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Polymorphism of the p53 codon 72 arg/pro and the risk of HPV type 16/18-associated cervical and oral cancer in India

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Abstract

Infection of high risk human papillomaviruses (HPVs) specifically the types 16 and 18 has been strongly implicated in the development of cervical cancer. The E6 oncoproteins of these high risk HPVs are known to bind and induce degradation of p53 tumour suppressor protein through the ubiquitin pathways. This degradation is controlled by a common polymorphism of the p53 gene encoding either a proline or an arginine at its codon 72 in exon 4. Recently, it has been demonstrated that the presence of homozygous arginine at codon 72 renders p53 about seven times more susceptible to E6-mediated proteolytic degradation as well as to cervical cancer than those with proline homozygotes or proline/arginine heterozygotes. In India, prevalence of HPV as well as cancers of the uterine cervix and the oral cavity are highest in the world. We have examined this allele-specific predisposition in cervical and oral cancer which is associated with HPV as well as in a non-HPV-linked cancer of the breast. We have carried out investigation in women comprising whole spectrum of cervical lesions with 128 HPV 16/18 positive and 35 HPV negative invasive cervical carcinomas and 34 cases of HPV (16/18) positive and 16 HPV negative cervical dysplasias (mild, moderate and severe) and 104 age-group-matched healthy women as controls. Additionally, we have analysed p53Arg-Pro polymorphism in 13 high risk HPV positive and 31 HPV negative oral cancers along with 20 normal controls and 77 breast cancers with 41 age-matched healthy controls.

We observed more than 2 fold higher risk for homozygous arginine (χ2 = 6.3, df = 2, p = 0.04; OR = 2.3; 95% CI: 1.08–5.16) for HPV 16/18-positive cervical carcinomas when comparison was made only between HPV positive cervical cancers and normal controls but most interestingly, no significant association either in the frequency of homozygous arginine or proline alleles or their heterozygotes could be observed when all the three groups i.e. HPV-positive, HPV-negative cervical cancers and controls were considered simultaneously. No difference was also observed for either arginine or proline polymorphism between women with precancerous lesions of the uterine cervix carrying HPV 16/18 infection and controls. Similarly, increased risk of oral or breast cancer could not be correlated with the polymorphism of arginine/proline allele.

Thus the interaction between HPV oncoproteins and the p53 gene polymorphism specifically, homozygous arginine at codon 72 appears to play no role in the development of either cervical or oral cancer and also it can not serve as a biomarker for early identification of cervical, oral or breast cancer.

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References

  1. Luthra UK, Prabhakar AK, Seth P, Agarwal SS, Murthy NS, Bhatnagar P, Das DK, Sharma BK: Natural history of precancerous and early cancerous lesions of uterine cervix. Acta Cytol 31: 226-234, 1987

    Google Scholar 

  2. Murthy NS, Juneja A, Sehgal A, Prabhakar AK, Luthra UK: Cancer projection by the turn of century-Indian science. Ind J Cancer 27: 74-82, 1990

    Google Scholar 

  3. WHO (World Health Organization). Control of cancer of the cervix uteri. A WHO meeting. Bull WHO 64: 607-618, 1986

    Google Scholar 

  4. zur Hausen H: Papillomavirus infections — a major cause of human cancers. Biochim Biophys Acta 1288: 55-78, 1996

    Google Scholar 

  5. IARC: The evaluation of carcinogenic risks in humans. Human papillomaviruses. IARC, Lyon 64, 1995

    Google Scholar 

  6. Vousden KH: Human papillomaviruses and cervical carcinoma: Cancer Cells 1: 43-50, 1989

    Google Scholar 

  7. Barbosa MS, Schlegel R: The E6 and E7 genes of HPV-18 are sufficient for inducing two-stage in vitro transformation of human keratinocytes. Oncogene 4: 1529-1532, 1989

    Google Scholar 

  8. Hawley NP, Vousden KH, Hubbert NL, Lowy DR, Schiller JT: HPV 16 E6 and E7 proteins cooperate to immortalize of human foreskin keratinocytes. EMBO J 8: 3905-3910, 1989

    Google Scholar 

  9. Munger K, Phelps WC, Bubb V, Howley PM, Schlegel R: The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 63: 4417-4421, 1989

