and 5 patients were with Gln/Gln. Demographic data of patients with different XRCC1 SNPs are described in [Table 2].
Figure 1: Electrophoresis of exon 10 of XRCC1 gene after polymerase chain reaction

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Figure 2: Restriction strategies for MspI to cut XRCC1 at 399th position for wild type and mutant

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Figure 3: Electrophoresis of XRCC1 gene after digestion with MspI for detecting Arg399Gln SNP where 1 represents Arg/Arg; 2, 4, and 5 represents Arg/Gln; and 3 represents Gln/Gln

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Figure 4: Electrophoresis of XRCC1 Arg399Gln after digestion with MspI for all 45 patients

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Table 2: Demographic profile and survival function of patients with XRCC1 gene Arg399Gln mutation analysis

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Kaplan–Meier survival curve was used to calculate patients' mean overall survival (OS) and estimated OS. Each patient's survival functions were calculated from the date of biopsy to the last date of follow-up, date of progression, or death. The mean OS for the entire cohort and Arg/Arg, Arg/Gln, and Gln/Gln cohort was 24.9, 24.8, 25.9, and 23.1 [Table 3] (P = 0.097), respectively, and estimated OS for the entire cohort and Arg/Arg, Arg/Gln, and Gln/Gln cohort was 36.3 (95% confidence interval [CI]: 33–39.5), 38.6 (95% CI: 35.3–41.9), 35.8 (95% CI: 28.6–42.9), and 26.4 (95% CI: 13.7–39.1) (P = 0.097) [Figure 5], respectively. In the patient cohort, 10/45 (22%) had expired during the follow-up. Among the expired patients, 4 out of 28 (14%) were Arg/Arg, 3 out of 12 (25%) were Arg/Gln, and 3 out of 5 (60%) were Gln/Gln (P = 0.035). Patient-related factors (age, gender, site of disease, stage, and tobacco usage) were compared among the three groups considered for the study, and there were no significant differences among the different genotypes. In the same cohort, mean progression-free survival for entire cohort and Arg/Arg, Arg/Gln, and Gln/Gln cohort was 23.7, 23.9, 25.2, and 19.1 months [Table 3] (P = 0.061), respectively. The estimated progression-free survival for entire cohort and Arg/Arg, Arg/Gln, and Gln/Gln cohort was 35.2 (95% CI: 31.4–39.1), 38.2 (95% CI: 34.3–42.1), 32.7 (95% CI: 26.2–39.1), and 22.3 (95% CI: 9.4–35.3) [Figure 6], respectively. In the patient cohort, 34/45 (73%) was alive with controlled disease, 2 (10%) were alive with disease, and 10 (20%) patients had expired at last follow-up evaluation.
Table 3: Outcome of patients with XRCC1 Arg399Gln in wild-type (Arg/Arg), heterozygous (Arg/Gln), and homozygous (Gln/Gln) mutations

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Figure 5: Kaplan–Meier survival curve with overall survival function with XRCC1 Arg399Gln mutation

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Figure 6: Kaplan–Meier Survival curve with progression-free survival function with XRCC1 Arg399Gln mutation

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 > Discussion Top


Gene polymorphism is the basis for physiological differences among the individuals. An individual's susceptibility/resistance to disease, response to treatment, and all other physiological differences can be explained on the basis of gene polymorphism.[13] DNA repair enzymes are the caretakers of our genome and their function is very much essential and related to cause of cancer, disease progression, and response to treatment. With reference to cancer, function of DNA repair enzymes is like a double-edged sword where underfunction of DNA repair enzymes leads to cancer and hyperactivity of DNA repair enzymes makes difficult to treat cancer patients using DNA-damaging agents as therapeutic agents.[14] In this regard, polymorphism in DNA repair enzymes is of interest with reference to cancer.

