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Recently, the succinate dehydrogenase subunit B gene, SDHB, has emerged as a novel tumor suppressor. In this study, we have examined the genetic and epigenetic alterations of the SDHB gene in sporadic gastric adenocarcinomas in order to investigate if the SDHB gene is involved in gastric carcinogenesis. The expression of SDHB proteins was also examined with immunohistochemistry and Western blot in 184 and eight gastric cancers, respectively. There was loss or reduced expression of SDHB in 45 (24.5%) of the 184 gastric cancers. Statistically, altered expression of SDHB was not associated with clinicopathological parameters, including tumor differentiation, location, depth of invasion, and lymph node metastasis ( P > 0.05). Western blot analysis showed a reduced expression of SDHB in four (50.0%) of the eight paired gastric cancer tissues. Genetic analysis showed one missense mutation, GCC → ACC (Ala → Thr) at codon 29. In addition, promoter hypermethylation was not detected in the gastric cancer samples. This is the first investigation of the genetic and protein expression analysis of the SDHB gene in gastric cancers. Our results suggest that genetic, epigenetic, and protein expression pattern alterations of the SDHB gene might play a minor role in the development or progression of gastric cancers. [ABSTRACT FROM AUTHOR]

The article discusses a study which evaluated the absence of E17K mutation in the pleckstrin homology domain of AKT1 in gastrointestinal and liver cancers in Korea. Lines of evidence which suggest that components of the AKT pathway are involved in the oncogenic transformation of normal cells are cited. The AKT1 mutation may be attributed to different geographical origin of the patients. Results also show that AKT activation plays an important role in tumorigenesis and tumor progression of gastrointestinal and hepatocellular carcinomas.

Gastric atrophy and intestinal metaplasia are generally considered precancerous lesions of the stomach; Cdx2 plays an important role in intestinal metaplasia and gastric carcinogenesis. To elucidate the potential etiological role of the Cdx2 gene in gastric carcinogenesis, we analyzed genetic mutations and allelic loss in the Cdx2 gene of 95 sporadic gastric cancers. We found two somatic missense mutations in the Cdx2 gene, P63L in exon 1 and E204K in exon 2, encoding the caudal-like protein activation region (codon 13–180) and the homeobox domain (codon 188–243) of the gene, in the gastric cancers. In addition, 9 (25.0%) of 36 informative cases showed allelic loss at D13S220 and/or D13S260. In 11 cases with a genetic alteration, Cdx2 nuclear staining was observed only in 8 cases of gastric mucosa with intestinal metaplasia. Loss or reduced expression of the Cdx2 gene in cancer cells was found in two cases with a somatic mutation and in three cases with LOH. Interestingly, all of the cases were intestinal-type gastric cancers. Thus, these results suggest that genetic alterations of the Cdx2 gene may contribute to the loss of Cdx2 expression and to the development of gastric cancer, especially in the intestinal-type. [ABSTRACT FROM AUTHOR]

KLF4, which is also known as the gut-enriched Kruppel-like factor, plays important roles during the proliferation and differentiation of gastrointestinal epithelial cells. A loss of KLF4 expression has been observed in human tumors, particularly in the gastrointestinal tract. In this study, the molecular basis of the KLF4 inactivation in gastric cancer was investigated by analyzing the somatic mutation, the allelic loss with two microsatellite markers, D9S53 and D9S105, and hypermethylation of the KLF4 gene in 47 gastric adenomas and 81 gastric adenocarcinomas. Mutational analysis revealed one mutation of the KLF4 gene in a diffuse-type advanced gastric adenocarcinoma, but not in the gastric adenoma. This mutation was a somatic missense mutation, GGG→AGG (Gly→Arg) at codon 107 in exon 3, which encodes a transcriptional activation domain of the protein. An allelic loss was found in 7 (22.6%) of the 31 informative gastric adenoma cases and 15 (31.3%) of the 48 informative cancer cases at one or both markers. In addition, promoter hypermethylation of the KLF4 gene was observed in only two gastric cancers. These results suggest that genetic and epigenetic alterations of the KLF4 gene might play a minor role in gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) regulates many cellular processes, including cellular proliferation and differentiation. Disruption of the TGF-β signaling pathway can lead to cancer. Serine–threonine receptor kinase-associated protein (STRAP), an inhibitor of TGF-β signaling, is an important regulator of cell proliferation. Here, in order to investigate the roles of STRAP in colorectal carcinogenesis, the expression of the STRAP protein was investigated in 59 colonic adenomas and 123 colorectal cancers by immunohistochemistry. Upregulation of STRAP protein was observed in 30 (50.8%) of 59 adenomas and 87 (70.7%) of 123 cancers, respectively. Statistically, overexpression of STRAP protein was not associated with clinicopathological parameters and 5 year survival ( P > 0.05). Interestingly, significant association was observed between STRAP and Ki-67 positivity ( P < 0.05), suggesting that STRAP contributes to an increased proliferate potential of tumor cells. These results indicate that upregulation of STRAP might play a role in tumor development as an early event for colorectal cancers. [ABSTRACT FROM AUTHOR]

