Genetic alterations in hepatocellular carcinomas: association between loss of chromosome 4q and p53 gene mutations

Abstract

The major risk factors for hepatocellular carcinomas (HCC) in high incidence areas include infection with hepatitis B and C viruses (HBV, HCV) and exposure to aflatoxin. Genetic alterations in 24 liver resection specimens from Shanghai and Qidong were studied. Hepatitis B virus was integrated in all patient samples, and a null phenotype for the GSTM1 enzyme was present in 63% of patients. Alteration of p53 was present in 95% (23/24) of cases: mutations of the p53 gene in 12 HCC, p53 overexpression in 13 and loss of heterozygosity (LOH) of chromosome 17p in 17. All seven HCCs with a p53 mutation from Qidong and three of five from Shanghai had the aflatoxin-associated point mutation with a G to T transversion at codon 249, position 3. No HCC had microsatellite instability. LOH of chromosome 4q, 1p, 16q and 13q was present in 50%, 46%, 42% and 38%, respectively, and 4q was preferentially lost in HCCs containing a p53 mutation: LOH of 4q was present in 75% (9/12) of HCC with, but only 25% (3/12) of HCC without, a p53 gene mutation ( P = 0.01). These data indicate a possible interaction between p53 gene mutation and 4q loss in the pathogenesis of HCC. © 1999 Cancer Research Campaign

Genetic mechanisms of hepatocarcinogenesis

“…Independent observations have shown a common deletion at 4q35 in moderately or poorly di erentiated HCC . LOH at 4q has also been observed to occur in late tumors with p53 mutations (Rashid et al, 1999), suggesting that chromosome 4q encodes one or more tumor suppressors that complements p53. Although some regions of LOH mapped to the same chromosomal arms deleted in preneoplastic cells or early HCC, it is likely that the extent of deletion at these sites increases with tumor progression.…”

Genetic aberration in primary hepatocellular carcinoma: correlation between p53 gene mutation and loss-of-hetero- zygosity on chromosome 16q21-q23 and 9p21-p23

“…The expression pattern of enzymes for detoxification of AFB1 and DNA repair process are critical in determining the susceptibility to carcinogens at individual levels. Mutant allele or gene deletion of such enzymes such as glutathione S-transferase M1 (GSTM1) has been reported with high frequency in HCC [7]. As for HBV infection, structural or functional alteration of oncogenes or tumor suppressor genes (TSGs) resulting from HBV insertion into host genome was reported in isolated HCC cases, while HBV X protein, showing binding activity with p53 protein and trans-activation properties, has been postulated to have great significance in malignant transformation [8], [9].…”

Chromosome instability in human lung cancers: possible underlying mechanisms and potential consequences in the pathogenesis

“…In this connection, it is interesting to note that haploinsufficiency of the MAD2 gene resulted in a defective mitotic spindle checkpoint in both human cancer cells and murine primary embryonic fibroblasts (MEFs) and that mad2 (+/7) mice developed lung tumors at unusually high rates after long latencies (Michel et al, 2001). Frequent loss of heterozygosity in 4q, where MAD2 resides, has been reported in lung cancer (Petersen et al, 1997a,b;Girard et al, 2000;Ullmann et al, 2001;Pei et al, 2001) as well as in other types of human cancers including Hodgkin's disease, hepatocellular carcinomas, and breast cancers (Dohner et al, 1992;Rashid et al, 1999;Shivapurkar et al, 1999).…”