XRCC1 is a DNA repair enzyme, and its involvement in DNA repair activity and its association with cancer are very well documented.[15] XRCC1 comprises three globular domains (N-terminal domain, C-terminal domain, and central domain) linked by two linker segments. DNA polymerase-β specifically binds with N-terminal domain; DNA ligase IIIα interacts with C-terminal (BRCT domain), and poly (ADP-ribose)-binding motif which is present in the central domain allows the recruitment of XRCC1 to polymeric ADP-ribose which forms on PARP1 and this PARP1 binds to SSBs. Three different SNPs in XRCC1 are reported across the globe such as Arg194Trp, Arg 280 His, Arg399Gln [Table 4].[5],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28] Out of these SNPs, Arg399Gln is of interest because the 399 amino acid is present in the BRCT domain which is known to interact with many other DNA repair enzymes.[29] There are only a few published data available linking HNSCC with XRCC1 Arg399Gln SNP, and also, there are not many reports available;, where Arg399Gln XRCC1 SNP data are correlated to patients' demographic data or survival functions.
Table 4: Literature on XRCC1 SNPs with their clinical implications

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In this study, 27% of patients were with Arg/Gln genotype and 11% of patients were Gln/Gln genotype; the prevalence was more or less similar to other reports as mentioned in [Table 5]. The homozygous Gln/Gln in the Western population was between 5% and 15%, whereas in our data, it is 11%. However, the main causative factor for HNSCC in the Western population is HPV and in our population is tobacco usage. However, there are no differences in the status of XRCC1 Arn399Gln SNP. Since the percentage of patients with Arg/Gln genotype is low, it can be assumed that Arg/Gln may not make individual susceptible for cancer. In clinical situations, SNPs show beneficial with expected favorable outcome from treatment or these SNPs may have detrimental effect on treatment outcome. To study the role of XRCC1 Arg399Gln SNP in disease progression and treatment of HNSCC patients, demographic data and follow-up and events were documented for all patients included in the study. Patients with Gln/Gln genotype had both poorer OS and progression-free survival compared with patients of Arg/Gln and Arg/Arg genotype. This data suggests that the treatment outcome was poorer in the patients with Gln/Gln genotype which is also reflected in number of events (Death in the cohort). In the entire cohort, 22% of the patients had event of which 14% were Arg/Arg, 25% were Arg/Gln, and 60% were Gln/Gln (P = 0.035).
Table 5: Prevalence* of XRCC1 Arg399Gln in Indian patient population and comparison with published literature

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With respect to recurrences of the disease, cohort with Gln/Gln had earlier recurrences compared with Arg/Arg. Three out of three patients (100%) (Gln/Gln) had recurrences in within 12 months, whereas 2/4 (50%) recurrences were observed in Arg/Arg after 12 months.

Although the role of XRCC1 in apoptosis of the cell is less known, hyperactivation or increased expression of DNA repair enzymes including XRCC1 results in decreased/inhibition of DNA damage agent-induced apoptosis.[30] Ionizing radiations while being used in the treatment of cancer to initiate apoptosis in localized tumors, hyperactivity, and high-level expression of DNA repair enzymes leads to decreased rate of apoptosis in the cell. Our observation reveals that patients with Gln/Gln genotype or Arg/Gln genotype with reference to XRCC1 gene have poorer mean survival, mean-estimated survival, higher events, and early progression of disease. This suggests that Gln/Gln variant of XRCC1 may be hyperactive in DNA repair activity due to which the ionizing radiation treatment does not work efficiently. More and more patients' data are needed to confirm this observation along with in vitro evidence to prove that Gln/Gln variant of XRCC1 is hyperactive.


 > Conclusions Top


In this study, observations of relatively large (n = 45) patient cohort from a prospective study with relatively long follow-up (mean follow-up: 21 months) are reported. The patient cohort is uniform; majority of the patients had oral cavity cancer, treated with radical surgery and radiation therapy from a single institute. There is a trend toward poorer outcome in XRCC1 Gln/Gln cohort, which signifies the prognostic implication of the SNP. However, due to small patient cohort, the statistical significance in survival function between the cohort groups were not reached. We could not differentiate the SNPs between genetic and somatic changes in genome as ethical clearances to collect additional normal tissue from the patients were not obtained.

Summary

XRCC1 SNPs in Indian patient population are comparable to the other published data. Patients with homozygous/heterozygous substitution of Arg399Gln in XRCC1 have significantly inferior survival functions, higher recurrence rate, and higher events (death) after radical treatment. Further studies are required to implicate XRCC1 Arg399Gln SNP in HNSCC to have prognostic significance.

Acknowledgment

The authors thank Vellore Institute of Technology, Vellore for providing “VIT SEED GRANT” for carrying out this research work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
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