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Clinically relevant characterization of lung adenocarcinoma subtypes based on cellular pathways: an international validation study.

Bryant CM, Albertus DL, Kim S, Chen G, Brambilla C, Guedj M, Arima C, Travis WD, Yatabe Y, Takahashi T, Brambilla E, Beer DG - PLoS ONE (2010)

Bottom Line: Further, AD with increased cell proliferation demonstrate significantly poorer outcome and an increased solid AD subtype component.Additional results suggest the ability to use a similar approach to determine a patient's sensitivity to targeted treatment.We then demonstrated the consistency of these findings using two independent AD cohorts from Asia (N = 87) and Europe (N = 89) using the identical analytic procedures.

View Article: PubMed Central - PubMed

Affiliation: Thoracic Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

ABSTRACT
Lung adenocarcinoma (AD) represents a predominant type of lung cancer demonstrating significant morphologic and molecular heterogeneity. We sought to understand this heterogeneity by utilizing gene expression analyses of 432 AD samples and examining associations between 27 known cancer-related pathways and the AD subtype, clinical characteristics and patient survival. Unsupervised clustering of AD and gene expression enrichment analysis reveals that cell proliferation is the most important pathway separating tumors into subgroups. Further, AD with increased cell proliferation demonstrate significantly poorer outcome and an increased solid AD subtype component. Additionally, we find that tumors with any solid component have decreased survival as compared to tumors without a solid component. These results lead to the potential to use a relatively simple pathological examination of a tumor in order to determine its aggressiveness and the patient's prognosis. Additional results suggest the ability to use a similar approach to determine a patient's sensitivity to targeted treatment. We then demonstrated the consistency of these findings using two independent AD cohorts from Asia (N = 87) and Europe (N = 89) using the identical analytic procedures.

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Overall Study Design.We developed cellular pathway expression summaries and tested the relationship of each to pathological subtypes of lung adenocarcinoma (AD). We also tested each pathway's association with survival. Because the cellular pathways are driving the pathological differences, the relationship between pathology and prognosis is secondary to the relationship between the cellular pathway and prognosis (indicated by a thinner line with both component colors). We also directly tested the relationship between pathology and prognosis to examine the need for molecular information.
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pone-0011712-g001: Overall Study Design.We developed cellular pathway expression summaries and tested the relationship of each to pathological subtypes of lung adenocarcinoma (AD). We also tested each pathway's association with survival. Because the cellular pathways are driving the pathological differences, the relationship between pathology and prognosis is secondary to the relationship between the cellular pathway and prognosis (indicated by a thinner line with both component colors). We also directly tested the relationship between pathology and prognosis to examine the need for molecular information.

Mentions: The current system of AD classification does not adequately capture the heterogeneity of these tumors and classification using clinical, pathological and gene-expression based approaches tend to be treated as separate modalities. Investigating the associations and interactions between them could yield powerful new insights into more effective and clinically-relevant ways to classify AD but has been hampered by previous gene expression studies examining only relatively small numbers of tumors. We have now combined our recent analysis of over 400 AD samples using gene expression profiling [3] with complete clinical information and a newly performed uniform pathological review of these tumors. We hypothesized that the heterogeneity of AD may reflect differences in the expression levels of cancer-related pathways. We have utilized sets of genes representing 27 separate cellular processes (referred to as pathways) to investigate relationships between tumors and separate AD subtypes. The relationships observed between gene expression, clinical information including survival, and AD pathology we suggest, have potential translational and clinical implications. Our overall study design is summarized in Figure 1 and was independently validated in two additional independent datasets.


Clinically relevant characterization of lung adenocarcinoma subtypes based on cellular pathways: an international validation study.

Bryant CM, Albertus DL, Kim S, Chen G, Brambilla C, Guedj M, Arima C, Travis WD, Yatabe Y, Takahashi T, Brambilla E, Beer DG - PLoS ONE (2010)

Overall Study Design.We developed cellular pathway expression summaries and tested the relationship of each to pathological subtypes of lung adenocarcinoma (AD). We also tested each pathway's association with survival. Because the cellular pathways are driving the pathological differences, the relationship between pathology and prognosis is secondary to the relationship between the cellular pathway and prognosis (indicated by a thinner line with both component colors). We also directly tested the relationship between pathology and prognosis to examine the need for molecular information.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908611&req=5

pone-0011712-g001: Overall Study Design.We developed cellular pathway expression summaries and tested the relationship of each to pathological subtypes of lung adenocarcinoma (AD). We also tested each pathway's association with survival. Because the cellular pathways are driving the pathological differences, the relationship between pathology and prognosis is secondary to the relationship between the cellular pathway and prognosis (indicated by a thinner line with both component colors). We also directly tested the relationship between pathology and prognosis to examine the need for molecular information.
Mentions: The current system of AD classification does not adequately capture the heterogeneity of these tumors and classification using clinical, pathological and gene-expression based approaches tend to be treated as separate modalities. Investigating the associations and interactions between them could yield powerful new insights into more effective and clinically-relevant ways to classify AD but has been hampered by previous gene expression studies examining only relatively small numbers of tumors. We have now combined our recent analysis of over 400 AD samples using gene expression profiling [3] with complete clinical information and a newly performed uniform pathological review of these tumors. We hypothesized that the heterogeneity of AD may reflect differences in the expression levels of cancer-related pathways. We have utilized sets of genes representing 27 separate cellular processes (referred to as pathways) to investigate relationships between tumors and separate AD subtypes. The relationships observed between gene expression, clinical information including survival, and AD pathology we suggest, have potential translational and clinical implications. Our overall study design is summarized in Figure 1 and was independently validated in two additional independent datasets.

Bottom Line: Further, AD with increased cell proliferation demonstrate significantly poorer outcome and an increased solid AD subtype component.Additional results suggest the ability to use a similar approach to determine a patient's sensitivity to targeted treatment.We then demonstrated the consistency of these findings using two independent AD cohorts from Asia (N = 87) and Europe (N = 89) using the identical analytic procedures.

View Article: PubMed Central - PubMed

Affiliation: Thoracic Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

ABSTRACT
Lung adenocarcinoma (AD) represents a predominant type of lung cancer demonstrating significant morphologic and molecular heterogeneity. We sought to understand this heterogeneity by utilizing gene expression analyses of 432 AD samples and examining associations between 27 known cancer-related pathways and the AD subtype, clinical characteristics and patient survival. Unsupervised clustering of AD and gene expression enrichment analysis reveals that cell proliferation is the most important pathway separating tumors into subgroups. Further, AD with increased cell proliferation demonstrate significantly poorer outcome and an increased solid AD subtype component. Additionally, we find that tumors with any solid component have decreased survival as compared to tumors without a solid component. These results lead to the potential to use a relatively simple pathological examination of a tumor in order to determine its aggressiveness and the patient's prognosis. Additional results suggest the ability to use a similar approach to determine a patient's sensitivity to targeted treatment. We then demonstrated the consistency of these findings using two independent AD cohorts from Asia (N = 87) and Europe (N = 89) using the identical analytic procedures.

Show MeSH
Related in: MedlinePlus