EPHB2 is a member of the Eph receptor tyrosine kinase family and a direct transcriptional target of β-catenin/TCF. EPHB2 plays an important role in maintaining the correct positioning of the proliferative compartment in the crypt-villous axis. A loss of EPHB2 expression has been observed in human tumors, particularly in colonic adenomas and carcinomas. A search was made for mutations at the A9 tract in exon 17, an allelic loss at the EPHB2 gene locus, and promoter hypermethylation of the EPHB2 gene in 81 sporadic gastric cancers in order to determine if genetic or epigenetic alterations of the EPHB2 gene are involved in the development and/or progression of gastric cancer. Unexpectedly, no frameshift mutation was found and there was a low frequency (20.8%) of allelic loss. In addition, promoter hypermethylation was detected in only one gastric cancer tissue sample. Therefore, genetic or epigenetic alterations of the EPHB2 gene might be an uncommon event in the development or progression of gastric cancers. [ABSTRACT FROM AUTHOR]

Beta-TrCP is a component of the ubiquitin ligase complex targeting β-catenin for proteasomal degradation, and is a negative regulator of Wnt/β-catenin signaling. To determine whether genetic alterations of the β-TrCP gene are involved in the development or progression of gastric cancer, we analyzed its somatic mutations in 95 gastric cancers by single-strand conformational polymorphism and sequencing. We found five missense mutations (5.3%): A99V, H342Y, H425Y, C206Y, and G260E. Tissue carrying mutations showed moderate to strong cytoplasmic and/or nuclear staining of β-catenin by immunohistochemistry. Thus, somatic mutations of the β-TrCP gene may contribute to the development of gastric cancer through β-catenin stabilization. [ABSTRACT FROM AUTHOR]

Background and Aim: Kruppel-like factor 6 ( KLF6) is a zinc finger tumor suppressor gene that is frequently mutated in several human cancers and is broadly involved in differentiation and development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. The aim of this study was to elucidate the potential etiological role of KLF6 in the development of hepatocellular carcinoma (HCC) in Korea. Methods: The gene mutation, allelic loss, and methylation status of the KLF6 gene was analyzed in a series of 85 Korean patients: 21 with dysplastic nodules and 85 with HCC. Results: No somatic mutations were observed in the patients with dysplastic nodules or with HCC. Allelic loss was found in five (6.8%) of 73 informative HCC tissues. Three of the five patients with allelic loss had HCC with hepatitis B virus infection and cirrhosis, and the remaining two had no viral infection and a non-specific background. In methylation analysis, unmethylated and methylated DNAs of the KLF6 gene were amplified in all corresponding non-neoplastic liver tissues. Only one HCC tissue showed methylated DNA without unmethylated DNA. Conclusions: The results suggest that genetic and epigenetic alteration of KLF6 may play a minor role in the development of HCC. [ABSTRACT FROM AUTHOR]

The peptidyl-prolyl isomerase Pin1 is strikingly overexpressed in human cancers and is a novel regulator of β-catenin. To determine whether somatic mutation of the Pin1 gene is involved in the development and/or progression of gastric cancer, we searched for mutations of the Pin1 gene in 95 gastric cancer specimens. The effect of Pin1 on β-catenin expression was further examined in wild- and mutant-type Pin1-transfected HEK 293T cells. We found only one missense mutation that led to the substitution of alanine by aspartic acid at codon 118 of the Pin1 gene. On transfection study, the mutant Pin1 showed an increased expression of β-catenin. However, the mutation had no effect on expression of the Pin1 protein in the case with Pin1 mutation. These results suggest that Pin1 may not play a role in the development or progression of gastric cancer. [ABSTRACT FROM AUTHOR]

