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Patterns of gene promoter methylation in squamous cell cancer of the head and neck

Oncogene volume 21, pages 4231–4236 (2002)Cite this article

Abstract

Promoter methylation is an important pathway in transcriptional silencing of known and candidate tumor suppressor genes in Head and Neck Squamous Cell Carcinoma (HNSCC). In order to study the association of tumor suppressor gene promoter methylation in HNSCC with patient clinical characteristics, especially alcohol consumption and tobacco smoking, we examined promoter methylation of the p16INK4a, DAP-kinase, E-Cadherin, and RASSF1A genes using methylation-specific PCR (MSP) in 80 patients. The prevalence of p16INK4a, DAP-kinase, E-Cadherin, and RASSF1A promoter methylation was 26/80 (32.5%), 19/80 (23.8%), 29/80 (36.3%), 6/80 (7.5%) respectively. In 48 cases (60%), at least one of these promoters was methylated. There was a significant association of methylation of any of these genes and ever smoking (P=0.006). p16INK4a gene promoter methylation was associated with a younger age of smoking initiation (P<0.03); E-Cadherin promoter methylation was associated with an increased number of pack years smoked (P<0.03). We also found an association of methylation of any gene and T status (OR=2.7, P<0.05). Tumors with p16INK4a methylation were significantly less likely to show lymph node metastasis (P<0.001). DAP-kinase promoter methylation was significantly associated with lymph node metastasis and this relationship was dependent upon p16INK4a promoter methylation status. Our results suggest that, in HNSCC, promoter methylation of these four genes accumulates with increasing tumor size. This may reflect distinct pathways of somatic inactivation leading to cancer; additional larger studies are needed to further investigate this possibility. Tobacco smoking may play an important role in both the occurrence of promoter methylation as well as delineating the precise pathway that eventually results in a tumorigenic phenotype.

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References

  • Agathanggelou A, Honorio S, Macartney DP, Martinez A, Dallol A, Rader J, Fullwood P, Chauhan A, Walker R, Shaw JA, Hosoe S, Lerman MI, Minna JD, Maher ER, Latif F . 2001 Oncogene 20: 1509–1518

  • Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP . 1998 Adv. Cancer Res. 72: 141–196

  • Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, Baylin SB, Herman JG . 1998 Proc. Natl. Acad. Sci. USA 95: 11891–11896

  • Belinsky SA, Nikula KJ, Baylin SB, Issa JP . 1995 Toxicol. Lett. 82: 335–340

  • Blot WJ, McLaughlin JK, Minn DM, Austin DF, Greenberg RS, Preston-Martin S, Bernstein L, Schoenberg JB, Stemhagen A, Fraumeni JF . 1988 Cancer Res. 48: 3282–3287

  • Brandeis M, Ariel M, Cedar H . 1993 Bioessays 15: 709–713

  • Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, Gao B, Randle D, Kondo M, Virmani A, Bader S, Sekido Y, Latif F, Milchgrub S, Toyooka S, Gazdar AF, Lerman MI, Zabarovsky E, White M, Minna JD . 2001 J. Natl. Cancer Inst. 93: 691–699

  • Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, Corio R, Lee D, Greenber B, Koch W, Sidransky D . 1996 Cancer Res. 56: 2488–2492

  • Dammann R, Li C, Yoon JH, Chin PL, Bates S, Pfeifer GP . 2000 Nat. Genet. 25: 315–319

  • Dammann R, Yang G, Pfeifer GP . 2001a Cancer Res. 61: 3105–3109

  • Dammann R, Takahashi T, Pfeifer GP . 2001b Oncogene 20: 3563–3567

  • Eguchi K, Kanai Y, Kobayashi K, Hirohashi S . 1997 Cancer Res. 57: 4913–4915

  • Esteller M, Corn PG, Baylin SB, Herman JG . 2001 Cancer Res. 61: 3225–3229

  • Esteller M, Sanchez-Cespedes M, Rosell R, Sidransky D, Baylin SB, Herman G . 1999 Cancer Res. 59: 67–70

  • Frixen UH, Behrens J, Sachs M, Eberle G, Voss B, Warda A, Lochner D, Birchmeier W . 1991 J. Cell. Biol. 113: 173–185

  • Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB . 1995 Cancer Res. 55: 5195–5199

  • Graff JR, Herman JG, Myohanen S, Baylin SB, Vertino PM . 1997 J. Biol. Chem. 272: 22322–22329

  • Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . 1996 Proc. Natl. Acad. Sci. USA 93: 9821–9826

  • Jost JP . 1993 Proc. Natl. Acad. Sci. USA 90: 4684–4688

  • Kim DH, Nelson HH, Wiencke JK, Zheng S, Christiani DC, Wain JC, Mark EJ, Kelsey KT . 2001a Cancer Res. 61: 3419–3424

