Tumor Biology

, Volume 36, Issue 10, pp 7817–7830 | Cite as

Susceptibility to oral cancers with CD95 and CD95L promoter SNPs may vary with the site and gender

  • Sarika Daripally
  • Sateesh Reddy Nallapalle
  • Saritha Katta
  • Vidudala V. T. S. Prasad
Research Article


We investigated risk association of oral cancers (tongue and buccal mucosa cancers) with FAS (−1377G > A and FAS −670 A > G) and FASL (−844 T > C) SNPs, in males and females. A case–control study of 535 oral cancer and 525 control subjects was performed. SNPs were detected in the genomic DNA isolated from peripheral blood using PCR-RFLP. We report FASL −844 T > C SNPs increased risk for buccal mucosa cancer in females but not in males. On the other hand, FAS genotypes did not alter the risk of the cancers in both females and males. However, co-occurrence of FAS −1377 GA and −670 GG, FAS −1377 AA and −670 GG genotypes, and combined genotypes of FAS and FASL (FAS −1377 AA + FAS −670 GG + FASL −844 CC) alter male susceptibility towards tongue cancer. In females, combined genotypes of FAS (−1377GA and −670 AA) were found to be a risk factor of buccal mucosa cancer (OR = 3.27, CI = 1.28–8.36; P ≤ 0.01). FASL variants (GA and AA) increased tongue cancer risk in females who were tobacco users compared to non-tobacco users. In conclusion, SNPs of the FAS and FASL might alter risk of tongue and buccal mucosa cancers differentially, in a gender-dependent manner.


FAS FASL Oral cancer risk Tongue cancer Buccal mucosa cancer Promoter polymorphism 



The research was funded by a grant from Indian Council of Medical Research, New Delhi, India (to VVTSP. Grant No: 5/8/10-3(Oto)/CFP/11-NCD-1). Mr. Sateesh works for the ICMR grant. Mrs. Sarika is thankful to Council of Scientific and Industrial Research, Government of India for the award of Junior Research Fellow. We would also like to thank Acharya Nagarjuna University, Nagarjuna Nagar, AP, India for registering Mrs. Sarika for her doctoral degree. The authors also acknowledge the technical help provided by the Research Assistants of the R&D, BIACH, and RI.

Ethical approval

The Research work is approved by the Institutional Ethics Committee (Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad-500034, India) and got renewed recently. The IEC Number/2014/85. Informed consent was obtained from the subjects.

Conflicts of interest


Supplementary material

13277_2015_3516_MOESM1_ESM.docx (18 kb)
Supplementary Table 1 Co-occurrence of FAS and FASL polymorphisms (DOCX 18 kb)


