A Gene Expression Signature Predicts Survival of Patients with Stage I Non-Small Cell Lung Cancer

Lü, Yan; Lemon, William J.; Liu, Peng Yuan; Yi, Yijun; Morrison, Carl; Yang, Ping; Sun, Zhifu; Szőke, János; Gerald, William L.; Watson, Mark A.; Govindan, Ramaswamy; You, Ming

doi:10.1371/journal.pmed.0030467

Cited by 273 publications

(215 citation statements)

References 51 publications

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“…To further elaborate, 3 large studies in lung cancer have been described, all of which were specifically designed to find a prognostic gene signature in early stage NSCLC using supervised classification on gene expression data from lung tumor samples with known clinical outcomes (25,35,36). Although the number of genes that overlap between the 3 independently derived gene sets is minimal, recent data suggest that because all 3 gene signatures could be independently validated in large patient cohorts (25,35,36), it is more likely that these gene signatures use different reporter genes to monitor the same biological pathways or processes. When comparing the pathways involved in the TTF-1 and NKX2-8 signatures, coactivation is associated with a higher likelihood of recurrence in our present study.…”

Section: Discussionmentioning

confidence: 99%

Characterizing the developmental pathways TTF-1 , NKX2–8 , and PAX9 in lung cancer

Hsu

Acharya²,

Balakumaran³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We investigated the clinical implications of lung developmental transcription factors ( TTF-1 , NKX2–8 , and PAX9 ) that we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the 3 genes were determined and used to risk stratify a non-small-cell lung cancer (NSCLC) clinical data set consisting of 91 early stage tumors. Coactivation of the TTF-1 and NKX2–8 pathways identified a cluster of patients with poor survival, representing ≈20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power. Importantly, the poor prognosis associated with coactivation of TTF-1 and NKX2–8 was validated in 2 other independent clinical data sets. Furthermore, lung cancer cell lines showing coactivation of the TTF-1 and NKX2–8 pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. This suggests that the cohort of patients with coactivation of TTF-1 and NKX2–8 pathways appears to be resistant to standard cisplatin therapy, suggesting the need for alternative therapies in this cohort of high-risk patients.

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Section: Discussionmentioning

confidence: 99%

Characterizing the developmental pathways TTF-1 , NKX2–8 , and PAX9 in lung cancer

Hsu

Acharya²,

Balakumaran³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…13). Recent reports suggest a similar approach is feasible using lung cancer tissue to identify high-and low-risk groups for recurrence and survival (14)(15)(16), although these approaches do not address early detection methodologies.…”

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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“…Recent genomic studies have begun to reveal systematic gene expression differences both between and within these histological subclasses. [2][3][4][5][6] These molecular physiological differences, detected by large-scale gene expression profiling, suggest a potential clinical utility for subclassification by clinical histological type, 7,8 but several studies have failed to find a predictive association between histological type and standard cytotoxic chemotherapy efficacy, accounting for current standard treatment strategies that do not take into account lung carcinoma histological type. [9][10][11] Despite the established lack of utility of distinguishing adenocarcinoma from squamous cell carcinoma for the selection of traditional chemotherapeutics in the treatment of lung carcinoma, there is growing evidence that the efficacy and toxicity of some emerging targeted or combination treatment strategies are associated with histological type.…”

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confidence: 99%

A novel five-antibody immunohistochemical test for subclassification of lung carcinoma

Ring¹,

Seitz

Beck

et al. 2009

Modern Pathology

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Malignant epithelial lung carcinoma can be subclassified by histology into several tumor types, including adenocarcinoma and squamous cell carcinoma. The need for a uniform method of classifying lung carcinomas is growing as clinical trials reveal treatment and side effect differences associated with histological subtypes. Diagnosis is primarily performed by morphological assessment. However, the increased use of needle biopsy has diminished the amount of tissue available for interpretation. These changes in how lung carcinomas are diagnosed and treated suggest that the development of improved molecular-based classification tools could improve patient management. We used a 551-patient surgical specimen lung carcinoma retrospective cohort from a regional hospital to assess the association of a large number of proteins with histological type by immunohistochemistry. Five of these antibodies, targeting the proteins TRIM29, CEACAM5, SLC7A5, MUC1, and CK5/6, were combined into one test using a weighted algorithm trained to discriminate adenocarcinoma from squamous cell carcinoma. Antibody-based classification on 600 lM tissue array cores with the fiveantibody test was compared to standard histological evaluation on surgical specimens in three independent lung carcinoma cohorts (combined population of 1111 patients). In addition, the five-antibody test was tested against the two-marker panel thyroid transcription factor-1 (TTF-1) and TP63. Both the five-antibody test and TTF-1/TP63 panel had similarly low misclassification rates on the validation cohorts compared to morphological-based diagnosis (4.1 vs 3.5%). However the percentage of patients remaining unclassifiable by TTF-1/TP63 (22%, 95% CI: 20-25%) was twice that of the five-antibody test (11%, 95% CI: 8-13%). The results of this study suggest the five-antibody test may have an immediate function in the clinic for helping pathologists distinguish lung carcinoma histological types. The results also suggest that if validated in prospectively defined clinical trials this classifier might identify candidates for targeted therapy that are overlooked with current diagnostic approaches.

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A Gene Expression Signature Predicts Survival of Patients with Stage I Non-Small Cell Lung Cancer

Cited by 273 publications

References 51 publications

Characterizing the developmental pathways TTF-1 , NKX2–8 , and PAX9 in lung cancer

Characterizing the developmental pathways TTF-1 , NKX2–8 , and PAX9 in lung cancer

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

A novel five-antibody immunohistochemical test for subclassification of lung carcinoma

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