Purpose. In the present study, the prognostic significance of CpG island methylator phenotype (CIMP) in stage II/III sporadic colorectal cancer was evaluated using a five-gene panel. Methods. Fifty stage II/III colorectal cancer patients who received radical resection were included in this study. Promoter methylation of p14ARF, hMLH1, p16INK4a, MGMT, and MINT1 was determined by methylation specific polymerase chain reaction (MSP). CIMP positive was defined as hypermethylation of three or more of the five genes. Impact factors on disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier method (log-rank test) and adjusted Cox proportional hazards model. Results. Twenty-four percent (12/50) of patients were characterized as CIMP positive. Univariate analysis showed stage III ( ) and CIMP positive ( ) patients who had significantly inferior DFS. In Cox regression analysis, CIMP positive epigenotype was independently related with poor DFS with HR = 2.935 and 95% CI: 1.193–7.220 ( ). In patients with CIMP positive tumor, those receiving adjuvant chemotherapy had a poor DFS than those without adjuvant chemotherapy ( ). Conclusions. CIMP positive was significantly correlated with decreased DFS in stage II/III colorectal cancer. Patients with CIMP positive locally advanced sporadic colorectal cancers may not benefit from 5-fluorouracil based adjuvant chemotherapy. 1. Introduction Colorectal cancer is a major cause of mortality and morbidity throughout the world. With adjuvant chemotherapy as standard management following surgery to treat stage III and stage II patients with high risk factors, the 5-year relative survival rate of locally advanced colorectal cancer was still 69.2% compared with 90.1% among patients with localized disease [1], which highlighted the need of better prognostic and predictive markers to identify those high-risk individuals. Promoter CpG island hypermethylation resulting in the transcriptional silencing of tumor suppressor genes has been widely observed in colorectal cancer and been increasingly recognized to contribute to the pathogenesis of colorectal cancer. The subset of colorectal cancers with exceptionally high frequency of CpG island methylation were referred to as CpG island methylator phenotype (CIMP) [2] and showed distinct clinicopathological characteristics [3–5]. Tumor-specific hypermethylated loci of p14ARF, hMLH1, p16INK4a, MGMT, and MINT1 were proved to be closely related with colorectal cancers [2, 6]. However, the prognostic and predictive value of CIMP in sporadic locally advanced
References
[1]
R. Siegel, D. Naishadham, and A. Jemal, “Cancer statistics, 2013,” CA Cancer Journal for Clinicians, vol. 63, no. 1, pp. 11–30, 2013.
[2]
M. Toyota, N. Ahuja, M. Ohe-Toyota, J. G. Herman, S. B. Baylin, and J.-P. J. Issa, “CpG island methylator phenotype in colorectal cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 15, pp. 8681–8686, 1999.
[3]
N. Hawkins, M. Norrie, K. Cheong et al., “CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability,” Gastroenterology, vol. 122, no. 5, pp. 1376–1387, 2002.
[4]
D. J. Weisenberger, K. D. Siegmund, M. Campan et al., “CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer,” Nature Genetics, vol. 38, no. 7, pp. 787–793, 2006.
[5]
A. Goel, T. Nagasaka, C. N. Arnold et al., “The CpG island methylator phenotype and chromosomal instability are inversely correlated in sporadic colorectal cancer,” Gastroenterology, vol. 132, no. 1, pp. 127–138, 2007.
[6]
A. M. Jubb, S. M. Bell, and P. Quirke, “Methylation and colorectal cancer,” Journal of Pathology, vol. 195, no. 1, pp. 111–134, 2001.
[7]
S. B. Edge and C. C. Compton, “The american joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM,” Annals of Surgical Oncology, vol. 17, no. 6, pp. 1471–1474, 2010.
[8]
G. Cai, Y. Xu, H. Lu et al., “Clinicopathologic and molecular features of sporadic microsatellite- and chromosomal-stable colorectal cancers,” International Journal of Colorectal Disease, vol. 23, no. 4, pp. 365–373, 2008.
[9]
L. A. E. Hughes, C. A. J. Khalid-de Bakker, K. M. Smits et al., “The CpG island methylator phenotype in colorectal cancer: progress and problems,” Biochimica et Biophysica Acta, vol. 1825, no. 1, pp. 77–85, 2012.
