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

Abstract

Primary hepatocellular carcinoma (PHC), epidemiologically associated with chronic hepatitis B virus (HBV) infection, has historically been felt to be caused by the activation or introduction of an oncogene. However, transforming sequences from human PHC have not been reproducibly isolated. In this paper, evidence is presented that suggests PHC may result instead from the loss of an anti-oncogene. Seven of 12 human primary liver tumors tested against a panel of restriction fragment length polymorphisms (RFLPs) demonstrated loss of constitutional heterozygosity for markers on chromosome 4. Tumor and nontumor liver tissue were typed for 11 chromosome 4 RFLPs. In addition, at least one RFLP on nine other chromosomes (1, 2, 6, 7, 9, 11, 13, 14, and 17) was tested for allelic loss. Seven of nine tumors constitutionally heterozygous for chromosome 4q markers showed allele loss in tumor tissue. Six of the seven samples were jointly informative for both 4p and 4q markers. Five of the six demonstrated loss for only 4q RFLPs. In one individual, in which two samples were taken from distant locations within the same tumor, both samples showed loss of the same alleles. Among the other chromosomes informative for allele loss, one tumor showed changes on 13q. No other changes were observed in RFLPs located on the eight other chromosomes tested. These results indicate that an anti-oncogene may be located on 4q and suggest a mechanism for PHC and other cancers seroepidemiologically related to virus infection. Liver cancer caused by chronic HBV infection or other environmental agents may be linked through genetic events responsible for the loss of a tumor suppressor locus (anti-oncogene) located on chromosome 4.

Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis

“…A tumour-suppressor gene relevant for HCC development has already been suspected at this location from several LOH studies (frequency: 17-77%) (Buetow et al, 1989;Zhang et al, 1990;Konishi et al, 1993;Yeh et al, 1996;Chou et al, 1998). A common chromosomal breakpoint mapped to 4q has also been found in 4 out of 50 HCCs (Pasquinelli et al, 1988) as well as an HBV integration site in an HCC at 4q32.1.…”

Functional evidence for a squamous cell carcinoma mortality gene(s) on human chromosome 4

“…LOH, including the interval we have defined, has also been reported in cases of carcinoma of the oesophagus (Hu et al, 2000;Rumpel et al, 1999), cervix (Mitra et al, 1994) and liver (Bluteau et al, 2002;Buetow et al, 1989). In addition, a comparative genomic hybridization study of small cell cancer of the lung revealed loss of the 4q11 -q23 region in 86% of cases (Petersen et al, 1997) and the same technique has revealed the loss of chromosome 4q in breast (Tanner et al, 1998) colon (Arribas et al, 1999) and prostate (Virgin et al, 1999) carcinoma.…”

Multiple Genetic Alterations, 4Q28, A New Suppressor Region, and Potential Gender Differences in Human Hepatocellular Carcinoma

“…The alteration of 1p as an early event in HCC has been implicated previously. 33 Although genetic alterations in 4q in HCC have been documented, 14,17,33,37,38 their relevance to the development and stage of HCC has not been determined. The role of genetic alteration in the 4q and 4q28 region in particular on the initiation and progression of HCC should be further examined.…”