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論文 |
論文
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Ooi, Akishi ; Inokuchi, Masafumi ; Harada, Shinichi ; Inazawa, Johji ; Tajiri, Ryousuke ; Sawada-Kitamura, Seiko ; Ikeda, Hiroko ; Kawashima, Hiroko ; Dobashi, Yoh
概要:
Oestrogen receptor-alpha (ERα), encoded by the ESR1 gene located on 6q25, is a nuclear transcription factor. Since it wa
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s reported in 2007 that more than 20% of breast cancers show ESR1 gene amplification, there has been considerable controversy about its frequency and clinical significance. We set out to assess the frequency and levels of ESR1 amplification in breast cancers. In a total of 106 breast needle biopsy specimens examined by immunohistochemistry, 78 tumours contained more than 10% ERα-positive cancer cells. In fluorescence in situ hybridization (FISH) analysis with an ESR1-specific probe, variously extended ESR1 signals were found in ERα-expressing cells. Some of these were indistinguishable from large clustered signals generally accepted to mean high-level gene amplification in homogeneously staining regions (HSRs), and could be considered to represent gene amplification. However, with RNase treatment, the 'HSR-like' signals changed to small compact signals, and are thus thought to represent concentrated RNA. FISH using two differently labelled probes corresponding to the non-overlapping 5'- and 3'-end portions of the ESR1 gene on touch smears showed a preserved spatial relationship of the 3' to 5' sequence of ESR1, therefore strongly suggesting that the RNA consisted of primary transcripts. Using touch smears obtained from 51 fresh tumours, precise enumeration of ESR1 signals with a correction by the number of centromere 6 on FISH after RNase A treatment revealed that three tumours (5.9%) had tumour cells with one to three additional copies of ESR1 as predominant subpopulations. This infrequent and low level of gene amplification of ESR1 was also detected as a 'gain' of the gene by analysis with multiplex ligation-dependent probe amplification (MLPA). The consistent results from immunohistochemistry, FISH, and MLPA in the present study settle the long-standing debate concerning gene amplification of ESR1 in breast carcinoma. © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
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| 2.
論文 |
論文
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Tajiri, Ryosuke ; Ooi, Akishi ; Fujimura, Takashi ; Dobashi, Yoh ; Oyama, Takeru ; Nakamura, Ritsuko ; Ikeda, Hiroko
概要:
A humanized monoclonal antibody against ERBB2 is used in neoadjuvant therapy for patients with gastric cancer. A critica
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l factor in determining patient eligibility and predicting outcomes of this therapy is the intratumoral heterogeneity of ERBB2 amplification in gastric adenocarcinomas. The aims of this study are to assess the underlying mechanisms of intratumoral heterogeneity of ERBB2 amplification; to characterize the diversity of coamplified oncogenes such as EGFR, FGFR2, MET, MYC, CCND1, and MDM2; and to examine the usefulness of multiple ligation-dependent probe amplification (MLPA) in the semicomprehensive detection of these gene amplifications. A combined analysis of immunohistochemistry and fluorescence in situ hybridization revealed ERBB2-amplified cancer cells in 51 of 475 formalin-fixed, paraffin-embedded gastric adenocarcinomas. The fraction of amplification-positive cells in each tumor ranged from less than 10% to almost 100%. Intratumoral heterogeneity of ERBB2 amplification, defined as less than 50% of cancer cells positive for ERBB2 amplification, was found in 41% (21/51) of ERBB2-amplified tumors. The combined analysis of MLPA and fluorescence in situ hybridization revealed that ERBB2 was coamplified with EGFR in 7 tumors, FGFR2 in 1 tumor, and FGFR2 and MET in 1 tumor; however, the respective genes were amplified in mutually exclusive cells. Coamplified ERBB2 and MYC coexisted within single nuclei in 4 tumors, and one of these cases had suspected coamplification in the same amplicon of ERBB2 with MYC. In conclusion, the amplification status of ERBB2 and other genes can be obtained semicomprehensively by MLPA and could be useful to plan individualized molecularly targeted therapy against gastric cancers. © 2014 Elsevier Inc.
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| 3.
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論文
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Oyama, Takeru ; Okamoto, Koichi ; Nakamura, Ritsuko ; Tajiri, Ryosuke ; Ikeda, Hiroko ; Ninomiya, Itasu ; Ooi, Akishi
概要:
EGFR and ERBB2 belong to the EGFR gene family. In esophageal squamous cell carcinomas (SCCs), amplification of EGFR or E
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RBB2 is usually mutually exclusive. EGFR amplification occurs in approximately 15% of SCCs, ERBB2 occurs in less than 5%. Here, we report the co-amplification of EGFR and ERBB2 in an ulcerative and infiltrating-type SCC that measured approximately 4.2 × 2.7 × 1.2cm with a superficial lesion occurring in the thoracic esophagus of a 72-year-old man. Multiplex ligation-dependent probe amplification using representative tumor sections showed gain of CCND1 and coincident amplification of ERBB2 or EGFR or neither. Immunohistochemistry and fluorescence in situ hybridization revealed that the tumor comprised three cancer-cell populations: well-differentiated SCC with high-level ERBB2 amplification and ERBB2 overexpression, more infiltrative poorly-differentiated SCC with high-level EGFR amplification and EGFR overexpression, and poorly-differentiated SCC lacking any ERBB2 or EGFR abnormality. These three populations each had low-level CCND1 amplification and nuclear cyclin D1 overexpression. This histological topology and gene amplification combinations suggested that genetic instability first produced CCND1 amplification, and then ERBB2 or EGFR gene amplification occurred. It is further speculated that during cancer progression and clonal selection indecisive predominance of either clone caused the rare co-amplification of ERBB2 and EGFR in a single chimeric tumor. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.<br />発行後1年より全文公開
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