Cancer Letters

Cancer Letters

Volume 120, Issue 1, 25 November 1997, Pages 39-43
Cancer Letters

Deletion of the M6P/IGF2r gene in primary hepatocellular carcinoma

https://doi.org/10.1016/S0304-3835(97)00289-9Get rights and content

Abstract

To evaluate the different alteration patterns of the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2r) gene in hepatocellular carcinoma (HCC), 41 HCCs were screened for homozygous deletion and loss of heterozygosity (LOH) at the M6P/IGF2r gene with a dinucleotide repeat polymorphic marker. Of these, three (8.8%) were heterozygous and LOH was observed in two (66.7%) of these informative cases. Five (14.7%) out of 34 informative cases showed homozygous deletions for the dinucleotide repeat polymorphic marker. The frequent allelic loss and homozygous deletion of the M6P/IGF2r gene suggest that the M6P/IGF2r gene functions as a tumor suppressor gene in the development of HCC.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world [1]. Hepatitis virus infection and aflatoxin are very important risk factors for HCC [2]. Molecular studies in HCC have shown that frequent loss of heterozygosity (LOH) has been observed on chromosomes 1p, 4q, 5q, 8p, 11p, 13q, 16q and 17p 3, 4, 5, 6, 7, 8, 9, 10, 11. Moreover, frequent allelic loss and/or mutation of p53 and Rb1 genes have been reported 11, 12, 13, 14. However, most of these genetic alterations have been detected at a late stage of hepatocarcinogenesis. Thus, genetic alterations in hepatocarcinogenesis are still unclear.

The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2r) is required for both the activation of TGFβ1, a growth inhibitor [15], and the degradation of IGF2, a mitogen [16]. Therefore, M6P/IGF2r plays an important role in negatively regulating cell growth [17]. Recently, frequent LOH and mutation of M6P/IGF2r in breast cancer and in non-cirrhotic and hepatitis virus negative HCCs have been reported. It has been proposed that these genes may function as a tumor suppressor gene in human cancers 17, 18.

Although the alterations of the M6P/IGF2r gene in carcinoma and its functions are comparable with tumor suppressor genes, the detailed alteration patterns and their association with clinicopathological features have not been studied in detail. We therefore analyzed the LOH and homozygous deletion of the M6P/IGF2r gene in primary HCCs.

Section snippets

HCC tissue selection and DNA extraction

We analyzed 41 HCC tissue specimens. Of these, 39 were obtained from surgical resections performed at the Yonsei University College of Medicine, Seoul, South Korea and two early HCCs were obtained from Nihon University School of Medicine, Tokyo, Japan. There were 28 (68.3%) patients positive for HBV, two (4.9%) positive for HCV, and the remaining 11 (27%) were unrelated to the viral markers. Twenty-four (59%) were present for liver cirrhosis. There were 35 males and six females and the mean age

LOH of the M6P/IGF2r gene

Forty-one HCCs were screened for LOH at the M6P/IGF2r gene loci with a polymorphic dinucleotide repeat sequence marker, IR2 [20]. Of these, seven failed to show any allelic band both in normal and in tumor samples because of the tetranucleotide deletion polymorphism of the IGF2r gene [25]. Two HCCs (66.7%) showed LOH among three informative (heterozygous) cases.

Homozygous deletion of the M6P/IGF2r gene

Five cases showed homozygous deletions for the dinucleotide repeat polymorphic marker (Fig. 1). In four cases, the signal from tumors

Discussion

To evaluate the different alteration patterns of the M6P/IGF2r gene in HCC, we observed LOH and homozygous deletion at M6P/IGF2r loci in 41 HCCs. We found both LOH and homozygous deletions of the M6P/IGF2r gene in HCC. This is the first report of homozygous deletion at the M6P/IGF2r gene in human HCCs. Our results suggest that the M6P/IGF2r gene might function as a tumor suppressor gene in the development of HCC.

The human M6P/IGF2r gene is located at 6q26-27 [26]. Allelic loss on chromosome 6q

Acknowledgements

We are indebted to Dr. Uchida of the Nihon University School of Medicine in Tokyo, Japan for kindly providing two HCC cases. This study was supported by a grant of the 1997 Good Health R&D Project (Grant # HMP-97-M-2-0010), Ministry of Health and Welfare, R.O.K.

References (31)

  • G. Laureys et al.

    Chromosomal mapping of the gene for the type II insulin-like growth factor receptor/cation-independent mannose 6-phosphate receptor in man and mouse

    Genomics

    (1988)
  • G. Gaidano et al.

    Deletions involving two distinct regions of 6q in B-cell non-Hodgkin lymphoma

    Blood

    (1992)
  • R.G. Simonetti et al.

    Hepatocellular carcinoma: a worldwide problem and the major risk factors

    Dig. Dis. Sci.

    (1991)
  • C.C. Harris

    Hepatocellular carcinogenesis: recent advances and speculations

    Cancer Cells

    (1990)
  • H.P. Wang et al.

    Deletions in human chromosome arms 11p and 13q in primary hepatocellular carcinomas

    Cytogenet. Cell Genet.

    (1988)
  • K.H. Buetow et al.

    Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma

    Proc. Natl. Acad. Sci. USA

    (1989)
  • H. Tsuda et al.

    Allele loss on chromosome 16 associated with progression of human hepatocellular carcinoma

    Proc. Natl. Acad. Sci. USA.

    (1990)
  • M. Fujimori et al.

    Allelotype study of primary hepatocellular carcinoma

    Cancer Res.

    (1991)
  • G.J. Walker et al.

    Loss of somatic heterozygosity in hepatocellular carcinoma

    Cancer Res.

    (1991)
  • T. Oda et al.

    p53 gene mutation spectrum in hepatocellular carcinoma

    Cancer Res.

    (1992)
  • M. Konishi et al.

    Genetic change and histopathological grades in human hepatocellular carcinomas

    Jpn. J. Cancer Res.

    (1993)
  • T. Kuroki et al.

    Accumulation of genetic changes during development and progression of hepatocellular carcinoma: loss of heterozygosity on chromosome arm 1p occurs at an early stage of hepatocarcinogenesis

    Gene Chromosome Cancer

    (1995)
  • Y. Yumoto et al.

    Loss of heterozygosity and analysis of mutation of p53 in hepatocellular carcinoma

    J. Gastroenterol. Hepatol.

    (1995)
  • Y. Murakami et al.

    Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas

    Cancer Res.

    (1991)
  • Y. Fujimoto et al.

    Alterations of tumor suppressor gene and allelic losses in human hepatocellular carcinomas in China

    Cancer Res.

    (1994)
  • Cited by (0)

    View full text