Predictive value of genetic variants XRCC1 rs1799782, APEX1 rs1760944, and MUTYH rs3219489 for adjuvant concurrent chemoradiotherapy outcomes in oral squamous cell carcinoma patients

Abstract

Genetic variations in DNA base excision repair (BER) genes may affect tumor sensitivity to chemotherapy and radiotherapy. Thus, we investigated the effects of single-nucleotide polymorphisms (SNPs) in key BER pathway genes on clinical outcomes in male patients who received concurrent chemoradiotherapy (CCRT). Seven SNPs from XRCC1, OGG1, APEX1, and MUTYH were genotyped using the Sequenom iPLEX MassARRAY system in samples from 319 men with advanced oral squamous cell carcinoma. The disease-free survival (DFS) rates of the MUTYH rs3219489 genotypes and those of the other genotypes differed significantly (log-rank test p = 0.027). Multivariate Cox proportional hazard analysis showed that the MUTYH rs3219489 GG genotype was associated with poor DFS (recessive model: hazard ratio [HR] = 2.01, 95% confidence interval [CI] = 1.31–3.10; p = 0.002). The CT + TT genotypes of XRCC1 rs1799782 (dominant model: HR = 0.65, 95% CI = 0.43–0.99; p = 0.044) and GG genotype of APEX1 rs1760944 (recessive model: HR = 1.64, 95% CI = 1.00–2.70; p = 0.050) were associated with overall survival (OS). Carrying the two risk genotypes, CC and GG of XRCC1 rs1799782 and APEX1 rs1760944, respectively, (HR = 2.95, 95% CI = 1.47–5.88; p = 0.002) increased mortality risk. Our findings showed that carrying the two risk genotypes of XRCC1 rs1799782 and APEX1 rs1760944 was associated with poor OS, while the GG genotype of MUTYH rs3219489 was associated with poor DFS. Patients carrying the risk genotypes may not benefit from CCRT; therefore, they will need alternative treatments.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Kaplan–Meier survival analysis and log-rank test of overall survival and disease-free survival curves for XRCC1 rs25489, XRCC1 rs1799782, APEX1 rs1760944, and MUTYH rs3219489 single-nucleotide polymorphisms in oral squamous cell carcinoma patients treated with concurrent chemoradiotherapy.

References

  1. 1.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  2. 2.

    Chiang C-J, Lo W-C, Yang Y-W, You S-L, Chen C-J, Lai M-S. Incidence and survival of adult cancer patients in Taiwan, 2002–2012. J Formos Med Assoc. 2016;115:13.

    Google Scholar 

  3. 3.

    Huang C-C, Ou C-Y, Lee W-T, Hsiao J-R, Tsai S-T, Wang J-D. Life expectancy and expected years of life lost to oral cancer in Taiwan: a nation-wide analysis of 22,024 cases followed for 10 years. Oral Oncol. 2015;51:349–54.

    PubMed  Article  Google Scholar 

  4. 4.

    Chuang S-L, Su WW-Y, Chen SL-S, Yen AM-F, Wang C-P, Fann JC-Y, et al. Population-based screening program for reducing oral cancer mortality in 2,334,299 Taiwanese cigarette smokers and/or betel quid chewers. Cancer. 2017;123:1597–609.

    PubMed  Article  Google Scholar 

  5. 5.

    Tsai K-Y, Su C-C, Lin Y-Y, Chung J-A, Lian I-B. Quantification of betel quid chewing and cigarette smoking in oral cancer patients. Community Dent Oral Epidemiol. 2009;37:555–61.

    PubMed  Article  Google Scholar 

  6. 6.

    Güneri P, Epstein JB. Late stage diagnosis of oral cancer: components and possible solutions. Oral Oncol. 2014;50:1131–6.

    PubMed  Article  Google Scholar 

  7. 7.