In addition to chromosomal translocation, the MYC gene in the N-terminal coding region showed clustered point mutations in Burkitt's lymphomas. A recent study showed that these point mutations inactivated the apoptosis activity of MYC and contributed to the tumor transformation. To see whether the point mutations of MYC are involved in tumors besides Burkitt's lymphomas, we analyzed the N-terminal cluster region of the mutations in 507 cancers from gastric, colorectal, breast and lung carcinomas, and acute leukemias, by polymerase chain reaction-based single-strand conformation polymorphism assay. However, there was no somatic mutation of the MYC gene in the cancers. The data suggest that the point mutation of the MYC gene in the N-terminal domain may be very rare and may not contribute to the development of common human cancers besides Burkitt's lymphomas. [ABSTRACT FROM AUTHOR]

To investigate whether the KLF6 gene plays an important role in the development and/or progression of colorectal cancers, we searched for mutations and allelic loss of the KLF6 gene in 123 colorectal adenocarcinomas by performing PCR-SSCP sequencing. We found five somatic missense mutations: S155N, G163S, G163D, P183L and G195S. Three of them affected the activation domain of KLF6 and four mutations were predicted to disrupt the putative phosphorylation sites. On LOH analysis, 63 cases were heterozygous for at least one marker and 27 cases (42.9%) showed allelic loss at these markers. These data further support that the KLF6 gene may be one of the candidate tumor suppressor genes in colorectal cancers and that genetic alteration of the KLF6 gene might play a role in the development of colorectal carcinomas. [ABSTRACT FROM AUTHOR]

Mounting evidence indicates that deregulation of apoptosis is involved in the mechanisms of cancer development. Caspase-9 plays a crucial role in the initiation phase of the intrinsic apoptosis pathway. To explore the possibility that the genetic alterations of caspase-9 might be involved in the development of human cancers, we analyzed the entire coding region and all splice sites of the human caspase-9 gene for the detection of somatic mutations in a series of 353 cancers, including 180 gastric, 104 colorectal and 69 lung adenocarcinomas. Overall, we detected three somatic mutations of caspase-9, but all of the mutations were silent mutations. The mutations were observed in 2 of 104 colorectal carcinomas and 1 of 180 gastric carcinomas. These data indicate that the caspase-9 gene is rarely mutated in gastric, colorectal and lung adenocarcinomas, and suggest that caspase-9 gene mutation may not contribute to the pathogenesis of these cancers. [ABSTRACT FROM AUTHOR]

CDX2 is a caudal-related homeobox transcription factor whose expression in the adult is normally restricted to the intestinal epithelium; it is implicated in the development and maintenance of the intestinal mucosa. The specific aim of this study was to elucidate the potential etiological role of CDX2 protein in colorectal carcinogenesis. We have analyzed the expression pattern of CDX2 protein in relation to the phenotype of 123 sporadic colorectal cancers by immunohistochemistry using tissue microarray. Strong CDX2 immunostaining was seen in the nuclei of corresponding normal intestinal epithelium. Interestingly, loss of CDX2 immunostaining was observed in 29 (23.6%) of 123 colorectal adenocarcinomas and its expression was correlated with the differentiation grade of the carcinoma (Chi-Square test, p<0.01). Clinically, CDX2 protein was immunopositive in 11 (91.7%) of 12 cases corresponding to stage A, 40 (85.1%) of 47 corresponding to stage B, 39 (69.6%) of 56 corresponding to stage C, and 4 (50.0%) of 8 corresponding to stage D. Statistically, CDX2 protein expression was related to tumor stage (Bartholomew test, p<0.05) and lymph node metastasis (Chi-Square test, p<0.05). These results indicate that loss of expression of CDX2 protein may play an important role in the tumorigenesis of colorectal cancers and that CDX2 expression represents a highly significant marker, which is able to identify a subset of patients at high risk. [ABSTRACT FROM AUTHOR]

ERBB2 is a member of the epidermal growth factor receptor (EGFR) family. Recent studies revealed that the kinase domain of the ERBB2 gene was mutated in human cancers, including gastric cancer. Despite the importance of cancer metastasis in the pathogenesis of cancers, data on the ERBB2 kinase domain mutation in cancer metastasis are lacking. In this study, to explore the possibility that ERBB2 mutation is involved in the metastasis mechanism, we analyzed the kinase domain of ERBB2 for the detection of somatic mutations in 58 gastric adenocarcinomas with lymph node metastasis. We found one ERBB2 mutation, which was detected in the lymph node metastasis, but not in the primary tumor of the same patient. The ERBB2 mutation was a missense mutation which substituted an amino acid in exon 21 (V832I). We simultaneously analyzed the somatic mutations of EGFR, K-RAS, PIK3CA and BRAF genes in the sample with the ERBB2 mutation, and found that this metastatic carcinoma did not harbor any of the mutations. Our data suggest that ERBB2 kinase domain mutation occasionally occurs in metastatic gastric carcinoma and might play a role in the metastatic process of some gastric carcinomas. [ABSTRACT FROM AUTHOR]