  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefPubMedGoogle Scholar
  3. 3.
    Cavallo F, De Giovanni C, Nanni P, Forni G, Lollini PL. 2011: the immune hallmarks of cancer. Cancer Immunol Immunother. 2011;60:319–26.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Nagata S. FAS ligand and immune evasion. Nat Med. 1996;2:1306–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Robson M, Offit K. Clinical practice. Management of an inherited predisposition to breast cancer. N Engl J Med. 2007;357:154–62.CrossRefPubMedGoogle Scholar
  6. 6.
    Tan P. Divide and conquer: progress in the molecular stratification of cancer. Yonsei Med J. 2009;50:464–73.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hageman J, van Waarde MA, Zylicz A, Walerych D, Kampinga HH. The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities. Biochem J. 2011;435:127–42.CrossRefPubMedGoogle Scholar
  8. 8.
    Zhou JH, Chen HZ, Ye F, Lu WG, Xie X. FAS-mediated pathway and apoptosis in normal cervix, cervical intraepithelial neoplasia and cervical squamous cancer. Oncol Rep. 2006;16:307–11.PubMedGoogle Scholar
  9. 9.
    Cao Y, Miao XP, Huang MY, Deng L, Lin DX, Zeng YX, et al. Polymorphisms of death pathway genes FAS and FASL and risk of nasopharyngeal carcinoma. Mol Carcinog. 2010;49:944–50.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhang Z, Wang LE, Sturgis EM, El-Naggar AK, Hong WK, Amos CI, et al. Polymorphisms of FAS and FAS ligand genes involved in the death pathway and risk and progression of squamous cell carcinoma of the head and neck. Clin Cancer Res. 2006;12:5596–602.CrossRefPubMedGoogle Scholar
  11. 11.
    Xu L, Zhou X, Jiang F, Qiu MT, Zhang Z, Yin R, et al. FASL rs763110 polymorphism contributes to cancer risk: an updated meta-analysis involving 43,295 subjects. PLoS ONE. 2013;8, e74543.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zhong-Xing Z, Yuan-Yuan M, Hai Zhen M, Jian-Gang Z, Li-Feng Z. FAS -1377G/A (rs2234767) polymorphism and cancer susceptibility: a meta-analysis of 17,858 cases and 24,311 controls. PLoS ONE. 2013;8, e73700.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang LH, Ting SC, Chen CH, Tsai CC, Lung O, Liu TC, et al. Polymorphisms in the apoptosis-associated genes FAS and FASL and risk of oral cancer and malignant potential of oral premalignant lesions in a Taiwanese population. J Oral Pathol Med. 2010;39:155–61.CrossRefPubMedGoogle Scholar
  14. 14.
    Karimi MY, Kapoor V, Sharma SC, Das SN. Genetic polymorphisms in FAS (CD95) and FAS ligand (CD178) promoters and risk of tobacco-related oral carcinoma: gene-gene interactions in high-risk Indians. Cancer Investig. 2013;31:1–6.CrossRefGoogle Scholar
  15. 15.
    Nallapalle SR, Daripally S, Prasad VVTS. Promoter polymorphism of FASL confers protection against female-specific cancers and those of FAS impact the cancers divergently. Tumor Biol. 2015;36:2709–24.CrossRefGoogle Scholar
  16. 16., Accessed 27 Nov 2013.
  17. 17.
    Sarkaria JN, Harari PM. Oral tongue cancer in young adults less than 40 years of age: rationale for aggressive therapy. Head Neck. 1994;16:107–11.CrossRefPubMedGoogle Scholar
  18. 18.
    Garavello W, Spreafico R, Gaini RM. Oral tongue cancer in young patients: a matched analysis. Oral Oncol. 2007;43:894–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Weitzel JN, Blazer KR, Mac Donald DJ, Culver JO, Offit K. Genetics, genomics, and cancer risk assessment: state of the art and future directions in the era of personalized medicine. CA Cancer J Clin. 2011. doi: 10.3322/caac.20128.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Alfano D, Votta G, Schulze A, Downward J, Caputi M, Stoppelli MP, et al. Modulation of cellular migration and survival by c-Myc through the downregulation of urokinase (uPA) and uPA receptor. Mol Cell Biol. 2010;30:1838–51.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fabregat I, Roncero C, Fernandez M. Survival and apoptosis: a dysregulated balance in liver cancer. Liver Int. 2007;27:155–62.CrossRefPubMedGoogle Scholar
  22. 22.
