Golgi protein 73 (GOLPH2) is a valuable serum marker

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http://gut.bmj.com/content/early/2010/09/28/gut.2010.214916.full.html

Gut published online September 28, 2010

doi: 10.1136/gut.2010.214916

Downloaded from gut.bmj.com on October 5, 2010 - Published by group.bmj.com

Yilei Mao,1 Huayu Yang,1 Haifeng Xu,1 Xin Lu,1 Xinting Sang,1 Shunda Du,1

Haitao Zhao,1 Wang Chen,1 Yiyao Xu,1 Tianyi Chi,1 Zhiying Yang,1 Jianqiang Cai,2

Hui Li,3 Jianguo Chen,4 Shouxian Zhong,1 Smruti R Mohanti,5 Reynold

-Soler,5

J Millis,5 Jiefu Huang,1 Hongbing Zhang3

1Department of Liver Surgery,

Peking Union Medical College

(PUMC) Hospital, PUMC,

Chinese Academy of Medical

Sciences, Beijing, China

2Cancer Institute and Hospital,

PUMC, Chinese Academy of

Medical Sciences, Beijing, China

3State Key Laboratory of

Medical Molecular Biology,

Department of Physiology and

Pathophysiology, Institute of

Basic Medical Sciences and

School of Basic Medicine,

PUMC, Chinese Academy of

Medical Sciences, Beijing, China

4Qidong Liver Cancer Institute,

Jiangsu Province, China

5Liver Transplantation and

Hepatobiliary Surgery, University

of Chicago, Illinois, USA

Correspondence to

Yilei Mao, Department of Liver

Surgery, Peking Union Medical

College Hospital, 1#

Shuaifuyuan, Dongcheng

District, Beijing, 100730 China;

maoy@...,

dolphinyahy@...

Revised 7 June 2010

Accepted 21 June 2010

Golgi protein 73 (GOLPH2) is a valuable serum marker

for hepatocellular carcinoma

ABSTRACT

Background and aims

Golgi protein 73 (GP73) as

a potential serum marker for hepatocellular carcinoma

(HCC) has not been validated in large cohort studies.

Furthermore, its significance in the assessment of

tumour recurrence after HCC resection remains

unknown. The aim of this study was to determine the

value of serum GP73 in the diagnosis of HCC.

Methods

Serum GP73 and alpha-fetoprotein (AFP) were

compared in a total of 4217 human subjects in this

multicentre study, including 1690 healthy adults, 337

hepatitis B virus (HBV) carriers, 512 patients with

cirrhosis, 789 patients with HCC, 61 patients with other

malignant liver lesions, 206 patients with benign liver

lesions and 622 patients with 14 different kinds of nonliver

cancers. The main outcome measures were the

specificity and sensitivity of GP73 in patients at risk for

the development of HCC.

Results

Using 8.5 relative units as a cut-off value, the

sensitivity and specificity of serum GP73 for HCC were

74.6% (95% CI 71.5% to 77.6%) and 97.4% (95% CI 96.8

to 98.3%), compared with 58.2% (95% CI 55.2% to

62.1%) and 85.3% (95% CI 83.4% to 88.1%) for AFP

(p<0.001) using 35 ng/ml as a cut-off value. The GP73

level was significantly increased in patients with HCC

compared with healthy controls (14.7 vs 1.2, p<0.001).

Although GP73 levels in HBV carriers (2.9) and patients

with cirrhosis (4.7) were somewhat elevated, they were

much lower than that in patients with HCC (p<0.001).

GP73 decreased following surgical resection of HCC

lesions and increased with tumour recurrence. Fourteen

types of non-liver cancers were analysed; all the benign

and other malignant liver lesions had moderate

elevations of GP73, albeit at a much lower level than in

HCC.

Conclusions

GP73 is an accurate serum marker for the

detection of HCC and its recurrence after surgery, with

higher sensitivity and specificity than AFP. Clinical

implementation of serum GP73 measurement as

a standard test for HCC is recommended.

INTRODUCTION

Hepatocellular carcinoma (HCC) is strongly

associated with either chronic hepatitis B virus

(HBV) or hepatitis C virus (HCV) infection,1e3

and is the fifth most common cancer and the third

leading cause of cancer death worldwide.1e4 In the

USA, the incidence of HCC is increasing faster

than that of any other cancer.5 Notably, HCC is

a leading cause of cancer death in China. In China,

7.18% of the entire population are HBV carriers

(93 million, two-thirds of the world’s total

number of carriers); Chinese HCC patients

account for >55% of new HCC cases worldwide

(Global Cancer Facts & Figures 2007, American

Cancer Society).4 6 A 10-year survey (1990e2001)

conducted in China indicates that HCC ranks first

among chronic diseases for the social cost and

burden in the WHO ‘disability-adjusted life year

(DALY)’ list.7 The 5-year survival rate of all HCC

is <5%, placing it among the cancers with

the worst prognosis.2 5 8 The prognosis can be

significantly improved by early diagnosis and

treatment.1

The use of serological markers in patients at the highest risk

for developing HCC can thus decrease the cancer-related

mortality and reduce medical costs. Alpha-fetoprotein (AFP) has

been the only standard serum marker for the detection of HCC

for the last 40 years, even though its sensitivity of 39e65% is

not very satisfactory.4 5 9 Identification of better early diagnostic

biomarkers is crucial.5 Recent studies have identified Golgi

protein 73 (GP73; also named Golgi phosphoprotein 2

(GOLPH2)), as a potential novel HCC serum marker.10 11 GP73

is a 400 amino acid, 73 kDa transmembrane glycoprotein that

normally resides within the cis-Golgi complex. Its mRNA was

first identified in a search for upregulated hepatic genes in a

patient with syncytial giant cell hepatitis.11 Although upregulated

GP73 was initially identified in hepatic viral infections with

unknown function, it can be excreted after modification.12e14

Subsequent studies showed that the GP73 serum level is elevated

in diverse viral and non-viral liver diseases, including hepatitis,

cirrhosis and HCC, and also in non-liver malignances.9e11 15e27

Of significance is that serum GP73 is dramatically elevated in

patients with HCC, and the sensitivity and specificity of GP73 for

HCC might be superior to those of AFP.9 11 19 20 23 24 However,

the potential value of GP73 as a better serum biomarker than AFP

is controversial.22 25 26 One possible explanation for continued

controversy is the lack of larger observational studies. There is

a consensus that comprehensive studies of large cohorts with

a broad spectrum of disease are needed to validate GP73 as an

HCC serum marker.9 24 25

In the present study, we compared GP73 and AFP in >4200

serum samples from healthy subjects and patients with various

benign and malignant liver diseases, non-liver cancers, plus

samples from patients with HCC collected before and after

surgery, from multiple centres in China and the USA.