Gene Expression Profiling Reveals Reproducible Human Lung Adenocarcinoma Subtypes in Multiple Independent Patient Cohorts

Hayes, D. Neil; Monti, Stefano; Parmigiani, Giovanni; Gilks, C Blake; Naoki, Katsuhiko; Bhattacharjee, Arindam; Socinski, Mark A.; Perou, Charles M.; Meyerson, Matthew

doi:10.1200/jco.2005.05.1748

Cited by 251 publications

(260 citation statements)

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“…There is increasing evidence that broad patterns of tumour behaviour can be captured as general phenotypes using profiling techniques such as gene expression arrays. Specifically, the squamoid gene expression subtype of lung adenocarcinoma is known to have higher rates of KRAS mutation and demonstrates gene expression correlated with LKB1 inactivation (Hayes et al, 2006). It is also interesting to note that as LKB1 mutation appears to pair with KRAS activation, specific combinations of therapy targeting parallel pathways might be appropriate.…”

Section: Mtor and Kras In The Clinicmentioning

confidence: 99%

Role of LKB1 in lung cancer development

Makowski

Hayes

2008

Br J Cancer

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Section: Mtor and Kras In The Clinicmentioning

confidence: 99%

Role of LKB1 in lung cancer development

Makowski

Hayes

2008

Br J Cancer

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“…12 Major advances in the phenotypic profiling of different lung cancer subtypes were obtained by molecular analysis of a large number of genes, which seemed to provide different signatures in different histological types, according to their up-or downregulation. [13][14][15] In a recent study on non-smallcell lung carcinoma, 16 four genes were found upregulated in squamous carcinomas by at least 20-fold compared to adenocarcinomas and/or normal lung parenchyma (PKP1, DSC3, p63 and CK17). Among these, the highest difference between squamous carcinoma and adenocarcinoma (and also between cancer and normal tissue) was observed for DSC3, which codes for desmocollin-3, a constitutive protein of desmosomes.…”

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confidence: 98%

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

et al. 2009

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Lung cancer classification in small-cell and non-small-cell types was recently challenged by data on the differential efficacy of new cytotoxic agents in specific histotypes. An accurate histotype definition has therefore gained interest in both preoperative and surgical materials, but is a hard task especially in undifferentiated large-cell tumors lacking morphological signs of squamous or glandular differentiation. The responsiveness of these latter subtypes to new drugs apparently more selective for adenocarcinomas or squamous carcinomas is not fully understood, also due to the heterogeneity of diagnostic criteria for this tumor entity. Current immunohistochemical markers are not fully specific and new molecules are to be explored. On the basis of gene expression profiling data, reporting a remarkable differential expression of desmocollin-3 (a protein localized in desmosomal junctions of stratified epithelial) between adeno-and squamous cancers, we immunostained 62 cases of resected undifferentiated large-cell lung carcinomas for desmocollin-3 (and for TTF-1, p63 and mucin stain), to test its ability to identify a (residual) squamous phenotype, if present. Desmocollin-3 was expressed in almost half of the undifferentiated large-cell cancers and was mutually exclusive with TTF-1 (positive in 39%; the remaining 18 % of cases was double negative). Special large-cell carcinoma variants expressed desmocollin-3 in 6 of 6 basaloid, 7 of 12 clear-cell types, again mutually exclusive with TTF-1 expression. None of seven sarcomatoid carcinomas reacted for either marker. In 31 cytological samples diagnosed as 'non-small-cell lung carcinoma', desmocollin-3 was again mutually exclusive with TTF-1 and stained all squamous carcinomas, 1 of 19 adenocarcinoma only, and 50% of large-cell carcinoma (all histologically confirmed). This combined morphophenotypic approach may represent a valid adjunct (for both surgical and cytological samples) in the selection of patients with lung cancer to medical treatments tailored according to different efficacy in different lung carcinomas of the squamous, adeno-and large-cell types. Modern Pathology ( Keywords: large-cell carcinoma; squamous differentiation; desmocollin-3; diagnosis Lung cancer is subdivided into four histotypes, including small-cell carcinoma (SCLC) on the one side, and carcinomas of squamous-, adeno-and large-cell types on the other. These latter tumor groups have different pathological features, but have generally been treated so far according to similar strategies, so that a clear-cut distinction among these types (except for SCLC) was not considered clinically relevant. 1 Indeed, the WHO classifications of lung carcinoma have always kept the different histological types separate and proposed individual categories for squamous carcinoma, adenocarcinoma and large-cell (anaplastic) carcinoma (LCC). 2 The latter category underwent major changes in the last classification scheme, 3 having undifferentiated pleomorphic and/or sarcomatoid variants been moved to a new group o...

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“…One promise of gene expression microarray studies in lung cancer has been to develop novel approaches to diagnostics for disease classification and patient stratification into high probability treatment outcome groups (9)(10)(11)(12). This overall strategy has found considerable success in the treatment of breast cancer, moving from research tool to clinical diagnostics, to identify best treatment outcome and recurrence using a 70-gene panel (MammaPrint; ref.…”

Section: Introductionmentioning

confidence: 99%

A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment

et al. 2008

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One area of intensive investigation is to understand complex cellular and signaling interactions in the tumor microenvironment. Using a novel, although straightforward, microarray approach, we defined a gene expression signature from the lung tumor microenvironment in the murine A/J-urethane model of human lung adenocarcinoma. The tumor microenvironment is reflected by the composition of the cell types present and alterations in mRNA levels, resulting in a ''Field Effect'' around the tumor. The genes composing the Field Effect expression signature include proteases and their inhibitors, inflammation markers, and immune signaling molecules. By several criteria, the Field Effect expression signature can be attributed to the macrophage lineage, suggesting a qualitative change in the expression pattern of tumor-associated macrophages (TAM) observed in lung tumors. The protein expression levels for a number of Field Effect genes were verified by Western blot analysis of lung homogenates, and for their expression in macrophages and parenchymal cells outside of the tumors by immunohistochemistry. In addition, the Field Effect expression signature was used to classify bronchoalveolar lavage (BAL) cells from tumor-bearing or age-matched control mice. Using a variety of statistical measures, the Field Effect expression signature correctly classified the BAL cells >94% of the time. Finally, the protein levels for several Field Effect genes were higher in cellfree BAL fluid, indicating they may be secreted by the TAMs. This work suggests that TAMs generate a unique gene expression signature within the tumor microenvironment, and this signature could potentially be used for identifying lung cancer from BAL cells and/or fluid. [Cancer Res 2008;68(1):34-43]

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Gene Expression Profiling Reveals Reproducible Human Lung Adenocarcinoma Subtypes in Multiple Independent Patient Cohorts

Abstract: DNA microarray analysis of lung adenocarcinomas identified reproducible tumor subtypes which differ significantly in clinically important behaviors such as stage-specific survival.

Cited by 251 publications

References 50 publications

Role of LKB1 in lung cancer development

Role of LKB1 in lung cancer development

Desmocollin-3: a new marker of squamous differentiation in undifferentiated large-cell carcinoma of the lung

A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment

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