Journal of Pathology and Translational Medicine

Original Articles

Loss of Heterozygosity at VHL, FHIT, and p16 Loci in Nonpapillary Renal Cell Carcinoma.: Won Sang Park, Seung Myung Dong, Yong Hyun Cho, Tae Gon Hwang, Su Young Kim, Min Sun Shin, Jae Ho Pi, Suk Hyung Lee, Nam Jin Yoo, Jung Young Lee; Korean J Pathol. 1999;33(1):8-14.

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Abstract PDF: The objectives of this study were to characterize the alterations of 3p and 9p in sporadic renal cell carcinomas (RCC) and to assess the relationship between the clinical stages or tumor size and the alteration of these chromosomes. Thirty eight archival, paraffin embedded tissue sections from 38 patients with RCC were analyzed for loss of heterozygosity (LOH) at 3p and 9p with 11 microsatellite markers. LOH was detected in 81.6% (31/38) and 37.8% (14/37) at 3p and 9p, respectively. The frequencies of LOH at VHL and FHIT locus were 75.6% and 72.2%, respectively. Twelve cases out of 38 showed LOH at both 9p21 and 3p. The loss of 3p in the samples tested was not related to clinical stages and tumor size, but that of 9p21 was significantly associated with advanced stage and larger tumor size. These results support that 3p deletion, including VHL and FHIT gene, play a critical role in the tumorigenesis of sporadic RCC, especially at early stage, and that 9p21 may contribute to the progression of sporadic RCC.

Altered Fhit Expression and Its Relationship with p53 Overexpression in Non-small Cell Lung Cancers.: Na Hye Myong, Seok Jun Yoon; Korean J Pathol. 2001;35(1):1-6.

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Abstract PDF: BACKGROUND
FHIT (Fragile histidine triad), the tumor suppressor gene at 3p14.2, encompasses the FRA3B fragile site and is a common target of deletions in primary human epithelial cancers, including those of the lung, head and neck, stomach, cervix, breast, and kidney. We investigated the association of Fhit expression with clinicopathologic features, including smoking history, and tried to correlate its altered expression with p53 overexpression in 45 non-small cell lung cancers.
METHODS
Immunohistochemical staining was performed on the paraffin sections, using primary anti-GST-Fhit and anti-human p53 antibodies. A four-tiered scoring system, incorporateing both intensity of staining and the percentage of cells stained was used. Composite scores < or = 3 were defined as a marked reduction or loss of Fhit or p53 protein expression.
RESULTS
Among the 45 tumors analyzed, 35 (77.8%) were markedly reduced or negative for Fhit protein expression. The reduced expression of Fhit protein was found to be significantly higher in smokers than in nonsmokers and also higher in squamous carcinoma compared with adenocarcinoma. Fhit and p53 alterations were found to be independent events, because there was no significant difference of Fhit-negativity between p53-positive and -negative groups.
CONCLUSION
These results indicate that the Fhit alteration preferentially occurs in smokers and in the squamous type of non-small cell lung carcinomas. In addition, the results support the notion that Fhit alterations play an important role in the pulmonary carcinogenesis.

Study of Microsatellite Alterations of 3p and 11q Chromosomes in Uterine Cervical Adenocarcinoma.: Eung Seok Lee, Hye Jin Jeong, Hee Jeoung Kim, Insun Kim; Korean J Pathol. 2001;35(2):137-143.

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Abstract PDF: BACKGROUND
Uterine cervical cancer is the most prevalent cancer in Korean women, and the incidence of adenocarcinoma has been increasing. Loss of heterozygosity (LOH) analysis is used to identify regions which harbor a putative tumor suppressor gene.
METHODS
DNA was extracted from the microdissected normal and malignant lesions of 34 uterine cervical adenocarcinomas, 2 adenosquamous cell carcinomas, 13 squamous cell carcinomas, and 10 endometrial adenocarcinomas. LOH and microsatellite instability (MSI) analysis were performed using microsatellite markers, D3S4103 (3p14.2), D3S1284 (3p12), D3S1289 (3p21.2-21.1), D3S1307 (3p25-ter), THRB (3p22-24.1), and D11S35 (11q22). The expression of Fhit protein was compared with the genetic abnormalities.
RESULTS
Microsatellite alterations at 3p were detected in 37% of cervical adenocarcinomas, 16% of squamous cell carcinomas, and 43% of endometrial adenocarcinomas. The alterations of 11q were found in 17% of cervical adenocarcinomas. Microsatellite alterations of D3S1307 and D11S35 were detected in uterine cervical adenocarcinomas with high frequency. The frequency of FHIT protein loss is higher in the cervical squamous cell carcinoma than in cervical and endometrial adenocarcinomas.
CONCLUSION
Tumor suppressor gene of uterine cervical adenocarcinoma may be located in 3p25-ter and 11q22.

