RARβ2 hypermethylation is associated with poor recurrence-free survival in never-smokers with adenocarcinoma of the lung

Clinical Epigenetics

Duk-Hwan Kim¹  Young Mog Shim³  Joungho Han²  Eun Yoon Cho²  Bo Bin Lee⁴  DongHao Jin⁴  Yujin Kim⁴ 

[1] Samsung Biomedical Research Institute, Rm B155, #50 Ilwon-dong, Kangnam-Ku 135-710, Seoul, South Korea;Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Ilwon-dong, Kangnam-Ku 135-710, Seoul, South Korea;Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50 Ilwon-dong, Kangnam-Ku 135-710, Seoul, South Korea;Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, #300 Chunchun-dong, Jangan-Ku, Kyunggido 440-746, Suwon, South Korea

关键词: Recurrence;    Never-smoker;    Methylation;    RARβ2;    Lung cancer;   

Others  :  1147709
DOI  :  10.1186/s13148-015-0066-4

 received in 2014-10-13, accepted in 2015-02-27,  发布年份 2015

【 摘 要 】

Background

This study was aimed at investigating if the effect of RARβ2 hypermethylation on recurrence-free survival (RFS) in non-small cell lung cancer (NSCLC) depends on one’s smoking status and specific interacting proteins.

Results

We retrospectively analyzed the expressions of five proteins using immunohistochemistry in archival formalin-fixed and paraffin-embedded tissues from 578 NSCLC patients who had undergone surgical resection from 1994 through 2004. Promoter methylation of RARβ2 was assessed by bisulfite pyrosequencing. Recurrence was found in 268 (46%) of 578 NSCLCs with a median follow-up period of 4.8 years. Overexpression of β-catenin, c-MET, cyclin D1, and EGFR occurred in 55%, 72%, 51%, and 41% of the patients, respectively. E-cadherin expression was negative in 62% of the patients, and RARβ2 hypermethylation was found in 37%. The abnormal expression of c-MET (P = 0.002) and EGFR (P = 0.001) was found to be highly prevalent in never-smokers. RARβ2 hypermethylation was significantly associated with poor recurrence-free survival (RFS) in 128 never-smokers with adenocarcinoma (P = 0.01) For parsimonious model building, the five proteins were clustered into three groups (β-catenin and E-cadherin; c-MET; cyclin D1 and EGFR) by an unsupervised hierarchical clustering and were included in a multivariate analysis. Cox proportional hazard analysis showed that RARβ2 hypermethylation was significantly associated with poor RFS in 128 never-smokers with adenocarcinoma (adjusted hazard ratio [HR] = 2.19, 95% confidence interval [CI] = 1.28 to 3.47; P = 0.009), after adjusting for interacting proteins.

Conclusions

The present study suggests that RARβ2 hypermethylation may be an independent prognostic factor of RFS in never-smokers with adenocarcinoma of the lung.

