Skip to main content

Advertisement

SpringerLink
Log in

The hMLH1 −93G>A Promoter Polymorphism is Associates with Outcomes in Oral Squamous Cell Carcinoma Patients

  • Head and Neck Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The aim of this study was to investigate the impact of hMLH1 polymorphisms on treatment outcomes in patients with oral squamous cell carcinoma (OSCC).

Methods

Genotypings were performed by direct DNA sequencing in peripheral blood leukocytes from 185 male OSCC patients. Patients received primary surgery with or without adjuvant radiotherapy. Two hMLH1 tag single nucleotide polymorphisms (SNPs)—rs1800734 (−93G>A in the promoter) and rs1540354 (in the third intron)—were chosen from the HapMap project. Overall survival (OS) and disease-free survival (DFS) were compared between different genotypes.

Results

The hMLH1 rs1800734 and rs1540354 polymorphisms were in weak linkage disequilibrium (r 2 = 0.456). OSCC patients with the rs1800734 AA genotype had a significantly poor prognosis in both OS and DFS. This SNP can also predict the outcomes of OSCC patients with postoperative adjuvant radiotherapy, especially in advanced stage; however, no significant differences in patient outcomes were found for the hMLH1 rs1540354 genotypes.

Conclusions

Our results demonstrate that the hMLH1 −93G>A SNP is found to be associated with patient outcomes in OSCC. This SNP can also predict their treatment outcome of radiotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Scully C, Bagan J. Oral squamous cell carcinoma: overview of current understanding of aetiopathogenesis and clinical implications. Oral Dis. 2009;15:388–399.

    Article  CAS  PubMed  Google Scholar 

  2. Department of Health, Executive Yuan, Taiwan, ROC. Cancer registry annual report in Taiwan area. Department of Health; 2012.

  3. Kademani D, Bell RB, Bagheri S, et al. Prognostic factors in intraoral squamous cell carcinoma: the influence of histologic grade. J Oral Maxillofac Surg. 2005;63:1599–1605.

    Article  PubMed  Google Scholar 

  4. da Silva SD, Ferlito A, Takes RP, et al. Advances and applications of oral cancer basic research. Oral Oncol. 2011;47:783–791.

    Article  PubMed  Google Scholar 

  5. Shah JP, Gil Z. Current concepts in management of oral cancer: surgery. Oral Oncol. 2009;45:394–401.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Scully C, Field JK, Tanzawa H. Genetic aberrations in oral or head and neck squamous cell carcinoma (SCCHN): 1. Carcinogen metabolism, DNA repair and cell cycle control. Oral Oncol. 2000;36:256–263.

    Article  CAS  PubMed  Google Scholar 

  7. Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol. 2006;7:335–346.

    Article  CAS  PubMed  Google Scholar 

  8. Hsieh P, Yamane K. DNA mismatch repair: molecular mechanism, cancer, and ageing. Mech Ageing Dev. 2008;129:391–407.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Imai K, Yamamoto H. Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis. 2008;29:673–680.

    Article  CAS  PubMed  Google Scholar 

  10. Kanaya T, Kyo S, Maida Y, et al. Frequent hypermethylation of MLH1 promoter in normal endometrium of patients with endometrial cancers. Oncogene. 2003;22:2352–2360.

    Article  CAS  PubMed  Google Scholar 

  11. Murata H, Khattar NH, Kang Y, Gu L, Li GM. Genetic and epigenetic modification of mismatch repair genes hMSH2 and hMLH1 in sporadic breast cancer with microsatellite instability. Oncogene. 2002;21:5696–5703.

    Article  CAS  PubMed  Google Scholar 

  12. Raevaara TE, Korhonen MK, Lohi H, et al. Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Gastroenterology. 2005;129:537–549.

    CAS  PubMed  Google Scholar 

  13. Bannister LA, Waldman BC, Waldman AS. Modulation of error-prone double-strand break repair in mammalian chromosomes by DNA mismatch repair protein Mlh1. DNA Repair (Amst). 2004;3:465–474.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang Y, Rohde LH, Emami K, et al. Suppressed expression of non-DSB repair genes inhibits gamma-radiation-induced cytogenetic repair and cell cycle arrest. DNA Repair (Amst). 2008;7:1835–1845.

    Article  CAS  PubMed  Google Scholar 

  15. Yan T, Seo Y, Kinsella TJ. Differential cellular responses to prolonged LDR-IR in MLH1-proficient and MLH1-deficient colorectal cancer HCT116 cells. Clin Cancer Res. 2009;15:6912–6920.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Lipkin SM, Rozek LS, Rennert G, et al. The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Nat Genet. 2004;36:694–699.

    Article  CAS  PubMed  Google Scholar 

  17. Allan JM, Shorto J, Adlard J, et al. MLH1 −93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer. Int J Cancer. 2008;123:2456–2459.

    Article  CAS  PubMed  Google Scholar 

  18. Mrkonjic M, Roslin NM, Greenwood CM, et al. Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. PLoS One. 2010;5(10):e13314.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Chen H, Taylor NP, Sotamaa KM, et al. Evidence for heritable predisposition to epigenetic silencing of MLH1. Int J Cancer. 2007;120:1684–1688.

