TIMP3 and CCNA1 hypermethylation in HNSCC is associated with an increased incidence of second primary tumors

Journal of Translational Medicine

André Luiz Vettore⁴  André Lopes Carvalho¹  Luiz Paulo Kowalski²  Cleyton Zanardo de Oliveira³  Ana Luiza Bomfim Longo⁵  Ana Carolina de Carvalho⁵  Marianna Marconato Rettori⁵ 

[1] Departament of Head and Neck Surgery, Barretos Cancer Hospital, 14784-400, Barretos, Brazil;Departament of Head and Neck Surgery, A.C. Camargo Hospital, 01509-010, São Paulo, Brazil;Statistics and Epidemiology Center, Barretos Cancer Hospital, 14784-400, Barretos, Brazil;Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 169857, Singapore, Singapore;Cancer Molecular Biology Laboratory, Department of Biological Sciences, Federal University of São Paulo, 04039-020, São Paulo, Brazil

关键词: CCNA1;    TIMP3;    epigenetics;    DNA methylation;    HNSCC Prognostic Marker;    Head and neck cancers;   

Others  :  824099
DOI  :  10.1186/1479-5876-11-316

 received in 2013-11-07, accepted in 2013-12-17,  发布年份 2013

【 摘 要 】

Background

Hypermethylation in the promoter regions is associated with the suppression of gene expression and has been considered a potential molecular marker for several tumor types, including head and neck squamous cell carcinomas (HNSCC).

Methods

To evaluate the gene hypermethylation profile as a prognostic marker, this retrospective study used a QMSP approach to determine the methylation status of 19 genes in 70 HNSCC patients.

Results

The methylation profile analysis of primary HNSCC revealed that genes CCNA1, DAPK, MGMT, TIMP3 and SFRP1 were frequently hypermethylated, with high specificity and sensitivity. TIMP3 and CCNA1 hypermethylation was significantly associated with lower rates of second primary tumor-free survival (p = 0.007 and p = 0.001; log-rank test, respectively).

Conclusion

This study, for the first time, presents CCNA1 and TIMP3 hypermethylation as a helpful tool to identify HNSCC subjects at risk of developing second primary carcinomas.

