Comprehensive allelotyping of human hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers in many parts of the world, however the molecular mechanisms underlying liver cell transformation remain obscure. A genome-wide scan of loss of heterozygosity (LOH) in tumors provides a powerful tool to search for genes involved in neoplastic processes. To identify recurrent genetic alterations in liver tumors, we examined DNAs isolated from 120 HCCs and their adjacent non tumorous parts for LOH using a collection of 195 microsatellite markers located roughly every 20 cM throughout 39 autosomal arms. The mean heterozygosity was 73%. Our ®ndings provide additional support that LOH for loci on chromosomal arms 1p, 4q, 6q, 8p, 13q and 16p is signi®cantly elevated in HCC. The highest percentage of LOH is found for a locus in 8p23 (42% of informative csaes). This corresponds to one of the most common genetic abnormalities reported to date in these tumors. In addition, high ratio of LOH (535%) is observed on chromosome arms which had not been implicated in previous studies, notably on 1q, 2q and 9q. No correlation was found between LOH of speci®c chromosomal regions and etiologic factors such as chronic infections with hepatitis B or C viruses. This ®rst report of an extensive allelotypic analysis of HCC should help in identifying new genes whose loss of function contributes to the development of liver cancer.

Molecular diagnosis of primary liver cancer by microsatellite DNA analysis in the serum

“…The marker pairs selected for HCC (74 markers from 17 chromosomal arms) included 1p (D1S160, D1S163, D1S170, D1S186, MYCL), 3p (D3S1317), 4p (D4S394), 4q (D4S398, D4S395, D4S392, D4S422, FGA, FABP2, D4S427, D4S415, D4S1615, D4S1554, D4S1426, D4S1598, D4S620, D4S1566, D4S1545, D4S2920, D4S2943, D4S2954), 5q (D5S409), 6q (D6S264), 8p (D8S261, D8S277), 8q (D8S85, D8S200, D8S555, D8S283), 9p (D9S169, D9S1747, D9S104), 10q (D10S109), 11p (D11S554, D11S436, D11S1344, D11S932, D11S1324), 11q (D11S938, D11S29), 12p (D12S93), 13q (D13S171, D13S153, Rb1, D13S133, D13S227, D13S159, D13S166, D13S168), 14q (D14S72, D14S51), 16p (D16S419, D16S409, D16S3106, D16S498), 16q (D16S415, D16S408, D16S512, D16S289, D16S402, D16S516, D16S422, D16S413), and 17p (D17S520, D17S1176, TP53, D17S513, D17S578, D17S796, D17S849) based on previous reports (Yeh et al, 1996;Nagai et al, 1997;Piao et al, 1998;Fujii et al, 2000;Okabe et al, 2000;Yeh et al, 2001). The marker pairs selected for CC (35 markers from 16 chromosomal arms) included 2p (BAT-26), 3p (D3S3667, D3S1578, D3S3582, D3S3560, D3S1581, D3S3729, D3S1588, D3S3648), 4 (D4S415, D4S413), 5q (D5S323, D5S417), 6p (D6S263), 6q (D6S292), 7q (D7S495, D7S486), 9p (D9S747, D9S171), 11p (D11S907, D11S569), 14q (D14S1436), 16q (D16S3094, D16S511, D16S534, D16S520), 17 (D17S695), 18q (D18S67, D18S51, D18S535), 20 (D20S85), 21q (D21S1245, D21S1436, D21S1270), and Xp (DXS538) (Ding et al, 1993;Fujii et al, 2000).…”

Distinct chromosomal abnormality pattern in primary liver cancer of non-B, non-C patients

“…Although far more than 50% of HCCs are attributable to chronic HBV infection, the mechanisms by which HBV contributes to tumor formation remain unclear. In an e ort to identify genetic abnormalities associated with HCC development, we and others had undertaken genome-wide explorations using loss of heterozygosity (LOH) assay and comparative genomic hybridization (Nagai et al, 1997;Boige et al, 1997;Marchio et al, 1997). The most frequent losses were found on chromosome arms 1p, 4q, 6q, 8p, 13q, 16q and 17p.…”

Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis

“…Thus there is a need for a largely unbiased screening to detect genetic events so far not connected with HCC development. Previous studies using loss of heterozygosity (LOH) analyses Nishida et al, 1992;Tsuda et al, 1992;Nagai et al, 1997) were restricted by the selection of LOH markers and the fact that by this technique only the detection of potential tumour suppressor gene loci is feasible. Furthermore data from LOH analyses in HCCs vary significantly between the different studies; the resulting LOHs are widely distributed throughout the genome and have therefore not contributed significantly to the identification of tumour-relevant genes.…”