PTEN/MMAC1 mutations in hepatocellular carcinomas

Abstract

Mutations in the PTEN/MMAC1 gene have been identi®ed in several types of human cancers and cancer cell lines, including brain, endometrial, prostate, breast, thyroid, and melanoma. In this study, we screened a total of 96 hepatocellular carcinoma (HCC) samples from Taiwan, where HCC is the leading cancer in males and third leading cancer in females, for mutations in the PTEN/MMAC1 gene. Complete sequence analysis of these samples demonstrated a missense mutation in exon 5 (K144I) and exon 7 (V255A) from HCC samples B6-21 and B6-2, respectively. A putative splice site mutation was also detected in intron 3 from sample B6-2. Both B6-21 and B6-2 were previously shown to contain missense mutations in the coding sequences of the p53 gene. Functional studies with the two missense mutations demonstrated that while mutation V255A in exon 7 resulted in a loss of phosphatase activity, mutation K144I in exon 5 retained its phosphatase activity. Additionally, we identi®ed a silent mutation (P96P) in exon 5 of the PTEN/MMAC1 gene from HCC sample B6-22. These data provide the ®rst evidence that the PTEN/MMAC1 gene is mutated in a subset of HCC samples.

Impact of PTEN expression on the outcome of hepatitis C virus‐positive cirrhotic hepatocellular carcinoma patients: Possible relationship with COX II and inducible nitric oxide synthase

“…3 Both a novel silent mutation in exon 5 and a putative splice mutation in intron 3 have been reported recently in the PTEN gene from human hepatocellular carcinoma (HCC), one of the most common malignancies in the world. 10 These mutations were absent in the control normal population suggesting that PTEN might be involved in hepatocarcinogenesis and that detection of PTEN mutations may be valuable as biomarker of HCC risk. 10 So far, most of the studies using immunohistochemistry for PTEN detection concluded that the expression of the protein is usually down-regulated in cancerous tissues in comparison to their normal counterparts.…”

“…9 Although PTEN mutations and allele loss at 10q23 have been reported to occur in HCC with a high frequency (30 -50%), the prognostic significance of PTEN mutation for HCC-patients remains a matter of controversy. 10 Different studies suggest that PTEN negatively regulates carcinoma cell growth by controlling Akt/PKB signaling pathway 11 whereas Akt/PKB can induce iNOS and COX II expression. 12 It has been shown recently that PI3K/Akt signaling pathway is involved in HCC 13 and that iNOS and COX II are factors with well established implication in hepatocarcinogenesis especially among HCV-positive and cirrhotic patients.…”

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

“…Loss of this important tumor suppressor gene product, which modulates PI3K activity, occurs in a variety of human neoplasms (Steck et al, 1997). Mutational inactivation of PTEN has been detected in human HCC (Fujiwara et al, 2000;Yao et al, 1999;Yeh et al, 1999). Another phosphoinositide-speci®c phosphatase SHIP has been described (Lioubin et al, 1996;Dame et al, 1996).…”

Molecular cloning and characterization of LAPTM4B, a novel gene upregulated in hepatocellular carcinoma

“…During initiation and progression of HCC, tumor-suppressor genes such as p53 (Li et al, 1993), p16, p21 (Qin et al, 1998), p27 (Tannapfel et al, 2000), beta-catenin (Wong et al, 2001), PTEN (Yao et al, 1999), and Rb were frequently deregulated or completely disrupted by point mutations, loss of heterozygosity (LOH), and methylation. On the other hand, oncogenes and certain cell cycle controllers, such as c-myc (Wu et al, 1996), c-Jun, c-fos (Twu et al, 1993), c-met (Boix et al, 1994;Grigioni et al, 1995), cets-1 (Ozaki et al, 2000), cyclin D1 (Peng et al, 1998;Deane et al, 2001;Joo et al, 2001), cyclin E (Peng et al, 1998), and gankyrin (Higashitsuji et al, 2000), were overexpressed or re-expressed in the later stage of hepatocellular carcinogenesis.…”