[10]
J. R. Jass, “Classification of colorectal cancer based on correlation of clinical, morphological and molecular features,” Histopathology, vol. 50, no. 1, pp. 113–130, 2007.
[11]
W. S. Samowitz, H. Albertsen, J. Herrick et al., “Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer,” Gastroenterology, vol. 129, no. 3, pp. 837–845, 2005.
[12]
R. L. Ward, K. Cheong, S.-L. Ku, A. Meagher, T. O'Connor, and N. J. Hawkins, “Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability,” Journal of Clinical Oncology, vol. 21, no. 20, pp. 3729–3736, 2003.
[13]
S. Lee, N.-Y. Cho, E. J. Yoo, J. H. Kim, and G. H. Kang, “CpG island methylator phenotype in colorectal cancers: comparison of the new and classic CPG island methylator phenotype marker panels,” Archives of Pathology and Laboratory Medicine, vol. 132, no. 10, pp. 1657–1665, 2008.
[14]
L. Barault, C. Charon-Barra, V. Jooste et al., “Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases,” Cancer Research, vol. 68, no. 20, pp. 8541–8546, 2008.
[15]
S. Lee, N.-Y. Cho, M. Choi, E. J. Yoo, J.-H. Kim, and G. H. Kang, “Clinicopathological features of CpG island methylator phenotype-positive colorectal cancer and its adverse prognosis in relation to KRAS/BRAF mutation,” Pathology International, vol. 58, no. 2, pp. 104–113, 2008.
[16]
J. H. Kim, S. H. Shin, H. J. Kwon, N. Y. Cho, and G. H. Kang, “Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers,” Virchows Archiv, vol. 455, no. 6, pp. 485–494, 2009.
[17]
S. Ogino, K. Nosho, G. J. Kirkner et al., “CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer,” Gut, vol. 58, no. 1, pp. 90–96, 2009.
[18]
S. Ogino, J. A. Meyerhardt, T. Kawasaki et al., “CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma,” Virchows Archiv, vol. 450, no. 5, pp. 529–537, 2007.
[19]
L. Shen, P. J. Catalano, A. B. Benson III, P. O'Dwyer, S. R. Hamilton, and J.-P. J. Issa, “Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil-based chemotherapy,” Clinical Cancer Research, vol. 13, no. 20, pp. 6093–6098, 2007.
[20]
R. Jover, T. Nguyen, L. Prezcarbonell et al., “5-fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer,” Gastroenterology, vol. 140, no. 4, pp. 1174–1181, 2011.
[21]
M. Van Rijnsoever, H. Elsaleh, D. Joseph, K. McCaul, and B. Iacopetta, “CpG island methylator phenotype is an independent predictor of survival benefit from 5-fluorouracil in stage III colorectal cancer,” Clinical Cancer Research, vol. 9, no. 8, pp. 2898–2903, 2003.
[22]
B.-H. Min, J. M. Bae, E. J. Lee et al., “The CpG island methylator phenotype may confer a survival benefit in patients with stage II or III colorectal carcinomas receiving fluoropyrimidine-based adjuvant chemotherapy,” BMC Cancer, vol. 11, article 344, 2011.
[23]
A. Rashid, L. Shen, J. S. Morris, J.-P. J. Issa, and S. R. Hamilton, “CpG island methylation in colorectal adenomas,” American Journal of Pathology, vol. 159, no. 3, pp. 1129–1135, 2001.
[24]
M. Toyota, N. Ahuja, H. Suzuki et al., “Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype,” Cancer Research, vol. 59, no. 21, pp. 5438–5442, 1999.
[25]
H. Yamamoto, Y. Min, F. Itoh et al., “Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancers with high-frequency microsatellite instability,” Genes Chromosomes and Cancer, vol. 33, no. 3, pp. 322–325, 2002.
[26]
H. Kim, Y. H. Kim, S. E. Kim, N.-G. Kim, S. H. Noh, and H. Kim, “Concerted promoter hypermethylation of hMLHI, p16INK4A, and E-cadherin in gastric carcinomas with microsatellite instability,” Journal of Pathology, vol. 200, no. 1, pp. 23–31, 2003.