【 授权许可】

   
2013 Rettori et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Whaley JT, Indelicato DJ, Morris CG, Hinerman RW, Amdur RJ, Mendenhall WM, Keole SR, Marcus RB Jr: Ewing tumors of the head and neck. Am J Clin Oncol 2010, 33:321-326.
• [2]Leemans CR, Braakhuis BJ, Brakenhoff RH: The molecular biology of head and neck cancer. Nat Rev Cancer 2011, 11:9-22.
• [3]Rabbani A, Hinerman RW, Schmalfuss IM, Amdur RJ, Morris CG, Peters KR, Robbins KT, Mendenhall WM: Radiotherapy and concomitant intraarterial cisplatin (RADPLAT) for advanced squamous cell carcinomas of the head and neck. Am J Clin Oncol 2007, 30:283-286.
• [4]Sturgis EM, Miller RH: Second primary malignancies in the head and neck cancer patient. Ann Otol Rhinol Laryngol 1995, 104:946-954.
• [5]Braakhuis BJ, Leemans CR, Brakenhoff RH: A genetic progression model of oral cancer: current evidence and clinical implications. J Oral Pathol Med 2004, 33:317-322.
• [6]Kelloff GJ, Lippman SM, Dannenberg AJ, Sigman CC, Pearce HL, Reid BJ, Szabo E, Jordan VC, Spitz MR, Mills GB, et al.: Progress in chemoprevention drug development: the promise of molecular biomarkers for prevention of intraepithelial neoplasia and cancer–a plan to move forward. Clin Cancer Res 2006, 12:3661-3697.
• [7]Priante AV, Castilho EC, Kowalski LP: Second primary tumors in patients with head and neck cancer. Curr Oncol Rep 2011, 13:132-137.
• [8]Franchin G, Minatel E, Gobitti C, Talamini R, Vaccher E, Sartor G, Politi D, Trovo MG, Barzan L: Radiotherapy for patients with early-stage glottic carcinoma: univariate and multivariate analyses in a group of consecutive, unselected patients. Cancer 2003, 98:765-772.
• [9]Lee JH, Machtay M, McKenna MG, Weinstein GS, Markiewicz DA, Krisch RE, Kligerman MM: Radiotherapy with 6-megavolt photons for early glottic carcinoma: potential impact of extension to the posterior vocal cord. Am J Otolaryngol 2001, 22:43-54.
• [10]Kowalski LP, Batista MB, Santos CR, Scopel AA, Salvajoli JV, Novaes PE, Trippe N: Prognostic factors in glottic carcinoma clinical stage I and II treated by surgery or radiotherapy. Am J Otolaryngol 1993, 14:122-127.
• [11]Slaughter DP, Southwick HW, Smejkal W: Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953, 6:963-968.
• [12]Homann N, Nees M, Conradt C, Dietz A, Weidauer H, Maier H, Bosch FX: Overexpression of p53 in tumor-distant epithelia of head and neck cancer patients is associated with an increased incidence of second primary carcinoma. Clin Cancer Res 2001, 7:290-296.
• [13]Lei D, Sturgis EM, Liu Z, Zafereo ME, Wei Q, Li G: Genetic polymorphisms of p21 and risk of second primary malignancy in patients with index squamous cell carcinoma of the head and neck. Carcinogenesis 2010, 31:222-227.
• [14]Zafereo ME, Sturgis EM, Aleem S, Chaung K, Wei Q, Li G: Glutathione S-transferase polymorphisms and risk of second primary malignancy after index squamous cell carcinoma of the head and neck. Cancer Prev Res (Phila) 2009, 2:432-439.
• [15]Jones PA, Baylin SB: The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002, 3:415-428.
• [16]Herman JG, Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003, 349:2042-2054.
• [17]Geiman TM, Robertson KD: Chromatin remodeling, histone modifications, and DNA methylation-how does it all fit together? J Cell Biochem 2002, 87:117-125.
• [18]Brabender J, Usadel H, Danenberg KD, Metzger R, Schneider PM, Lord RV, Wickramasinghe K, Lum CE, Park J, Salonga D, et al.: Adenomatous polyposis coli gene promoter hypermethylation in non-small cell lung cancer is associated with survival. Oncogene 2001, 20:3528-3532.
• [19]Brait M, Begum S, Carvalho AL, Dasgupta S, Vettore AL, Czerniak B, Caballero OL, Westra WH, Sidransky D, Hoque MO: Aberrant promoter methylation of multiple genes during pathogenesis of bladder cancer. Cancer Epidemiol Biomarkers Prev 2008, 17:2786-2794.
