2010 Fiscal Year Final Research Report
Comprehensive analysis of pulmonary neuroendocrine carcinoma, Evaluation of pathologic classification and application for clinical diagnosis
| Project/Area Number |
20590358
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Japanese Foundation For Cancer Research |
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Principal Investigator |
MOTOI Noriko Japanese Foundation For Cancer Research, 癌研究所病理部, 研究員 (70292878)
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| Co-Investigator(Renkei-kenkyūsha) |
ISHIKAWA Yuichi 財団法人癌研究会, 癌研究所病理部, 部長 (80222975)
MATSUURA Masaaki 財団法人癌研究会, がんゲノム研究部, 部長 (40173794)
NAKAGAWA Ken 財団法人癌研究会, 癌研究所, 研究員 (60085595)
NISHIO Makoto 財団法人癌研究会, 癌研究所, 研究員 (00281593)
SHIMOJI Takashi 財団法人癌研究会, ゲノムセンター, 研究員 (40370150)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 肺癌 / 神経内分泌癌 / 小細胞癌 / 大細胞神経内分泌癌 / 網羅的発現解析 / 分子病理診断 / 遺伝子発現解析 / 免疫染色 |
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| Research Abstract |
Background : The underlying oncogenic molecular alterations can influence the clinical features and phenotypes of lung cancer. Pulmonary neuroendocrine tumors include various histologic categories ; high grade neuroendocrine tumor (HGNET) (e.g. small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC)), low grade NET (LGNET, e.g. typical and atypical carcinoid). It is still controversial whether non-small cell lung carcinoma (NSCLC) with neuroendocrine (NE) morphology or with NE phenotype should be included to NET or not. The goal of this study is to clarify the genetic and immunohistochemical profiling of pulmonary neuroendocrine tumors and to evaluate the clinicopathologic relevance of each tumor category, including NSCLC with NE features and with NE phenotypes, and to investigate new candidate for diagnosis and therapy.
Methods : Surgically resected lung cancers, including HGNET and LGNET, 5 NSCLC with NE-morphology (NS-NEm), NSCLC with NE-phenotype (NS-NEp), and NS
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CLC, were examined. Comprehensive gene expression analysis was done using Affymetrix U133A-plus2. Out of differentially expressed NE-related genes, expression levels of selected genes (ASCL1, CDH2, NeuroD1, etc.) were examined by quantitative realtime-PCR (qRTPCR) and by QuantiGene Assay (QG). Protein expressions of neuroendocrine markers were examined by immunohistochemistry (IHC) using tissue microarray (TMA) of formalin-fixed paraffin-embedded materials. Methylation status of ASCL1 promoter region in NET was also examined.
Results : Molecular profile revealed that HGNET and LGNET were differentially clustered. Among HGNET, SCLC and LCNEC showed similar mRNA expression profile of examined neuronal differentiation, cell proliferation and apoptosis related genes. LGNET showed different profile to both HGNET and NSCLC. NS-NEm and NS-NEp showed very low level of NE marker genes, but high level of KI67 and Survivin expressions. IHC expression levels of ASCL1 and KI67 (MIB1) were correlated well with mRNA expression levels of each gene. No difference of methylation status of ASLC1 gene in NET was revealed.
Conclusions : Both SCLC and LCNEC could be categorized as a high grade neuroendocrine tumor (HGNET) from a molecular stand point. In contrast, gene expression profile of SC-NEm and NS-NEp showed different from that of HGNET. ASCL1 could be used as neuronal differentiation markers for clinical differential diagnosis. On the methylation point of view, no difference was detected between NET and other lung cancer. Further examination will be needed to clarify the mechanism of neural gene expression in NET and criteria of NE differentiation marker for practical use. Less
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