Song J, Noh JH, Lee JH, Eun JW, Ahn YM, Kim SY, Lee SH, Park WS, Yoo NJ, Lee JY, Nam SW. Increased expression of histone deacetylase 2 is found in human gastric cancer. APMIS 2005;113:264–8.Accumulated evidence has established that aberrant regulation of histone deacetylases (HDACs) is one of the major causes of the development of human malignancies. Among different iso-enzymes of HDAC and sirtuins grouped as the HDAC super family, little is known as to how histone deacetylase 2 (HDAC2) causes carcinogenesis in solid tumors. Here, in order to investigate the possible role of HDAC2 in gastric carcinogenesis, we analyzed the expression of HDAC2 in 71 gastric adenocarcinomas by immunohistochemistry. Moderate to strong expression of HDAC2 was found in 44 (62%) out of a total of 71 tumors. The majority of positive tumors, which were detected in the nucleus but not in normal gastric epithelium, did not express HDAC2 or showed only weak positive staining. Interestingly, we also noted that HDAC2 expression appeared to be associated with tumor aggressiveness as HDAC2 expression was observed to be statistically significant in advanced gastric cancer (P=0.0023, Chi-square test) and in positive lymph node metastasis (P=0.0713, Chi-square test). Taken together, these results suggest that HDAC2 may play an important role in the aggressiveness of gastric cancer. [ABSTRACT FROM AUTHOR]

Park JY, Park WS, Nam SW, Kim SY, Lee SH, Yoo NJ, Lee JY, Park CK, Mutations ofβ-cateninandAXIN Igenes are a late event in human hepatocellular carcinogenesis.Liver International: DOI: 10.1111/j.1478-3231.2004.0995.x.© Blackwell Munksgaard 2004Hepatocellular carcinoma (HCC) is a well-known cancer involving the Wnt pathway in its carcinogenesis.However, it is not clear whether these genetic changes are early genetic events in hepatocarcinogenesis or not.In this study, we performed mutational analysis of theβ-cateninandAXIN Igenes, and immunohistochemistry forβ-catenin in a series of 114 hepatocellular nodular lesions, including premalignant lesions such as low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs).Results:In the present study, mutations of theβ-cateninandAXIN Igenes were detected in 16% (13 out of 81) and 6.2% (five of 81) of the HCCs, respectively. However, no mutations were found in 14 LGDNs and 19 HGDNs. Moreover, abnormal nuclearβ-catenin immunostaining was observed in 30 of 81 HCCs, but not in dysplastic nodules.Taken together, our data suggest thatβ-catenin stabilization because of eitherβ-cateninorAXIN Imutation might be a late event for malignant progression rather than an early genetic event involving the initiation of HCC development. [ABSTRACT FROM AUTHOR]

Lee JW, Soung YH, Kim SY, Park WS, Nam SW, Min WS, Kim SH, Lee JY, Yoo NJ, Lee SH. Mutational analysis of theARAFgene in human cancers. APMIS 2005;113:54–7.Deregulation of RAS signal transduction has been implicated in the malignant growth of human cancer cells. TheBRAFgene, encoding a RAF family member in the downstream pathway of RAS, is somatically mutated in a number of human cancers, raising the possibility that other RAF family members might be mutated in human cancers. In this study we analyzed the genomic DNAs for the detection of somatic mutations of theARAFgene in 60 human cancer cell lines and 323 primary human cancer tissues, including colorectal carcinomas, gastric carcinomas, ovarian tumors and acute leukemias. The MOLT-4 leukemia cell line was found to harbor anARAFgene mutation resulting in an amino acid substitution (A451T) at the activation segment in the kinase domain of ARAF. In the cancer tissues we could not detect anyARAFgene mutation. Our data indicate that, in contrast to theBRAFgene, theARAFgene is rarely mutated in human cancers, and suggest that alterations of the RAS pathway byARAFgene mutation may not play an important role in the pathogenesis of human cancers. [ABSTRACT FROM AUTHOR]

