Frequencies of HER‐2/neu overexpression relating to HLA haplotype in patients with gastric cancer

Kono, Koji; Takahashi, Akihiro; Amemiya, Hidetake; Ichihara, Fumiko; Sugai, Hidemitsu; Iizuka, Hidehiko; Fujii, Hideki; Matsumoto, Yoshirô

doi:10.1002/ijc.10179

Cited by 19 publications

(20 citation statements)

References 31 publications

(32 reference statements)

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“…When anti-HER-2 immunotherapy such as cancer vaccination is considered for HER-2-positive patients, the candidates are restricted to a certain HLA haplotype (Kono et al, 2002a). It is important to clarify the HER-2 status relating to the HLA haplotype in patients with oesophageal SCC.…”

Section: Correlation Of Her-2 Expression In Primary Tumours and Metasmentioning

confidence: 99%

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

et al. 2005

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The utilisation of antitumour T cells induced by cancer vaccination with HER-2 peptides or antibodies (Herceptin) against HER-2, as immunotherapy for oesophageal cancer, is a novel and attractive approach. It is important to clarify the frequencies of HER-2 expression and gene amplification in patients with oesophageal squamous cell carcinoma (SCC) and to evaluate the relationship between HER-2 status and HLA haplotype, since the candidates for HER-2 peptide-based vaccination are restricted to a certain HLA haplotype. We determined the frequency of HER-2 expression using the HercepTestt for immunohistochemistry and HER-2 gene amplification by fluorescence in situ hybridisation (FISH) assay in oesophageal SCC (n ¼ 66). HER-2-positive tumours (1 þ /2 þ /3 þ ) analysed by a HercepTest were observed in 30.3% of all the patients and HER-2 gene amplification evaluated by FISH was observed in 11.0% of all the patients, in which all HercepTest (3 þ ) tumours were found to have gene amplification and three of six moderately positive (2 þ ) tumours showed gene amplification. Furthermore, HER-2-positive cells were present more diffusely and were larger within each tumour in the patients who were HercepTest 3 þ than those who were HercepTest 1 þ . Moreover, the survival rate in HER-2-positive group was significantly worse than that in HER-2-negative group. Also, the survival rate in the patients with HER-2 gene amplification was significantly worse than that without HER-2 gene amplification. In addition, oesophageal SCC patients with both HLA-A24-positive and HER-2-positive tumours (1 þ /2 þ /3 þ ) accounted for 26% of these cases, and both HLA-A2-and HER-2-positive tumours accounted for 18% of them.

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Section: Correlation Of Her-2 Expression In Primary Tumours and Metasmentioning

confidence: 99%

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

et al. 2005

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“…Strong amplification of the region 17q12-21 was reported in the intestinal type of gastric cancer. 59 Amplification and/or overexpression of some genes on chromosome 17q21.1, such as ERBB-2 (HER2/ neu) 8,9,60,61 and TOP2A (for topoisomerase IIa), 62 have been reported in gastric cancer and breast cancer, and might represent prognostic factors. Recently, an antineoplastic drug that targets the HER2 gene has been used to treat breast cancer and there are reports of overexpression of the HER2/neu gene in gastric cancer.…”

Section: Genetic Alterations In Gastric Cancermentioning

confidence: 99%

“…Recently, an antineoplastic drug that targets the HER2 gene has been used to treat breast cancer and there are reports of overexpression of the HER2/neu gene in gastric cancer. 61 Therefore, the same antineoplastic drug might be useful for the treatment of gastric cancer. It has also been reported that gain at 17q is a powerful prognostic factor and a candidate gene on 17q23 is PPM1D, whose expression is associated with prognosis in neuroblastoma.…”

Section: Genetic Alterations In Gastric Cancermentioning

confidence: 99%

Genetic alterations in 102 primary gastric cancers by comparative genomic hybridization: gain of 20q and loss of 18q are associated with tumor progression

et al. 2004

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Gastric cancer is one of the most common cancers. Molecular events in the carcinogenesis of gastric cancer remain, however, largely undefined. We investigated changes in DNA copy number in 102 gastric cancers by CGH. We found changes in DNA copy number in all cases, with frequent (^30% of patients) gains at 20q, 8q, 20p, 7q, 17q, 5p, and 13q. Frequent (^20%) losses were found at 19p, 18q, 5q, 21q, 4p, 4q, 15q, and 17p. The mean number of total alterations was significantly lower in grade 3 and scirrhous-type carcinomas (10.81 in grade 3 vs 13.98 in grade 1 and grade 2, 9.31 in scirrhous-type vs 13.18 in medullary-and intermediate-type). The mean number of losses and total alterations were higher in tumors at pT2, pT3 and pT4 (4.68 and 12.77 in pT2, pT3, and pT4 vs 2.55 and 9.22 in pT1). The mean number of losses was higher in carcinomas with lymph node metastasis (4.83). The mean number of gains and total alterations were higher in carcinomas with venous invasion (8.44 and 13.28). Several chromosomal alterations were linked in a statistically significant manner to specific clinicopathological parameters. Gain of 17q, 20p, and 20q and loss of 4p were associated with the pattern of the cancer-stroma relationship; loss of 18q was associated with pT category; gain of 5p was associated with pN category; loss of 4q and loss of 21q were associated with lymphatic invasion; gain of 7p and loss of 4q and 18q were associated with venous invasion; and loss of 18q was associated with pathological stage. These data suggest that gain of 20q and loss of 18q might play an important role in the development and progression of gastric cancer. Moreover, some genes on 20q and 18q might be target genes of gastric cancer.