    Ferris RL, Geiger JL, Trivedi S, Schmitt NC, Heron DE, Johnson JT, et al. Phase II trial of post-operative radiotherapy with concurrent cisplatin plus panitumumab in patients with high-risk, resected head and neck cancer. Ann Oncol. 2016;27:2257–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Adelstein D, Gillison ML, Pfister DG, Spencer S, Adkins D, Brizel DM, et al. NCCN guidelines insights: head and neck cancers, version 2.2017. J Natl Compr Canc Netw. 2017;15:761–70.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Chitapanarux I, Traisathit P, Komolmalai N, Chuachamsai S, Sittitrai P, Pattarasakulchai T, et al. Ten-year outcome of different treatment modalities for squamous cell carcinoma of oral cavity. Asian Pac J Cancer Prev. 2017;18:1919–24.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Zhang H, Dziegielewski PT, Biron VL, Szudek J, Al-Qahatani KH, O’Connell DA, et al. Survival outcomes of patients with advanced oral cavity squamous cell carcinoma treated with multimodal therapy: a multi-institutional analysis. J Otolaryngol Head Neck Surg. 2013;42:30.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Santosh A, Jones T, Harvey J. A review on oral cancer biomarkers: understanding the past and learning from the present. J Cancer Res Ther. 2016;12:486–92.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Taghavi N, Yazdi I. Prognostic factors of survival rate in oral squamous cell carcinoma: clinical, histologic, genetic and molecular concepts. Arch Iran Med. 2015;18:314–9.

    PubMed  Google Scholar 

  13. 13.

    Quintela-Fandino M, Hitt R, Medina PP, Gamarra S, Manso L, Cortes-Funes H, et al. DNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy. J Clin Oncol. 2006;24:4333–9.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Jadhav KB, Gupta N. Clinicopathological prognostic implicators of oral squamous cell carcinoma: need to understand and revise. N Am J Med Sci. 2013;5:671–9.

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Hornhardt S, Rossler U, Sauter W, Rosenberger A, Illig T, Bickeboller H, et al. Genetic factors in individual radiation sensitivity. DNA Repair. 2014;16:54–65.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Wallace SS. Base excision repair: a critical player in many games. DNA Repair. 2014;19:14–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Gavande NS, VanderVere-Carozza PS, Hinshaw HD, Jalal SI, Sears CR, Pawelczak KS, et al. DNA repair targeted therapy: the past or future of cancer treatment? Pharm Ther. 2016;160:65–83.

    CAS  Article  Google Scholar 

  18. 18.

    Visnes T, Grube M, Hanna BMF, Benitez-Buelga C, Cazares-Korner A, Helleday T. Targeting BER enzymes in cancer therapy. DNA Repair. 2018;71:118–26.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    López-Verdín S, Lavalle-Carrasco J, Carreón-Burciaga RG, Serafín-Higuera N, Molina-Frechero N, González-González R, et al. Molecular markers of anticancer drug resistance in head and neck squamous cell carcinoma: a literature review. Cancers. 2018;10:376.

    PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Hu JJ, Smith TR, Miller MS, Mohrenweiser HW, Golden A, Case LD. Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity. Carcinogenesis. 2001;22:917–22.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Shen MR, Jones IM, Mohrenweiser H. Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans. Cancer Res. 1998;58:604–8.

    CAS  PubMed  Google Scholar 

  22. 22.

    Li DJ, Xiao D. Association between the XRCC1 polymorphisms and clinical outcomes of advanced NSCLC treated with platinum-based chemotherapy: a meta-analysis based on the PRISMA statement. BMC Cancer. 2017;17:501.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Mahimkar MB, Samant TA, Kannan S, Tulsulkar J, Pai PS, Anantharaman D. Polymorphisms in GSTM1 and XPD genes predict clinical outcome in advanced oral cancer patients treated with postoperative radiotherapy. Mol Carcinog. 2012;51:E94–103.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Senghore T, Wang WC, Chien HT, Chen YX, Young CK, Huang SF, et al. Polymorphism of Mismatch Repair Pathway Genes Predict Clinical Outcomes in Oral Squamous Cell Carcenoma Patients receiving Ajuvant Concurrent Chemradiotherapy. Cancers. 2019;11:598.

    CAS  PubMed Central  Article  Google Scholar 

  25. 25.

    Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4.

    PubMed  Article  Google Scholar 

  26. 26.

    Wu Y-G, Li H-F, Ren Y-J, Zou D-B, Zhang K-N, Xiao X. The association of XRCC1 polymorphism with osteosarcoma risk, clinicopathologic features, and prognosis in a Chinese Han population. Cancer Manag Res. 2018;10:4959–67.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Thakur S, Sarkar B, Cholia RP, Gautam N, Dhiman M, Mantha AK. APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions. Exp Mol Med. 2014;46:e106.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Wang J, Guo C, Gong X, Ao F, Huang Y, Huang L, et al. The impacts of genetic polymorphisms in genes of base excision repair pathway on the efficacy and acute toxicities of (chemo)radiotherapy in patients with nasopharyngeal carcinoma. Oncotarget. 2017;8:78633–41.

