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)