hMLH1 and hMSH2 expression in human hepatocellular carcinoma

Wang, Linan; Bani-Hani, Ahmad H.; Montoya, Damian P.; Roche, Patrick C.; Thibodeau, Stephen N.; Burgart, Lawrence J.; Roberts, Lewis R.

doi:10.3892/ijo.19.3.567

Cited by 37 publications

(50 citation statements)

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“…Immunohistochemical studies for MGMT (Matsukura et al, 2001) and hMLH1 (Wang et al, 2001) were performed as described previously. In the present study, mouse monoclonal antibody against hMLH1 protein (clone G168-728; PharMingen, San Diego, CA, USA) (Wang et al, 2001) was used.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection

et al. 2003

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Inactivations of DNA repair genes, O 6 -methylguanine-DNA methyltransferase (MGMT) and hMLH1, by promoter hypermethylation have been reported in several types of primary human neoplasia. This epigenetic inactivation mechanism remains elusive in hepatocellular carcinoma (HCC). To investigate the relation between the expression of MGMT and hMLH1 and the CpG methylation within their promoters in HCCs with or without hepatitis viral infection, we performed immunohistochemistry and urea/bisulphite sequencing on 46 HCCs, corresponding noncancerous tissues, and 20 normal liver tissues. MGMT-and hMLH1-negative HCCs were 60.9% (28 out of 46) and 21.8% (10 out of 46), respectively. HCCs lacking both proteins were 10.9% (five out of 46). The frequency and extent of CpG methylation in the MGMT promoter increased along with hepatitis viral infection and pathological progression. MGMT-negative tumours showed very frequent and widespread methylation in the promoter compared with MGMT-positive tumours. Half of the hMLH1-negative HCCs showed promoter hypermethylation. These data suggested that MGMT gene silencing in a subset of HCCs was likely caused by epigenetic alteration, such as promoter hypermethylation, and that the promoter hypermethylation silenced the hMLH1 gene in half of the hMLH1-negative tumours. A correlation between the promoter methylation status and viral infection, although it was weak, intimated that hepatitis viral infections could play a role in the CpG methylation of the MGMT promoter.

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Section: Immunohistochemistrymentioning

confidence: 99%

“…In the present study, mouse monoclonal antibody against hMLH1 protein (clone G168-728; PharMingen, San Diego, CA, USA) (Wang et al, 2001) was used. Positive staining was identified by the presence of brown staining in the nucleus and/or cytoplasm.…”

Section: Immunohistochemistrymentioning

confidence: 99%

CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection

et al. 2003

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“…Therefore, the polypyrimidine tract, in which we found mutations, may be a mutational target in MSI-positive tumours, and mutations therein may be involved in carcinogenesis and the progression of MSI-positive tumours. Microsatellite instabilityhigh is found rarely in hepatocellular carcinomas, and we could not detect any mutations in the polypyrimidine tract in the 48 cases of hepatocellular carcinoma (Saeki et al, 2000;Yamamoto et al, 2000;Wang et al, 2001).…”

Section: Discussionmentioning

confidence: 80%

Mutations in the ST7/RAY1/HELG locus rarely occur in primary colorectal, gastric, and hepatocellular carcinomas

et al. 2003

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Human cancers frequently show a loss of heterozygosity on chromosome 7q31, which indicates the existence of broad-range tumour-suppressor gene(s) at this locus. Truncating mutations in the ST7 gene at this locus are seen frequently in primary colon cancer and breast cancer cell lines. Therefore, the ST7 gene represents a novel candidate gene for the tumour suppressor at this locus. However, more recent studies have reported that ST7 mutations are infrequent or absent in primary cancer and cell lines. To ascertain the frequency of mutations of the ST7 gene in cancer cells, we examined mutations in the ST7 coding sequence in 48 colorectal, 48 gastric, and 48 hepatocellular carcinomas using polymerase chain reaction -single-strand conformational polymorphism and direct sequencing. We detected somatic mutations, which were located near the exon -intron junction in intron 8, in only three out of 144 cases. We conclude that mutations in the ST7 gene are rare in primary colorectal, gastric, and hepatocellular carcinomas. (Zenklusen et al, 2001). These results suggest that the ST7 gene is a candidate tumour-suppressor gene within this critical region. However, there have been reports that somatic mutation in the ST7 gene is extremely rare (Hughes et al, 2001;Thomas et al, 2001;Brown et al, 2002;Dong and Sidransky, 2002). Thus, the previous data on ST7 gene mutations show conflicting results.In this study, we investigated the true frequency of ST7 gene mutations by examining 48 primary colorectal cancers, 48 primary gastric cancers that frequently show LOH on 7q31 (Nishizuka et al, 1997), and 48 primary hepatocellular carcinomas that show highlevel expression of the ST7/RAY1 gene (Vincent et al, 2000;Zenklusen et al, 2001). We surveyed mutations in the entire ST7 coding sequence using polymerase chain reaction -single-strand conformational polymorphism (PCR -SSCP) analysis and direct DNA sequencing. MATERIALS AND METHODS Tissue specimens and DNA extractionSpecimens from 48 colorectal, 48 gastric, and 48 hepatocellular carcinomas and corresponding noncancerous tissues were obtained at surgery from Japanese patients. The samples were frozen immediately in liquid nitrogen and stored at À801C until use. High-molecular-weight DNA was extracted using the standard phenol/chloroform procedure.

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“…Previously published studies that addressed this question varied tremendously in terms of HCC etiology, a characteristic that depends largely on the geographical origin of the patients, and in the number of tumors analyzed that was between 8 and 56 (5,6,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)39). Furthermore, the type and number of markers also varied considerably from a single mononucleotide repeat marker (14) to 55 microsatellite markers, mostly dinucleotide repeated sequences (19); few studies also included trinucleotide, tetranucleotide and hexanucleotide repeats whose genetic stability may involve DNA repair pathways other than MMR (6,9,16). Most studies screened MSI using PCR technique, but the definition of MSI was not always clearly specified, which makes the comparisons between the published data even more hazardous.…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of MMR protein expression by immunohistochemistry (IHC) is also very popular, with MSH2 and MLH1 being performed in routine while MSH6 and PMS2 are analyzed in rare studies. In HCC, MSI has been investigated by IHC (14,18,20), and by PCR using highly variable sets of microsatellite loci (5, 6, 9-11, 13-20, 39) ( Table I). …”

mentioning

confidence: 99%

Low Levels of Microsatellite Instability at Simple Repeated Sequences Commonly Occur in Human Hepatocellular Carcinoma

Goumard

Desbois-Mouthon

Wendum

et al. 2017

CGP

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hMLH1 and hMSH2 expression in human hepatocellular carcinoma

Cited by 37 publications

References 0 publications

CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection

CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection

Mutations in the ST7/RAY1/HELG locus rarely occur in primary colorectal, gastric, and hepatocellular carcinomas

Low Levels of Microsatellite Instability at Simple Repeated Sequences Commonly Occur in Human Hepatocellular Carcinoma

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