• [20]Carvalho AL, Jeronimo C, Kim MM, Henrique R, Zhang Z, Hoque MO, Chang S, Brait M, Nayak CS, Jiang WW, et al.: Evaluation of promoter hypermethylation detection in body fluids as a screening/diagnosis tool for head and neck squamous cell carcinoma. Clin Cancer Res 2008, 14:97-107.
• [21]Longo AL, Rettori MM, de Carvalho AC, Kowalski LP, Carvalho AL, Vettore AL: Evaluation of the methylation profile of exfoliated cell samples from head and neck squamous cell carcinoma patients. Head Neck 2013. [Epub ahead of print]
• [22]Hou P, Ji M, Yang B, Chen Z, Qiu J, Shi X, Lu Z: Quantitative analysis of promoter hypermethylation in multiple genes in osteosarcoma. Cancer 2006, 106:1602-1609.
• [23]Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB: Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 1994, 7:536-540.
• [24]Rettori MM, de Carvalho AC, Bomfim Longo AL, de Oliveira CZ, Kowalski LP, Carvalho AL, Vettore AL: Prognostic significance of TIMP3 hypermethylation in post-treatment salivary rinse from head and neck squamous cell carcinoma patients. Carcinogenesis 2013, 34:20-27.
• [25]Vidal DO, Paixao VA, Brait M, Souto EX, Caballero OL, Lopes LF, Vettore AL: Aberrant methylation in pediatric myelodysplastic syndrome. Leuk Res 2007, 31:175-181.
• [26]Eads CA, Lord RV, Wickramasinghe K, Long TI, Kurumboor SK, Bernstein L, Peters JH, DeMeester SR, DeMeester TR, Skinner KA, Laird PW: Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res 2001, 61:3410-3418.
• [27]Harden SV, Tokumaru Y, Westra WH, Goodman S, Ahrendt SA, Yang SC, Sidransky D: Gene promoter hypermethylation in tumors and lymph nodes of stage I lung cancer patients. Clin Cancer Res 2003, 9:1370-1375.
• [28]Hoque MO, Topaloglu O, Begum S, Henrique R, Rosenbaum E, Van Criekinge W, Westra WH, Sidransky D: Quantitative methylation-specific polymerase chain reaction gene patterns in urine sediment distinguish prostate cancer patients from control subjects. J Clin Oncol 2005, 23:6569-6575.
• [29]Fackler MJ, McVeigh M, Mehrotra J, Blum MA, Lange J, Lapides A, Garrett E, Argani P, Sukumar S: Quantitative multiplex methylation-specific PCR assay for the detection of promoter hypermethylation in multiple genes in breast cancer. Cancer Res 2004, 64:4442-4452.
• [30]Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, Kang GH, Widschwendter M, Weener D, Buchanan D, et al.: CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 2006, 38:787-793.
• [31]Muller HM, Widschwendter A, Fiegl H, Ivarsson L, Goebel G, Perkmann E, Marth C, Widschwendter M: DNA methylation in serum of breast cancer patients: an independent prognostic marker. Cancer Res 2003, 63:7641-7645.
• [32]de Carvalho F, Colleoni GW, Almeida MS, Carvalho AL, Vettore AL: TGFbetaR2 aberrant methylation is a potential prognostic marker and therapeutic target in multiple myeloma. Int J Cancer 2009, 125:1985-1991.
• [33]Warren S, Gates O: Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer 1932, 16:1358-1414.
• [34]Hinerman RW, Mendenhall WM, Morris CG, Amdur RJ, Werning JW, Villaret DB: Postoperative irradiation for squamous cell carcinoma of the oral cavity: 35-year experience. Head Neck 2004, 26:984-994.
• [35]Fijuth J, Mazeron JJ, Le Pechoux C, Piedbois P, Martin M, Haddad E, Calitchi E, Pierquin B, Le Bourgeois JP: Second head and neck cancers following radiation therapy of T1 and T2 cancers of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 1992, 24:59-64.
• [36]Goldenberg D, Harden S, Masayesva BG, Ha P, Benoit N, Westra WH, Koch WM, Sidransky D, Califano JA: Intraoperative molecular margin analysis in head and neck cancer. Arch Otolaryngol Head Neck Surg 2008, 130:39-44.
• [37]Hall GL, Shaw RJ, Field EA, Rogers SN: Sutton, DN Woolgar, JA, Lowe D, Liloglou T, Field JK, Risk JM: p16 Promoter methylation is a potential predictor of malignant transformation in oral epithelial dysplasia. Cancer Epidemiol Biomarkers Prev 2012, 17:2174-2179.
• [38]Liu Y, Zhou ZT, He QB, Jiang WW: DAPK promoter hypermethylation in tissues and body fluids of oral precancer patients. Med Oncol 2012, 29:729-733.