    Article  CAS  PubMed  Google Scholar 

  20. Samowitz WS, Curtin K, Wolff RK, et al. The MLH1 −93G>A promoter polymorphism and genetic and epigenetic alterations in colon cancer. Genes Chromosomes Cancer. 2008;47:835–844.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Shih CM, Chen CY, Lee IH, Kao WT, Wang YC. A polymorphism in the hMLH1 gene (−93G>A) associated with lung cancer susceptibility and prognosis. Int J Mol Med. 2010;25:165–170.

    CAS  PubMed  Google Scholar 

  22. Edge SB, American joint committee on cancer. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.

    Google Scholar 

  23. Anneroth G, Batsakis J, Luna M. Review of the literature and a recommended system of malignancy grading in oral squamous cell carcinomas. Scand J Dent Res. 1987;95:229–249.

    CAS  PubMed  Google Scholar 

  24. Huang SH, Chang PY, Liu CJ, Lin MW, Hsia KT. O6-methylguanine-DNA methyltransferase gene coding region polymorphisms and oral cancer risk. J Oral Pathol Med. 2010;39:645–650.

    Article  CAS  PubMed  Google Scholar 

  25. Zhao JH. 2LD, GENECOUNTING and HAP: Computer programs for linkage disequilibrium analysis. Bioinformatics. 2004;20:1325–1326.

    Article  CAS  PubMed  Google Scholar 

  26. Raptis S, Mrkonjic M, Green RC, et al. MLH1 −93G>A promoter polymorphism and the risk of microsatellite-unstable colorectal cancer. J Natl Cancer Inst. 2007;99:463–474.

    Article  CAS  PubMed  Google Scholar 

  27. Whiffin N, Broderick P, Lubbe SJ, et al. MLH1−93G>A is a risk factor for MSI colorectal cancer. Carcinogenesis. 2011;32:1157–1161.

    Article  CAS  PubMed  Google Scholar 

  28. Czerninski R, Krichevsky S, Ashhab Y, Gazit D, Patel V, Ben-Yehuda D. Promoter hypermethylation of mismatch repair genes, hMLH1 and hMSH2 in oral squamous cell carcinoma. Oral Dis. 2009;15:206–213.

    Article  CAS  PubMed  Google Scholar 

  29. Gonzalez-Ramirez I, Ramirez-Amador V, Irigoyen-Camacho ME, et al. hMLH1 promoter methylation is an early event in oral cancer. Oral Oncol. 2011;47:22–26.

    Article  CAS  PubMed  Google Scholar 

  30. Arita M, Zhong X, Min Z, Hemmi H, Shimatake H. Multiple sites required for expression in 5′-flanking region of the hMLH1 gene. Gene. 2003;306:57–65.

    Article  CAS  PubMed  Google Scholar 

  31. Mei M, Liu D, Dong S, Ingvarsson S, Goodfellow PJ, Chen H. The MLH1 −93G promoter variant influences gene expression. Cancer Epidemiol. 2010;34:93–95.

    Article  CAS  PubMed  Google Scholar 

  32. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–316.

    Article  PubMed  Google Scholar 

  33. Sanguansin S, Petmitr S, Punyarit P, Vorasubin V, Weerapradist W, Surarit R. HMSH2 gene alterations associated with recurrence of oral squamous cell carcinoma. J Exp Clin Cancer Res. 2006;25:251–257.

    CAS  PubMed  Google Scholar 

  34. Lo YL, Hsiao CF, Jou YS, et al. Polymorphisms of MLH1 and MSH2 genes and the risk of lung cancer among never smokers. Lung Cancer. 2010;72:280–286.

    Article  PubMed  Google Scholar 

  35. Park SH, Lee GY, Jeon HS, et al. −93G>A polymorphism of hMLH1 and risk of primary lung cancer. Int J Cancer. 2004;112:678–682.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This study was supported by grants from the National Science Council NSC 99-2314-B-010-044-MY3, Aim for Top University plan from the Department of Education, Taiwan, and Department of Health, Taipei City Government 96001-62-015.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan

    Li-Han Lin MS, Ming-Fang Cheng MD & Kan-Tai Hsia DDS, PhD

  2. Institute of Public Health, National Yang-Ming University, Taipei, Taiwan

    Ming-Wei Lin PhD

  3. Department of Dentistry, Zhongxiao Branch, Taipei City Hospital, Taipei, Taiwan

    Kwei Mar DDS

  4. Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Chun-Shu Lin MD

  5. Department of Tropical Medicine, National Yang-Ming University, Taipei, Taiwan

    Dar-Der Ji PhD

  6. Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

    Wei-Ping Lee MD, PhD

  7. Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Wei-Ping Lee MD, PhD

  8. Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Herng-Sheng Lee MD, PhD & Ming-Fang Cheng MD

  9. Division of Laboratory Medicine, Hualien Armed Forces General Hospital, Hualien, Taiwan

    Ming-Fang Cheng MD

Authors
  1. Li-Han Lin MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ming-Wei Lin PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kwei Mar DDS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun-Shu Lin MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dar-Der Ji PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei-Ping Lee MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Herng-Sheng Lee MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ming-Fang Cheng MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kan-Tai Hsia DDS, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kan-Tai Hsia DDS, PhD.

Additional information

Li-Han Lin and Ming-Wei Lin contributed equally to this work.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, LH., Lin, MW., Mar, K. et al. The hMLH1 −93G>A Promoter Polymorphism is Associates with Outcomes in Oral Squamous Cell Carcinoma Patients. Ann Surg Oncol 21, 4270–4277 (2014). https://doi.org/10.1245/s10434-014-3897-x

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-014-3897-x

Keywords

Search

Navigation