    Google Scholar 

  10. Tanaka A, Noda T, Yajima H, Hatanaka M, Ito Y: Identification of a transforming gene of human papillomavirus type 16. J Virol 63: 1465-1469, 1989

    Google Scholar 

  11. Halbert CL, Demers GW, Galloway DA: The E7 gene of human papillomavirus type 16 is sufficient for immortalization of human epithelial cells. J Virol 65: 473-478, 1991

    Google Scholar 

  12. Crook T, Morgenstern JP, Crawford L, Banks L: Continued expression of HPV-16 E7 protein is required for maintenance of the transformed phenotype of cells co-transformed by HPV 16 plus EJ-ras. EMBO J 8: 513-519, 1989

    Google Scholar 

  13. Werness BA, Levine AJ, Howley PM: Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248: 76-79, 1990

    Google Scholar 

  14. Dyson N, Howley PM, Munger K, Harlow E: The human papilloma virus-16 E7 oncoprotein is able to bind to the retrinoblastoma gene product. Science 243: 934-937, 1989

    Google Scholar 

  15. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM: The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63: 1129-1136, 1990

    Google Scholar 

  16. Crook T, Wrede D, Vousden KH: p53 point mutation in HPV negative human cervical carcinoma cell lines. Oncogene 6: 873-875, 1991

    Google Scholar 

  17. Scheffner M, Munger K, Byrne JC, Howley PM: The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci USA 88: 5523-5527, 1991

    Google Scholar 

  18. Vogelstein B, Kinzler KW: p53 Function and dysfunction. Cell 70: 523-526, 1992

    Google Scholar 

  19. Matlashewski GJ, Tuck S, Pim D, Lamb P, Schneider J, Crawford LV: Primary structure polymorphism at amino acid residue 72 of human p53. Mol Cell Biol 7: 961-963, 1987

    Google Scholar 

  20. Beckman G, Birgander R, Sjalander A, Saha N, Holmberg PA, Kivela A Beckman L: Is p53 polymorphism maintained by natural selection? Hum Hered 44: 266-270, 1994

    Google Scholar 

  21. Storey A, Thomas M, Kalita A, Harwood C, Gardiol D, Mantovani F, Breuer J, Leigh IM, Matlashewski G, Banks L: Role of a p53 polymorphism in the development of human papillomavirus-associated cancer. Nature 393: 229-234, 1998

    Google Scholar 

  22. Rosenthal AN, Ryan A, Al-Jehani RM, Storey A, Harwood CA, Jacobs IJ: p53 codon 72 polymorphism and risk of cervical cancer in UK. Lancet 352: 871-872, 1998

    Google Scholar 

  23. Helland A, Langerod A, Johnsen H, Olsen AO, Skovlund E, Borresen-Dale AL: p53 Polymorphism and risk of cervical cancer. Nature 396: 530-531, 1998

    Google Scholar 

  24. Josefsson AM, Magnusson PK, Ylitalo N, Quarforth-Tubbin P, Ponten J, Adami HO, Gyllensten UB: p53 Polymorphism and risk of cervical cancer. Nature 396: 531, 1998

    Google Scholar 

  25. Minaguchi T, Kanamori Y, Matsushima M, Yoshikawa H, Taketani Y, Nakamura Y: No evidence of correlation between polymorphism at codon 72 of p53 and risk of cervical cancer in Japanese patients with human papillomavirus 16/18 infection. Cancer Res 58: 4585-4586, 1998

    Google Scholar 

  26. Hildesheim A, Schiffman M, Brinton LA, Fraumeni JF Jr, Herrero R, Bratti MC, Schwartz P, Mortel R, Barnes W, Greenberg M, McGowan L, Scott DR, Martin M, Herrera JE, Carrington M: p53 polymorphism and risk of cervical cancer. Nature 396: 531-532, 1998

    Google Scholar 

  27. Lanham S, Campbell I, Watt P, Gornall R: p53 Polymorphism and risk of cervical cancer. Lancet 352: 1631, 1998

    Google Scholar 

  28. Giannoudis A, Graham DA, Southern SA, Herrington CS: p53 codon 72 ARG/PRO polymorphism is not related to HPV type or lesion grade in low-and high-grade squamous intra-epithelial lesions and invasive squamous carcinoma of the cervix. Int J Cancer 83: 66-69, 1999