Expression of p16, Rb and FHIT Proteins in Urothelial Carcinoma of the Urinary Bladder.: Sun Hee Han, Ju Han Lee, Seo Hee Kim, Jungsuk An, Eung Seok Lee, Young Sik Kim; Korean J Pathol. 2008;42(5):294-298.

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Abstract PDF: BACKGROUND
The goal of this study was to investigate the expression of p16, retinoblastoma (Rb) and fragile histidine triad (FHIT) proteins in urothelial carcinomas of the urinary bladder, and to evaluate the relationship between clinicopathlogic parameters and each protein expression level. METHODS: The expression of p16, Rb, and FHIT proteins were studied in 176 patients with urothelial carcinoma of the urinary bladder by immunohistochemistry. RESULTS: The diffuse positive expression of the p16 protein was significantly associated with high grade and advanced tumor depth (p=0.007 and p=0.020). The loss of the Rb protein was significantly associated with old age and disease recurrence (p=0.020 and 0.037). The loss of the FHIT protein was significantly associated with advanced tumor depth (p=0.002). CONCLUSION: Our data suggest that p16 and FHIT proteins may be involved in the progression of urothelial carcinoma. In addition, p16 may be a useful prognostic marker for individual urothelial carcinoma patients.

Expressions of p130Cas and FHIT, and Their Relationships with Prognostic Factors for Breast Carcinomas.: Hyun Joo Choi, Ji Han Jung, Jinyoung Yoo, Seok Jin Kang, Chang Suk Kang; Korean J Pathol. 2005;39(1):41-47.

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Abstract PDF: BACKGROUND
BCAR1/p130Cas protein is the human homologue of rat p130Cas protein, and it is a docking protein involved in the intracellular signaling pathways. This protein also causes the proliferating human breast cancer cells to be resistant to antiestrogen drugs. The fragile histidine triad (FHIT) protein is presumed to have a tumor suppressor function in a number of human tumors. The aim of this study was to investigate expressions of p130Cas and FHIT in breast carcinomas and to evaluate their relationship with the clinicopathological prognostic factors.
METHODS
A total of 93 cases of invasive breast carcinomas was retrospectively reviewed. The expressions of p130Cas and FHIT were examined by immunohistochemical methods.
RESULTS
p130Cas expression was observed in all breast carcinomas: p130Cas immunoreactivity was strongly positive in 39 cases (41.9%), moderately positive in 49 cases (52.7%) and weakly positive in 5 cases (5.4%) of 93 cases. It was statistically correlated with the p53 (p=0.035) and c-erbB-2 (p=0.024) expressions. The FHIT protein expression was markedly reduced or completely negative in 59 cases (63.4%), but it was not correlated with the clinicopathological prognostic factors. There was no significant correlation between p130Cas and FHIT expressions.
CONCLUSIONS
This study seems to provide meager information on whether these proteins may be useful prognostic factors, and so this topic needs further study.

Expression of FHIT and p21 in Gastric Adenocarcinoma.: Hyun Joo Choi, Byung Kee Kim, Jinyoung Yoo, Seok Jin Kang, Chang Suk Kang; Korean J Pathol. 2004;38(1):35-41.

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Abstract PDF: BACKGROUND
The fragile histidine triad (FHIT) gene, located on the human chromosome 3p14.2, is frequently inactivated by its deletion in a number of human tumors, including gastric carcinomas. Its protein product, FHIT is presumed to have a tumor suppressor function. p21, one of the tumor markers acts as a regulator of the cell cycle, and inhibits cell proliferation.
METHODS
The association of the expressions of FHIT and p21 protein, with clinicopathological features, such as age, gender, tumor size, histological type, depth of invasion, lymph node metastasis, lymphatic and vascular invasion, grade and stage were investigated, and correlation of their expressions with p21 expression in 82 gastric adenocarcinomas attempted by immunohistochemical staining.
RESULTS
Of the 82 tumors analyzed, 58 (70.7%) were markedly reduced, or completely negative, for FHIT protein expression. The loss of FHIT expression was correlated with the depth of invasion (p=0.000), lymph node metastasis (p=0.001), lymphatic invasion (p=0.000), histological grade (p=0.000) and tumor stage (p=0.000). The loss of p21 expression was correlated with lymph node metastasis (p=0.026) and lymphatic invasion (p= 0.017), but not with the histological grade and tumor stage. The comparison of the FHIT and p21 protein expressions showed significant correlation (p=0.035).
CONCLUSIONS
The loss of FHIT and p21 expressions may be a useful indicator of the post diagnostic prognosis. Also, FHIT could be related to cell cycle arrest.

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