Cancer Letters

Cancer Letters

Volume 134, Issue 1, 11 December 1998, Pages 23-28
Cancer Letters

Absence of APC gene mutation in the mutation cluster region in hepatocellular carcinoma

https://doi.org/10.1016/S0304-3835(98)00238-9Get rights and content

Abstract

APC gene mutations have been demonstrated not only in colorectal carcinoma but also in a variety of human cancers. To define the possible role of mutations of the APC gene in hepatocarcinogenesis, we examined 46 pairs of hepatocellular carcinomas and corresponding non-tumorous liver tissue by polymerase chain reaction and single strand conformation polymorphism. All 46 hepatocellular carcinomas had no altered electrophoretic mobility to suggest the presence of APC gene mutation in the mutation cluster region. We also examined the possible loss of heterozygosity of APC and MCC gene loci by fragment length polymorphism analysis and by polymerase chain reaction. None of the cases showed a loss of heterozygosity at the APC and MCC gene loci. The results suggested that the possibility of APC and MCC as the gene defect in the genesis of human hepatocellular carcinoma may be very rare.

Introduction

Hepatocellular carcinoma (HCC) is one of the most malignant tumors and is the first ranking cancer-related death in Taiwan. Hepatitis B virus, hepatitis C virus, aflatoxin B1 exposure and cirrhosis are considered as the major risk factors [1]. Nevertheless, the molecular mechanism is still uncertain. Carcinogenesis is a multiple process characterized by multiple genetic alterations, including activation of oncogenes and inactivation of tumor suppressor genes [2]. The adenomatous polyposis coli (APC) gene has been mapped on chromosome 5q21 by cytogenetic and linkage analysis [3], [4]. Germline mutations of the APC gene have been found in patients with familial adenomatous polyposis (FAP) and in sporadic colorectal cancers [5], [6]. Somatic mutation of the gene has been also detected not only in patients with colorectal carcinoma [5], [7], but also in patients with pancreatic cancer [8], gastric cancer [9], oral squamous cell carcinoma [10], hepatoblastoma [11], breast cancer [12], brain tumor [13] and desmoid tumor [14]. These observations suggest that the APC gene is involved in the oncogenesis of various human tumors. Allelic loss of 5q has also frequently been detected in patients with HCC [15], [16]. In addition, the MCC (mutated in colorectal cancer) gene is an another potential tumor suppressor gene located on chromosome 5q21 and is thought to be important for colorectal carcinogenesis [17]. The aim of the present study was to determine the frequency of APC gene mutation in the mutation cluster region (MCR) in a series of surgically resected HCCs in Taiwan by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. We were also interested in analyzing whether the loss of heterozygosity (LOH) of APC/MCC gene loci plays an important role in hepatocarcinogenesis.

Section snippets

Tissue specimens and DNA extraction

Forty-six pairs of HCC tissue and adjacent non-tumorous liver tissue were obtained by surgical resection from patients at Chang Gung Memorial Hospital, Lin Kou, Taiwan. There were 38 men and eight women, aged between 32 and 80 years. Thirty-two patients were hepatitis B virus surface antigen-positive and 11 had serum antibodies against hepatitis C virus. The remaining three patients were negative for both hepatitis B virus surface antigen and hepatitis C virus antibody. Twenty-four patients had

PCR-SSCP analysis

There was no mobility shift in any of the cases, providing evidence against the presence of APC gene mutation within the MCR region in any of these HCCs. Representative data are illustrated in Fig. 1.

LOH in the APC gene

Representative data are illustrated in Fig. 2. Normal DNA obtained from heterozygous patients showed three bands at the APC exon 11 locus, i.e. a 133 bp uncut band from the allele lacking the RsaI restriction enzyme site and two cut bands (85 and 48 bp) representing the allele that contained this

Discussion

APC gene mutations have been demonstrated not only in colorectal carcinoma but also in a variety of human cancers [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]. These mutations are almost always found in the 5′ half of the coding sequence and more than 95% are chain-terminating mutations that would result in the expression of truncated protein [18]. The APC mutations are accepted to be fundamental for colorectal tumor initiation. To our knowledge, there has been no report on

Acknowledgements

This study was supported by grants from the National Science Council (NSC86-2314-B182A-065 and NSC87-2314-B182A-080) and the National Health Research Institute (DOH 85-HR-516 and 86-HR-516) and by the Chang Gung Medical Research Fund (NMRP841and NMRP117).

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