    Walerych D, Napoli M, Collavin L, Del Sal G. The rebel angel: mutant p53 as the driving oncogene in breast cancer. Carcinogenesis. 2012;33:2007–17.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Okuyama H, Endo H, Akashika T, Kata K, Inoue M. Downregulation of c-MYC protein levels contributes to cancer cell survival under dual deficiency of oxygen and glucose. Cancer Res. 2010;70:10213–23.CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang Z, Qiu L, Wang M, Tong N, Li J, Zhang Z. The FAS ligand promoter polymorphism, rs763110 (−844C > T), contributes to cancer susceptibility: evidence from 19 case–control studies. Eur J Hum Genet. 2009;17:1294–303.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kang S, Dong SM, Seo SS, Kim JW, Park SY. FAS -1377G/A polymorphism and the risk of lymph node metastasis in cervical cancer. Cancer Genet Cytogenet. 2008;180:1–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Zeng J, Fang Y, Li P. FAS -1377 A/G polymorphism in breast cancer: a meta-analysis. Tumour Biol. 2014;35:2575–81.CrossRefPubMedGoogle Scholar
  27. 27.
    Geng P, Li J, Ou J, Xie G, Wang N, Xiang L, et al. Association of FAS -1377G/A polymorphism with susceptibility to cancer. PLoS ONE. 2014;9, e88748.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lai HC, Lin WY, Lin YW, Chang CC, Yu MH, Chen CC, et al. Genetic polymorphisms of FAS and FASL (CD95/CD95L) genes in cervical carcinogenesis: an analysis of haplotype and gene-gene interaction. Gynecol Oncol. 2005;99:113–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Sun T, Miao X, Zhang X, Tan W, Xiong P, Lin D. Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma. J Natl Cancer Inst. 2004;96:1030–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Watson CJ, O’Kane H, Maxwell P, Sharaf O, Petak I, Hyland PL, et al. Identification of a methylation hotspot in the death receptor FAS/CD95 in bladder cancer. Int J Oncol. 2012;l40:645–54.Google Scholar
  31. 31.
    Ghanim V, Herrmann H, Heller G, Peter B, Hadzijusufovic E, Blatt K, et al. 5-azacytidine and decitabine exert proapoptotic effects on neoplastic mast cells: role of FAS-demethylation and FAS re-expression, and synergism with FAS-ligand. Blood. 2012;119:4242–52.CrossRefPubMedGoogle Scholar
  32. 32.
    Yurchenko M, Shlapatska LM, Sidorenko SP. The multilevel regulation of CD95 signaling outcome. Exp Oncol. 2012;34:153–9.PubMedGoogle Scholar
  33. 33.
    Sancho-Martinez I, Martin-Villalba A. Tyrosine phosphorylation and CD95: a FAScinating switch. Cell Cycle. 2009;8:838–42.CrossRefPubMedGoogle Scholar
  34. 34.
    Strasser A, Jost PJ, Nagata S. The many roles of FAS receptor signaling in the immune system. Immunity. 2009;30:180–92.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Askenasy N, Yolcu ES, Yaniv I, Shirwan H. Induction of tolerance using FAS ligand: a double-edged immunomodulator. Blood. 2005;105:1396–404.CrossRefPubMedGoogle Scholar
  36. 36.
    Clark VJ, Ptak SE, Tiemann I, Qian Y, Coop G, Di Stone AC, et al. Combining sperm typing and linkage disequilibrium analyses reveals differences in selective pressures or recombination rates across human populations. Genetics. 2007;175:795–804.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kolovou G, Damaskos D, Anagnostopoulou K, Cokkinos DV. Apolipoprotein E gene polymorphism and gender. Ann Clin Lab Sci. 2009;39:120–33.PubMedGoogle Scholar
  38. 38.
    Lorenz AL, Kahre T, Mihailov E, Nikopensius T, Lotman EM, Metspalu A, et al. Are Methylenetetrahydrofolate Reductase (MTHFR) Gene polymorphisms C677T and A1298C associated with higher risk of pediatric migraine in boys and girls? J Biomed Sci Eng. 2014;7:464–72.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Sarika Daripally
    • 1
    • 2
  • Sateesh Reddy Nallapalle
    • 1
  • Saritha Katta
    • 1
  • Vidudala V. T. S. Prasad
    • 1
  1. 1.Research and DevelopmentBasavatarakam Indo-American Cancer Hospital and Research InstituteHyderabadIndia
  2. 2.Acharya Nagarjuna UniversityGunturIndia

Personalised recommendations