  • Kim DH, Nelson HH, Wiencke JK, Christiani DC, Wain JC, Mark EJ, Kelsey KT . 2001b Oncogene 29: 1765–1770

  • Kok K, Naylor SL, Buys CH . 1997 Adv. Cancer Res. 71: 27–92

  • Li E, Bestor TH, Jaenisch R . 1992 Cell 69: 915–926

  • Lo K-W, Kwong J, Hui A B-Y, Chan S Y-Y, To K-F, Chan A S-C, Chow L S-N, Teo PML, Johnson PJ, Huang DP . 2001 Cancer Res. 61: 3877–3881

  • Maestro R, Gasparotto D, Vukosavljevic T, Barzan L, Sulfaro S, Boiocchi M . 1993 Cancer Res. 53: 5775–5779

  • Morrissey C, Martinez A, Zatyka M, Agathanggelou A, Honorio S, Astuti D, Morgan NV, Moch H, Richards FM, Kishida T, Yao M, Schraml P, Latif F, Maher ER . 2001 Cancer Res. 61: 7277–7281

  • Nagai MA . 1999 Braz. J. Med. Biol. Res. 32: 897–904

  • Navarro P, Gomez M, Pizarro A, Gamallo C, Quintanilla M, Cano A . 1991 J. Cell Biol. 115: 517–533

  • Raveh T, Droguett G, Horwitz MS, DePinho RA, Kimchi A . 2001 Nat. Cell Biol. 3: 1–7

  • Reed AL, Califano J, Cairns P, Westra WH, Jones RM, Koch W, Ahrendt S, Eby Y, Sewell D, Nawroz H, Bartek J, Sidransky D . 1996 Cancer Res. 56: 3630–3633

  • Riese U, Dahse R, Fiedler W, Theuer C, Koscielny S, Ernst G, Beleites E, Claussen U, von Eggeling F . 1999 Int. J. Mol. Med. 4: 61–65

  • Rosas SLB, Koch W, Carvalho MG, Wu L, Califano J, Westra W, Jen J, Sidransky D . 2001 Cancer Res. 61: 939–942

  • Sanchez-Cespedes M, Esteller M, Wu L, Nawroz-Danish H, Yoo GH, Koch WM, Jen J, Herman JG, Sidransky D . 2000 Cancer Res. 60: 892–895

  • Saracci R . 1987 Epidemiol. Rev. 9: 175–193

  • Schipper JH, Frixen UH, Behrens J, Unger A, Jahnke K, Birchmeier W . 1991 Cancer Res. 51: 6328–6337

  • Serrano M, Hannon GJ, Beach D . 1993 Nature 366: 704–707

  • Spitz MR, Trizna Z . 1999 Head and Neck Cancer. Harrison LB, Sessions RB and Hong WK. (eds) Philadelphia: Lippincott-Raven pp 11–22

  • Vleminckx K, Vakaet L Jr, Mareel M, Fiers W, van Roy F . 1991 Cell 66: 107–119

  • Yarbrough WG, Shores C, Witsell DL, Weissler MC, Fidler ME, Gilmer TM . 1994 Laryngoscope 104: 1337–1347

  • Yoon JH, Dammann R, Pfeifer GP . 2001 Int. J. Cancer 94: 212–217

  • Zochbauer-Muller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD . 2001 Cancer Res. 61: 249–255

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Acknowledgements

Supported by: CA78609, ES08357, ES00002 and 1P01-DE12467-05.

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Authors and Affiliations

  1. Department of Cancer Cell Biology, Harvard School of Public Health, Boston, 02115, Massachusetts, MA, USA

    Masayuki Hasegawa, Edward Peters, Elin Ringstrom & Karl T Kelsey

  2. Department of Environmental Health, Environmental Epidemiology Program, Harvard School of Public Health, Boston, 02115, Massachusetts, MA, USA

    Heather H Nelson

  3. Department of Dentistry and Oral Medicine, Brigham and Women's Hospital, Boston, 02115, Massachusetts, MA, USA

    Edward Peters

  4. Department of Adult Oncology, Department of Medicine, Dana Farber Cancer Institute, Brigham and Women's Hospital, Boston, 02115, Massachusetts, MA, USA

    Marshall Posner

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  1. Masayuki Hasegawa
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  2. Heather H Nelson
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  6. Karl T Kelsey
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Correspondence to Karl T Kelsey.

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Hasegawa, M., Nelson, H., Peters, E. et al. Patterns of gene promoter methylation in squamous cell cancer of the head and neck. Oncogene 21, 4231–4236 (2002). https://doi.org/10.1038/sj.onc.1205528

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