Mutation Analysis of the Putative Tumor Suppressor GenePTEN/MMAC1in Hepatocellular Carcinoma

Abstract

Loss of heterozygosity of chromosome 10q has been reported in hepatoma. Areas with a high rate of loss of genetic material could harbor putative tumor suppressor genes. PTEN/MMAC1, a candidate tumor suppressor gene located at chromosome 10q23.3, has recently been identified and found to be homozygously deleted or mutated in several different types of human tumors. To determine whether the PTEN/MMAC1 gene is a target of 10q loss of heterozygosity in hepatoma, we examined 42 primary hepatomas for mutations in PTEN/MMAC1 by using nested reverse transcriptase polymerase chain reaction (RT-PCR) of the RNA and single-stranded conformation polymorphism (SSCP) analysis of all genomic exons. Although 2 of 42 hepatoma tissues had aberrant transcripts, 5 matched noncancerous liver tissues also had aberrant transcripts. Southern blot analysis of the entire genomic DNA revealed no genomic change. Therefore, like the TSG101 or FHIT gene, aberrant transcripts of PTEN/MMAC1 using the nested RT-PCR method were a common phenomenon for both cancerous and noncancerous liver tissues, which may not be related to oncogenesis. None of the 42 cases had small deletions, point mutations, or insertions. Our results suggest that the PTEN/MMAC1 gene may not play a role in the pathogenesis of hepatoma.

Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma

“…For the five mutations, three samples were found to be PTEN immunoreaction negative and two specimens were found to be immunoreaction positive. Mutation of PTEN seems to play a minor role in the pathogenesis of hepatocellular carcinomas, which is consistent with other reports 9 …”

“…[5][6][7][8] But until now, the regulation of PTEN expression is still unclear, especially in HCC. [9][10][11] To determine the role of PTEN in the tumorigenesis of HCC, we examined the PTEN expression and identified the mutation and promoter methylation in 56 HCC samples and six liver cell lines.…”

A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells

“…Both PTEN and DMBT1 were only altered in 25 ± 30% of glioblastomas, and in a signi®cant number of tumors with heterozygous deletions of 10q, alterations in either PTEN or DMBT1 could not be found (Liu et al, 1997;Tohma et al, 1998;Maier et al, 1998;Somerville et al, 1998;von Deimling et al, 2000). This lack of mutations in these genes was also demonstrated for other tumors which show frequent loss of distal regions of 10q, such as carcinomas of the respiratory tract (Petersen et al, 2000), melanoma (Herbst et al, 1999), endometrial cancers (Simpkins et al, 1998), hepatocellular carcinomas (Fujiwara et al, 2000;Yeh et al, 2000) and prostate carcinoma (Dong et al, 1998). Since Northern blot analysis indicates that WDR11 is expressed in a wide variety of human tissues, it may be a target for inactivation in these tumors as well.…”

Akt as a therapeutic target in cancer

“…In these mice, hepatocytes were hyperproliferative and displayed an abnormal activation of Akt [308] . Furthermore, although mutations in the PTEN gene rarely occur in HCC, frequent loss of heterozygosity of PTEN allele has been identified in 20 -30% of HCC patients [309][310][311][312] . In addition, downregulation of PTEN expression may be partly due to PTEN promoter methylation [313] .…”