Deletion of the M6P/IGF2r gene in primary hepatocellular carcinoma
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.
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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.
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