Kim CJ, Cho YG, Jeong SW, Kim YS, Kim SY, Nam SW, Lee SH, Yoo NJ, Lee JY, Park WS. Altered expression of KCNK9 in colorectal cancer. APMIS 2004;112:588–94.K+ channels have been reported to be involved in the proliferation of many types of cells, including some human carcinoma and tumor cell lines. KCNK9, a TASK channel, is amplified and overexpressed in several types of human cancer. In the present study, we examined the expression and somatic mutations of KCNK9 in 124 colorectal cancers by immunohistochemistry using tissue microarray and PCR-SSCP. Immunopositivity was observed in 57 (46.0%) of 124 colorectal cancers. Clinically, KCNK9 was immunopositive in 4 (30.7%) of 13 cases which were stage A, 26 (55.3%) of 47 which were stage B, 23 (41.1%) of 56 which were stage C, and 4 (50%) of 8 which were stage D. Statistically, KCNK9 protein expression was not related to tumor stage (Bartholomew test, p>0.05) and lymph node metastasis (Chi-Square test, p=0.8338). In the mutation study of theKCNK9gene, we found only one sequence variation (ACG→ACC, Thr→Thr) at codon 170 both in corresponding normal and tumor DNAs. These results indicate that overexpression rather than mutation of theKCNK9gene may contribute to the development of colorectal cancers and suggest that the development of KCNK9-targeted agents may provide new possibilities in the treatment of colorectal cancer. [ABSTRACT FROM AUTHOR]

Yoo NJ, Lee JW, Kim YJ, Soung YH, Kim SY, Nam SW, Park WS, Lee JY, Lee SH. Loss of caspase-2, -6 and -7 expression in gastric cancers. APMIS 2004;112:330–5.Caspases play an essential role during apoptotic cell death, and alterations of caspases are known to contribute to human cancer development. In the current study, we analyzed the expression of caspase-2, -6 and -7 in 120 gastric carcinomas by immunohistochemistry using a tissue microarray approach. Caspase-2, -6 and -7 were expressed in 42 (35%), 63 (53%) and 39 (33%) of the gastric cancers, respectively. By contrast, the surface mucous cells and mucosal glandular cells in the normal gastric mucosa showed strong immunoreactivity for caspase-2, -6 and -7. Taken together, these results indicate that caspase-2, -6 and -7 expression in gastric cancer cells is decreased compared to in normal gastric mucosal cells, and suggest that loss of caspase-2, -6 and -7 expression might be involved in the mechanisms of gastric cancer development. [ABSTRACT FROM AUTHOR]

Lee SH, Lee JW, Soung YH, Kim SY, Nam SW, Park WS, Kim SH, Yoo NJ, Lee JY. Colorectal tumors frequently express phosphorylated mitogen-activated protein kinase. APMIS 2004;112:233–8. Mounting evidence suggests that activation of the mitogen-activated protein (MAP) kinase pathway plays an important role in tumorigenesis. MAP kinase/ERK kinase (MEK), a crucial constituent of this pathway, is activated by phosphorylation, and the phosphorylated MEK (pMEK) in turn activates ERK kinase. The expression of pMEK has been described in some human malignancies, but not in primary human colon tumors. In this study, we analyzed the expression of pMEK in 123 colorectal tumors by immunohistochemistry. pMEK was detected either in the cytoplasm (63 cases) or nucleus (40 cases) in 93 of the 123 tumors (76%). Tubular adenomas and villous adenomas also expressed pMEK in 30% and 40% of the tumors, respectively. By contrast, the epithelial cells in the normal colonic mucosa showed no or only weak expression of pMEK in the cytoplasm. Taken together, these results indicate that MEK is frequently phosphorylated in colorectal tumors, and suggest that phosphorylation of MEK may play a role in the development of colorectal tumors. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the mutation of HIPK2 gene in keratoacanthoma and squamous cell carcinoma of the skin.

A letter to the editor is presented on the relationship between keratoacanthoma and genital-mucosal human papilloma virus infection in Korean patients.

Soung YH, Lee JW, Kim SY, Nam SW, Park WS, Kim SH, Lee JY, Yoo NJ, Lee SH. Mutation of FADD gene is rare in human colon and stomach cancers. APMIS 2004;112:595–7.Failure of apoptosis is one of the hallmarks of cancer. As an adaptor, FADD plays a crucial role during death receptor-mediated apoptosis. We previously reported that theFADDgene is somatically mutated in non-small cell lung cancers. To explore the possibility that the genetic alterations of theFADDgene might be involved in the development of other human cancers, we analyzed the entire coding region and all splice sites of the humanFADDgene to detect somatic mutations in 116 stomach cancers and 98 colon cancers. Overall, we detected a somatic missense mutation of theFADDgene in a colon carcinoma, which was predicted to change an amino acid (R140H) in the death domain (DD) of the FADD protein. This is the first report ofFADDgene mutation in gastrointestinal cancers, and our data suggest that theFADDgene is rarely mutated in human colon and stomach cancers. [ABSTRACT FROM AUTHOR]