• [39]Martone T, Gillio-Tos A, De Marco L, Fiano V, Maule M, Cavalot A, Garzaro M, Merletti F, Cortesina G: Association between hypermethylated tumor and paired surgical margins in head and neck squamous cell carcinomas. Clin Cancer Res 2007, 13:5089-5094.
• [40]Sogabe Y, Suzuki H, Toyota M, Ogi K, Imai T, Nojima M, Sasaki Y, Hiratsuka H, Tokino T: Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma. Int J Oncol 2009, 32:1253-1261.
• [41]Supic G, Kozomara R, Jovic N, Zeljic K, Magic Z: Prognostic significance of tumor-related genes hypermethylation detected in cancer-free surgical margins of oral squamous cell carcinomas. Oral Oncol 2011, 47:702-708.
• [42]Tan HK, Saulnier P, Auperin A, Lacroix L, Casiraghi O, Janot F, Fouret P, Temam S: Quantitative methylation analyses of resection margins predict local recurrences and disease-specific deaths in patients with head and neck squamous cell carcinomas. Br J Cancer 2008, 99:357-363.
• [43]Weiss D, Basel T, Sachse F, Braeuninger A, Rudack C: Promoter methylation of cyclin A1 is associated with human papillomavirus 16 induced head and neck squamous cell carcinoma independently of p53 mutation. Mol Carcinog 2011, 50:680-688.
• [44]Nayak CS, Carvalho AL, Jeronimo C, Henrique R, Kim MM, Hoque MO, Chang S, Jiang WW, Koch W, Westra W, et al.: Positive correlation of tissue inhibitor of metalloproteinase-3 and death-associated protein kinase hypermethylation in head and neck squamous cell carcinoma. Laryngoscope 2007, 117:1376-1380.
• [45]Taioli E, Ragin C, Wang XH, Chen J, Langevin SM, Brown AR, Gollin SM, Garte S, Sobol RW: Recurrence in oral and pharyngeal cancer is associated with quantitative MGMT promoter methylation. BMC Cancer 2009, 9:354. BioMed Central Full Text
• [46]Marsit CJ, Houseman EA, Nelson HH, Kelsey KT: Genetic and epigenetic tumor suppressor gene silencing are distinct molecular phenotypes driven by growth promoting mutations in nonsmall cell lung cancer. J Cancer Epidemiol 2008, 2008:215809.
• [47]Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP: Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol 1997, 74:111-122.
• [48]de Carvalho AC, Kowalski LP, Campos AH, Soares FA, Carvalho AL, Vettore AL: Clinical significance of molecular alterations in histologically negative surgical margins of head and neck cancer patients. Oral Oncol 2012, 48:240-248.
• [49]Stetler-Stevenson WG, Aznavoorian S, Liotta LA: Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol 1993, 9:541-573.
• [50]Sun W, Zaboli D, Wang H, Liu Y, Arnaoutakis D, Khan T, Khan Z, Koch WM, Califano JA: Detection of TIMP3 promoter hypermethylation in salivary rinse as an independent predictor of local recurrence-free survival in head and neck cancer. Clin Cancer Res 2012, 18:1082-1091.
• [51]Girard F, Strausfeld U, Fernandez A, Lamb NJ: Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 1991, 67:1169-1179.
• [52]Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G: Cyclin A is required at two points in the human cell cycle. EMBO J 1992, 11:961-971.
• [53]Rivera A, Mavila A, Bayless KJ, Davis GE, Maxwell SA: Cyclin A1 is a p53-induced gene that mediates apoptosis, G2/M arrest, and mitotic catastrophe in renal, ovarian, and lung carcinoma cells. Cell Mol Life Sci 2006, 63:1425-1439.
• [54]Gonzalez-Moles MA, Scully C, Ruiz-Avila I: Molecular findings in oral premalignant fields: update on their diagnostic and clinical implications. Oral Dis 2012, 18:40-47.
• [55]Brennan JA, Mao L, Hruban RH, Boyle JO, Eby YJ, Koch WM, Goodman SN, Sidransky D: Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. N Engl J Med 1995, 332:429-435.
• [56]Poh CF, Zhang L, Anderson DW, Durham JS, Williams PM, Priddy RW, Berean KW, Ng S, Tseng OL, MacAulay C, Rosin MP: Fluorescence visualization detection of field alterations in tumor margins of oral cancer patients. Clin Cancer Res 2006, 12:6716-6722.
• [57]Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH: A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 2003, 63:1727-1730.