    Google Scholar 

  29. Klaes R, Ridder R, Schaefer U, Benner A, von Knebel Doeberitz M: No evidence of p53 allele-specific predisposition in human papillomavirus-associated cervical cancer. J Mol Med 77: 299-302, 1999

    Google Scholar 

  30. Hayes VM, Hofstra RM, Buys CH, Hollema H, van der Zee AG: Homozygous arginine-72 in wild type p53 and risk of cervical cancer. Lancet 352: 1756, 1998

    Google Scholar 

  31. Yamashita T, Yaginuma Y, Saitoh Y, Kawai K, Kurakane T, Hayashi H, Ishikawa M: Codon 72 polymorphism of p53 as a risk factor for patients with human papillomavirus-associated squamous intraepithelial lesions and invasive cancer of the uterine cervix. Carcinogenesis 20: 1733-1736, 1999

    Google Scholar 

  32. Wang YC, Lee HS, Chen SK, Chang YY, Chen CY: Prognostic significance of p53 codon 72 polymorphism in lung carcinomas. Eur J Cancer 35: 226-230, 1999

    Google Scholar 

  33. Zehbe I, Voglino G, Wilander E, Genta F, Tommasino M: Codon 72 polymorphism of p53 and its association with cervical cancer. Lancet 354: 218-219, 1999

    Google Scholar 

  34. Peller S, Halperin R, Schneider D, Kopilova Y, Rotter V: Polymorphisms of the p53 gene in women with ovarian or endometrial carcinoma. Oncol Rep 6: 193-197, 1999

    Google Scholar 

  35. Murata M, Tagawa M, Kimura H, Kakisawa K, Shirasawa H, Fujisawa T: Correlation of the mutation of p53 gene and the polymorphism at codon 72 in smoking-related non-small cell lung cancer patients. Int J Oncol 12: 577-581, 1998

    Google Scholar 

  36. Cuzick J, Terry G, Ho L, Hollingworth T, Anderson M: Human papillomavirus type 16 in cervical smears as predictor of high-grade cervical intraepithelial neoplasia. Lancet 339: 959-960, 1992

    Google Scholar 

  37. Das BC, Sharma JK, Gopalkrishna V, Das DK, Singh V, Gissmann L, zur Hausen H, Luthra, UK: A high frequency of human papillomavirus DNA sequences in cervical carcinomas of Indian women as revealed by Southern blot hybridization and polymerase chain reaction. J Med Virol 36: 239-245, 1992a

    Google Scholar 

  38. Balaram P, Nalinakumari KR, Abraham E, Balan A, Hareendran NK, Bernard HU, Chan SY: Human papillomaviruses in 91 oral cancers from Indian betel quid chewers-high prevalence and multiplicity of infections. Int J Cancer 61: 450-454, 1995

    Google Scholar 

  39. Wrede D, Luqmani YA, Coombes RC, Vousden KH: Absence of HPV 16 and 18 DNA in breast cancer. Br J Cancer 65: 891-894, 1992

    Google Scholar 

  40. Gopalkrishna V, Singh UR, Sodhani P, Sharma JK, Hedau ST, Mandal AK, Das BC: Absence of human papillomavirus DNA in breast cancer as revealed by polymerase chain reaction. Breast Cancer Res Treat 39: 197-202, 1996

    Google Scholar 

  41. Das BC, Sharma JK, Gopalkrishna V, Luthra UK: Analysis by polymerase chain reaction of the physical state of human papillomavirus type 16 DNA in cervical preneoplastic and neoplastic lesions J Gen Virol 73: 2327-2336, 1992b

    Google Scholar 

  42. Maniatis T, Fritsch EF, Sambrook J: In: Molecular Cloning — A laboratory Manual. Cold Spring Harbor Laboratory, 1989

  43. van Duin M, Snijders PJ, Vossen MT, Klaassen E, Voorhorst F, Verheijen RH, Helmerhorst TJ, Meijer CJ, Walboomers JM: Analysis of human papillomavirus type 16 E6 variants in relation to P53 codon 72 polymorphism genotypes in cervical carcinogenesis. J Gen Virol 81: 317-325, 2000