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Costa EF, Santos ES, Liutti VT, Leal F, Santos VC, Rinck-Junior JA, et al. Association between polymorphisms in genes related to DNA base-excision repair with risk and prognosis of oropharyngeal squamous cell carcinoma. J Cancer Res Clin Oncol. 2016;142:1917–26.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Yen CY, Liu SY, Chen CH, Tseng HF, Chuang LY, Yang CH, et al. Combinational polymorphisms of four DNA repair genes XRCC1, XRCC2, XRCC3, and XRCC4 and their association with oral cancer in Taiwan. J Oral Pathol Med. 2008;37:271–7.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Senghore T, Chien HT, Wang WC, Chen YX, Young CK, Huang SF, et al. Polymorphisms in ERCC5 rs17655 and ERCC1 rs735482 Genes Associated with the Survival of Male Patients with Postoperative Oral Squamous Cell Carcenoma Treated with Adjuvant Concurrent Chemoradiotherapy. J Clin Med. 2019;8:33.

    CAS  PubMed Central  Article  Google Scholar 

  32. 32.

    Cui Z, Yin Z, Li X, Wu W, Guan P, Zhou B. Association between polymorphisms in XRCC1 gene and clinical outcomes of patients with lung cancer: a meta-analysis. BMC Cancer. 2012;12:71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Gu AQ, Wang WM, Chen WY, Shi CL, Lu JH, Han JQ. XRCC1 genetic polymorphisms and sensitivity to platinum-based drugs in non-small cell lung cancer: an update meta-analysis based on 4708 subjects. Int J Clin Exp Med. 2015;8:145–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Krokan HE, Bjørås M. Base excision repair. Cold Spring Harb Perspect Biol. 2013;5:a012583.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Hsia KT, Liu CJ, Mar K, Lin LH, Lin CS, Cheng MF, et al. Impact of apurinic/apyrimidinic endonuclease 1/redox factor-1 on treatment response and survival in oral squamous cell carcinoma. Head Neck. 2016;38:550–9.

    PubMed  Article  Google Scholar 

  36. 36.

    Koukourakis MI, Giatromanolaki A, Kakolyris S, Sivridis E, Georgoulias V, Funtzilas G, et al. Nuclear expression of human apurinic/apyrimidinic endonuclease (HAP1/Ref-1) in head-and-neck cancer is associated with resistance to chemoradiotherapy and poor outcome. Int J Radiat Oncol Biol Phys. 2001;50:27–36.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Xiao X, Yang Y, Ren Y, Zou D, Zhang K, Wu Y. rs1760944 polymorphism in the APE1 region is associated with risk and prognosis of osteosarcoma in the Chinese Han population. Scic Rep. 2017;7:9331.

    Article  CAS  Google Scholar 

  38. 38.

    Mazzei F, Viel A, Bignami M. Role of MUTYH in human cancer. Mutat Res. 2013;743-744:33–43.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Turco E, Ventura I, Minoprio A, Russo MT, Torreri P, Degan P, et al. Understanding the role of the Q338H MUTYH variant in oxidative damage repair. Nucleic Acids Res. 2013;41:4093–103.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Shinmura K, Goto M, Suzuki M, Tao H, Yamada H, Igarashi H, et al. Reduced expression of MUTYH with suppressive activity against mutations caused by 8-hydroxyguanine is a novel predictor of a poor prognosis in human gastric cancer. J Pathol. 2011;225:414–23.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Singh A, Singh N, Behera D, Sharma S. Genetic Investigation of Polymorphic OGG1 and MUTYH Genes Towards Increased Susceptibility in Lung Adenocarcinoma and its Impact on Overall Survival of Lung Cancer Patients Treated with Platinum Based Chemotherapy. Pathol Oncol Res. 2017;25:1327–40.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the study participants.

Funding

Support for this study was obtained from Ministry of Science and Technology, Taiwan (MOST107-2314-B-038-071, MOST108-2314-B-038-088, and MOST106-2314-B-182-025-MY3), Health and Welfare Surcharge on Tobacco Products (MOHW109-TDU-B-212-134016), and Chang Gung Memorial Hospital (CMRPG3H0793, CMRPG3J0591, CMRPG3J0592 and CMRPB53).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Shiang-Fu Huang or Chih-Ching Yeh.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Senghore, T., Chien, H., Wang, W. et al. Predictive value of genetic variants XRCC1 rs1799782, APEX1 rs1760944, and MUTYH rs3219489 for adjuvant concurrent chemoradiotherapy outcomes in oral squamous cell carcinoma patients. Pharmacogenomics J (2020). https://doi.org/10.1038/s41397-020-0170-5

Download citation

Search