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“…Trastuzumab also suppresses DNA repair capacity (18) through as yet unknown pathways, contributing to the ability of the antibody to enhance the anti-tumor effect of DNA-damaging agents such as cisplatin (18) and radiotherapy (19). In vivo, trastuzumab inhibits angiogenesis and induces antibody-dependent cellular cytotoxicity (13,14), potentially contributing to its activity. Loss or blockade of the Fc␥RIII receptor on leukocytes has been shown to severely impair the anti-tumor effect of trastuzumab in vivo (15), indicating involvement of Fc-receptor-dependent mechanisms.…”

mentioning

confidence: 99%

Genes Affecting the Cell Cycle, Growth, Maintenance, and Drug Sensitivity Are Preferentially Regulated by Anti-HER2 Antibody through Phosphatidylinositol 3-Kinase-AKT Signaling

Lammayot

Gold

et al. 2005

Journal of Biological Chemistry

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The molecular mechanisms by which the anti-HER2 antibodies trastuzumab and its murine equivalent 4D5 inhibit tumor growth and potentiate chemotherapy are not fully understood. Inhibition of signaling through the phosphatidylinositol 3-kinase (PI3K)-AKT pathway may be particularly important. Treatment of breast cancer cells that overexpress HER2 with trastuzumab inhibited HER2-HER3 association, decreased PDK1 activity, reduced Thr-308 and Ser-473 phosphorylation of AKT, and reduced AKT enzymatic activity. To place the role of PI3K-AKT in perspective, gene expression was studied by using Affymetrix microarrays and real time reverse transcription-PCR. Sixteen genes were consistently down-regulated 2.0 -4.9-fold in two antibody-treated breast cancer cell lines. Fourteen of the 16 genes were involved in three major functional areas as follows: 7 in cell cycle regulation, particularly of the G 2 -M; 5 in DNA repair/replication; and 2 in modifying chromatin structure. Of the 16 antibody-regulated genes, 64% had roles in cell growth/maintenance and 52% contributed to the cell cycle. Direct inhibition of PI3K with an inhibitor markedly reduced expression of 14 genes that were also affected by the antibody. Constitutive activation of AKT1 blocked the effect of the anti-HER2 antibody on cell cycle arrest and on eight differentially expressed genes. The antibody enhanced docetaxel-induced growth inhibition but did not increase the fraction of apoptotic cells induced with docetaxel alone. In contrast, the antibody plus docetaxel markedly down-regulated two genes, HEC and DEEPEST, required for passage through G 2 -M. Thus, anti-HER2 antibody preferentially affects genes contributing to cell cycle progression and cell growth/maintenance, in part through the PI3K-AKT signaling. Transcriptional regulation by anti-HER2 antibody through PI3K-AKT pathway may potentiate the growth inhibitory activity of docetaxel by affecting cell cycle progression.The human epidermal growth factor receptor 2 (HER2, 1 also known as c-Neu or ErbB-2) encodes a 185-kDa transmembrane tyrosine kinase growth factor receptor. The ligand that binds to the homodimers of HER2 has not yet been identified. Rather, HER2 functions as a preferred co-receptor to form heterodimers with HER1 (epidermal growth factor receptor), HER3, or HER4. Of these heterodimers, HER2-HER3 is particularly important for intracellular signaling (1). HER2 signaling has been linked to a variety of cellular responses to growth factors under both normal and pathophysiological conditions. HER2 signaling is required not only during normal development of the mammary gland but also during development of the glia, neurons, and heart (1, 2). Amplification of the HER2 gene and overexpression of HER2 protein have been documented in ϳ30% of breast and 15% of ovarian cancers (3). In many (but not all) reports, HER2 overexpression has been associated with a more aggressive course of disease. Although the underlying mechanisms for this association are still not well characterized, HER2 overexpression...

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Frequencies of HER‐2/neu overexpression relating to HLA haplotype in patients with gastric cancer

Cited by 19 publications

References 31 publications

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma

Genetic alterations in 102 primary gastric cancers by comparative genomic hybridization: gain of 20q and loss of 18q are associated with tumor progression

Genes Affecting the Cell Cycle, Growth, Maintenance, and Drug Sensitivity Are Preferentially Regulated by Anti-HER2 Antibody through Phosphatidylinositol 3-Kinase-AKT Signaling

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