    Google Scholar 

  44. Nagpal JK, Patnaik S, Das BR: Prevalence of high-risk human papilloma virus types and its association with p53 codon 72 polymorphism in tobacco addicted oral squamous cell carcinoma (OSCC) patients of Eastern India. Int J Cancer 97: 649-653, 2002

    Google Scholar 

  45. Tandle AT, Sanghvi V, Saranath D: Determination of p53 genotypes in oral cancer patients from India. Br J Cancer 84: 739-742, 2001

    Google Scholar 

  46. Kuo MY, Huang JS, Hsu HC, Chiang CP, Kok SH, Kuo YS, Hong CY: Infrequent p53 mutations in patients with areca quid chewing-associated oral squamous cell carcinomas in Taiwan. J Oral Pathol Med 28: 221-225, 1999

    Google Scholar 

  47. Weston A, Godbold JH: Polymorphisms of H-ras-1 and p53 in breast cancer and lung cancer: A meta-analysis. Environ Health Perspect 105(suppl 4): 919-926, 1997

    Google Scholar 

  48. Weston A, Caporaso NE, Perrin LS, Sugimura H, Tamai S, Krontiris TG, Trump BF, Hoover RN, Harris CC: Relationship of H-ras-1, L-myc, and p53 polymorphisms with lung cancer risk and prognosis. Environ Health Perspect 98: 61-67, 1992

    Google Scholar 

  49. Jin X, Wu X, Roth JA, Amos CI, King TM, Branch C, Honn SE, Spitz MR: Higher lung cancer risk for younger African-Americans with the Pro/Pro p53 genotype carcinogenesis 16: 2205-2208, 1995

    Google Scholar 

  50. Tagawa M, Murata M, Kimura H: Prognostic value of mutations and a germ line polymorphism of the p53 gene in non-small cell lung carcinoma: Association with clinicopathological features. Cancer Lett 128: 93-99, 1998

    Google Scholar 

  51. Mittra I, Badwe RA, Desai PB, Yeole BB, Jussawala DJ: Early detection of breast cancer in developing countries. Lancet 1: 710-720, 1989

    Google Scholar 

  52. NCRP (National Cancer Registry Programme): Indian Council of Medical Research, 2001

  53. Buller RE, Sood A, Fullenkamp C, Sorosky J, Powills K, Anderson B: The influence of the p53 codon 72 polymorphism on ovarian carcinogenesis and prognosis. Cancer Gene Ther 4: 239-245, 1997

    Google Scholar 

  54. de la Calle-Martin O, Fabregat V, Romero M, Soler J, Vives J, Yague J: AccII polymorphism of the p53 gene. Nucleic Acids Res 18: 4963, 1990

    Google Scholar 

  55. Kaelbling M, Burk RD, Atkin NB, Johnson AB, Klinger HP: Loss of heterozygosity on chromosome 17p and mutant p53 in HPV-negative cervical carcinomas. Lancet 340: 140-142, 1992

    Google Scholar 

  56. Mullokandov MR, Kholodilov NG, Atkin NB, Burk RD, Johnson AB, Klinger HP: Genomic alterations in cervical carcinoma: Losses of chromosome heterozygosity and human papilloma virus tumor status. Cancer Res 56: 197-205, 1996

    Google Scholar 

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Authors and Affiliations

  1. Division of Molecular Oncology, Institute of Cytology and Preventive Oncology, Maulana Azad Medical College Campus, Bahadur Shah Zafar Marg, New Delhi, 110 002, India

    Sanjay Katiyar, Suresh Hedau, Neeraj Jain, V. Gopalkrishna & Bhudev C. Das

  2. Department of Genetics, University of Delhi South Campus, Benito Juarez Marg, New Delhi, 110 021, India

    B.K. Thelma

  3. Division of Epidemiology and Biostatistics, Institute of Cytology and Preventive Oncology, Maulana Azad Medical College Campus, Bahadur Shah Zafar Mag, New Delhi, 110 002, India

    N.S. Murthy

  4. Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110 025, India

    Syed Akhtar Husain

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Katiyar, S., Thelma, B., Murthy, N. et al. Polymorphism of the p53 codon 72 arg/pro and the risk of HPV type 16/18-associated cervical and oral cancer in India. Mol Cell Biochem 252, 117–124 (2003). https://doi.org/10.1023/A:1025546610920

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