【 授权许可】

   
2015 Kim et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Jermal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al.: Cancer statistics, 2008. CA Cancer J Clin 2008, 58:71-96.
• [2]Kim JS, Kim JW, Han J, Shim YM, Park J, Kim DH: Cohypermethylation of p16 and FHIT promoters as a prognostic factor of recurrence in surgically resected stage I non-small cell lung cancer. Cancer Res 2006, 66:4049-54.
• [3]Moghal N, Neel BG: Evidence of impaired retinoic acid receptor-thyroid hormone receptor AF-2 cofactor activity in human lung cancer. Mol Cell Biol 1995, 15:3945-59.
• [4]Bérard J, Laboune F, Mukuna M, Massé S, Kothary R, Bradley WE: Lung tumors in mice expressing an antisense RARbeta2 transgene. FASEB J 1996, 10:1091-7.
• [5]Toulouse A, Morin J, Dion PA, Houle B, Bradley WE: RARbeta2 specificity in mediating RA inhibition of growth of lung cancer-derived cells. Lung Cancer 2000, 28:127-37.
• [6]Virmani AK, Rathi A, Zöchbauer-Müller S, Sacchi N, Fukuyama Y, Bryant D, et al.: Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas. J Natl Cancer Inst 2000, 92:1303-7.
• [7]Zöchbauer-Müller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, Minna JD: Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res 2001, 61:249-55.
• [8]Kim JS, Lee H, Kim H, Shim YM, Han J, Park J, et al.: Promoter methylation of retinoic acid receptor beta 2 and the development of second primary lung cancers in non-small-cell lung cancer. J Clin Oncol 2004, 22:3443-50.
• [9]Kurie JM, Lotan R, Lee JJ, Lee JS, Morice RC, Liu DD, et al.: Treatment of former smokers with 9-cis-retinoic acid reverses loss of retinoic acid receptor-beta expression in the bronchial epithelium: results from a randomized placebo-controlled trial. J Natl Cancer Inst 2003, 95:206-14.
• [10]Vermeulen SJ, Bruyneel EA, van Roy FM, Mareel MM, Bracke ME: Activation of the E-cadherin/catenin complex in human MCF-7 breast cancer cells by all-trans-retinoic acid. Br J Cancer 1995, 72:1447-53.
• [11]Byers S, Pishvaian M, Crockett C, Peer C, Tozeren A, Sporn M, et al.: Retinoids increase cell-cell adhesion strength, beta-catenin protein stability, and localization to the cell membrane in a breast cancer cell line: a role for serine kinase activity. Endocrinol 1996, 137:3265-73.
• [12]Easwaran V, Pishvaian M, Salimuddin , Byers S: Cross-regulation of β-catenin-LEF/TCF and retinoid signaling pathways. Curr Biol 1999, 9:1415-8.
• [13]Shah S, Hecht A, Pestell RG, Byers SW: Trans-repression of β-catenin activity by nuclear receptors. J Biol Chem 2003, 278:48137-45.
• [14]Otero JJ, Fu W, Kan L, Cuadra AE, Kessler JA: Beta-catenin signaling is required for neural differentiation of embryonic stem cells. Dev 2004, 131:3545-57.
• [15]Li Y, Wu RL, Wang X, Chen WS: Effects of retinoic acid on the signal transduction of beta-catenin/Tcf of cultured bronchial epithelial cells. Zhonghua Yi Xue Za Zhi 2004, 84:1130-1.
• [16]Liu T, Lee YN, Malbon CC, Wang HY: Activation of the beta-catenin/Lef-Tcf pathway is obligate for formation of primitive endoderm by mouse F9 totipotent teratocarcinoma cells in response to retinoic acid. J Biol Chem 2002, 277:30887-91.
• [17]Boyle JO, Langenfeld J, Lonardo F, Sekula D, Reczek P, Rusch V, et al.: Cyclin D1 proteolysis: a retinoid chemoprevention signal in normal, immortalized, and transformed human bronchial epithelial cells. J Natl Cancer Inst 1999, 91:373-9.
• [18]Niu MY, Ménard M, Reed JC, Krajewski S, Pratt MA: Ectopic expression of cyclin D1 amplifies a retinoic acid-induced mitochondrial death pathway in breast cancer cells. Oncogene 2001, 20:3506-18.
• [19]Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T: Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res 2004, 64:8919-23.
• [20]Sonobe M, Manabe T, Wada H, Tanaka F: Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer 2005, 93:355-63.
• [21]Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin 2005, 55:74-108.
• [22]Subramanian J, Govindan R: Molecular genetics of lung cancer in people who have never smoked. Lancet Oncol 2008, 9:676-82.
• [23]Rudin CM, Avila-Tang E, Harris CC, Herman JG, Hirsch FR, Pao W, et al.: Lung cancer in never smokers: molecular profiles and therapeutic implications. Clin Cancer Res 2009, 15:5646-61.
• [24]Subramanian J, Govindan R: Lung cancer in ‘Never-smokers’: a unique entity. Oncol (Williston Park) 2010, 24:29-35.
• [25]Yano T, Miura N, Takenaka T, Haro A, Okazaki H, Ohba T, et al.: Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival. Cancer 2008, 113:1012-8.
• [26]Lee HY, Chang YS, Han JY, Liu DD, Lee JJ, Lotan R, et al.: Effects of 9-cis-retinoic acid on the insulin-like growth factor axis in former smokers. J Clin Oncol 2005, 23:4439-49.
• [27]Edge SB, Byrd DR, Compton CC, Fritz AF, Greene FL, Trotti A: American Joint Committee on cancer. In AJCC cancer staging manual. 7th edition. Springer, New York; 2010:253-70.
• [28]Ko E, Lee BB, Kim Y, Lee EJ, Cho EY, Han J, et al.: Association of RASSF1A and p63 with poor recurrence-free survival in node-negative stage I-II non-small cell lung cancer. Clin Cancer Res 2013, 19:1204-12.
• [29]Lee ES, Issa JP, Roberts DB, Williams MD, Weber RS, Kies MS, et al.: Quantitative promoter hypermethylation analysis of cancer-related genes in salivary gland carcinomas: comparison with methylation-specific PCR technique and clinical significance. Clin Cancer Res 2008, 14:2664-72.