Predictive value of CpG island methylator phenotype for tumor recurrence in hepatitis B virus-associated hepatocellular carcinoma following liver transplantation

BMC Cancer, Aug 2010

Background CpG island methylator phenotype (CIMP), in which multiple genes concordantly methylated, has been demonstrated to be associated with progression, recurrence, as well as overall survival in some types of cancer. Methods We examined the promoter methylation status of seven genes including P16, CDH1, GSTP1, DAPK, XAF1, SOCS1 and SYK in 65 cases of HCC treated with LT by methylation-specific PCR. CIMP+ was defined as having three or more genes that are concordantly methylated. The relationship between CIMP status and clinicopathological parameters, as well as tumor recurrence was further analyzed. Results CIMP+ was more frequent in HCC with AFP > 400 ng/ml than those with AFP ≤ 400 ng/ml (P = 0.017). In addition, patients with CIMP+ were prone to have multiple tumor numbers than those with CIMP- (P = 0.007). Patients with CIMP+ tumors had significantly worse recurrence-free survival (RFS) than patients with CIMP-tumors by Kaplan-Meier estimates (P = 0.004). Multivariate analysis also revealed that CIMP status might be a novel independent prognostic factor of RFS for HCC patients treated with LT (HR: 3.581; 95% CI: 1.473-8.710, P = 0.005). Conclusion Our results suggested that CIMP could serve as a new prognostic biomarker to predict the risk of tumor recurrence in HCC after transplantation.

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Predictive value of CpG island methylator phenotype for tumor recurrence in hepatitis B virus-associated hepatocellular carcinoma following liver transplantation

BMC Cancer Predictive value of CpG island methylator phenotype for tumor recurrence in hepatitis B virus-associated hepatocellular carcinoma following liver transplantation Li-Ming Wu 0 Feng Zhang 0 Lin Zhou 0 Zhe Yang 0 Hai-Yang Xie 0 Shu-Sen Zheng 0 0 Key Lab of Combined Multi-organ Transplantation, Ministry of Public Health. Key Lab of Organ Transplantation, Zhejiang Province, China and Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine , Hangzhou , China Background: CpG island methylator phenotype (CIMP), in which multiple genes concordantly methylated, has been demonstrated to be associated with progression, recurrence, as well as overall survival in some types of cancer. Methods: We examined the promoter methylation status of seven genes including P16, CDH1, GSTP1, DAPK, XAF1, SOCS1 and SYK in 65 cases of HCC treated with LT by methylation-specific PCR. CIMP+ was defined as having three or more genes that are concordantly methylated. The relationship between CIMP status and clinicopathological parameters, as well as tumor recurrence was further analyzed. Results: CIMP+ was more frequent in HCC with AFP > 400 ng/ml than those with AFP 400 ng/ml (P = 0.017). In addition, patients with CIMP+ were prone to have multiple tumor numbers than those with CIMP- (P = 0.007). Patients with CIMP+ tumors had significantly worse recurrence-free survival (RFS) than patients with CIMP-tumors by Kaplan-Meier estimates (P = 0.004). Multivariate analysis also revealed that CIMP status might be a novel independent prognostic factor of RFS for HCC patients treated with LT (HR: 3.581; 95% CI: 1.473-8.710, P = 0.005). Conclusion: Our results suggested that CIMP could serve as a new prognostic biomarker to predict the risk of tumor recurrence in HCC after transplantation. - Background Primary liver cancer is one of the most common solid tumors, rated fifth in incidence and the third in mortality worldwide [1]. Hepatocellular carcinoma (HCC) accounts for between 85% and 90% of primary liver cancers [2]. China is one of the highest prevalent areas of HCC, mainly because of chronic hepatitis B carriers accounting for more than 10% of its population [3]. The prognosis of patients with HCC remains generally poor, even after surgical resection or chemotherapy. Liver transplantation (LT) offers a potential curative option for patients with small HCC, but post-operative tumor recurrence remains one of the most prevalent causes of unsatisfactory long-term survival [4]. Therefore, identification of reliable prognostic factors for tumor recurrence and death could have significant clinical importance. Patients in a low-risk group, for example, would be more appropriated candidates for LT, which is benefit for establishing a new set of election and prognostic criteria. Over the past few years, both our group and others have focused on searching for reliable molecular biomarkers to better distinguish subtypes of patients who have different risk of tumor recurrence in HCC patients treated with LT [5-7]. Investigators in our group have established a retrospective cohort of HCC patients who underwent LT at our institution, and analyzed some potential tumor biomarkers within this valuable clinical research database. Yet little is known about the epigenetic biomarkers for selection and prognostic prediction after LT. Recently, as an important mechanism of inactivation of tumor suppressor genes (TSGs), DNA methylation has shown promise as a potential biomarker for early detection, therapy monitoring, assessment of prognosis or prediction of therapy response in a variety of malignancies [8-11], including HCC [12,13]. However, in recent years, a methylator phenotype based on concurrently methylated of multiple TSGs, also called the CpG island methylator phenotype (CIMP), is being considered to have more clinical value than a single gene methylation. [14]. Numerous studies have suggested that CIMP status might be associated with progression, recurrence, as well as long-term survival in different types of cancer, such as non-small cell lung cancer (NSCLC) [15], acute lymphoblastic leukemia [16], neuroblastoma [17], esophageal adenocarcinoma [18]and colon cancer [19]. In HCC, Zhang et al. [20] detected a panel of CIMP including nine TSGs in 50 HCC patients with surgical resection, and found that CIMP status was correlated with elevated preoperative serum AFP level. More recently, Cheng et al. [21] examined the promoter methylation status of 10 genes in 60 cases of HCC with surgical resection, and the results suggested that CIMP could serve as a molecular marker of late stage and poorly prognostic HCC development. However, the predictive value of CIMP for tumor recurrence in HCC patients, especially in HCC treated with LT, remains unclear. Therefore, it is worthy of developing a panel consist of representative genes from key molecular pathways or a selection reflecting the C (...truncated)


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Li-Ming Wu, Feng Zhang, Lin Zhou, Zhe Yang, Hai-Yang Xie, Shu-Sen Zheng. Predictive value of CpG island methylator phenotype for tumor recurrence in hepatitis B virus-associated hepatocellular carcinoma following liver transplantation, BMC Cancer, 2010, pp. 399, 10, DOI: 10.1186/1471-2407-10-399