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J Thorac Oncol. 2018 Oct;13(10):1496-1507. doi: 10.1016/j.jtho.2018.05.039. Epub 2018 Jun 19.

Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naïve Lesions.

Author information

1
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
2
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
3
Department of Respiratory Medicine, Higashi-Hiroshima Medical Center, Higashi-Hiroshima, Japan.
4
Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
5
Department of Pathology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
6
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address: aikchoon.tan@ucdenver.edu.

Abstract

INTRODUCTION:

Data regarding the pre-treatment intertumor heterogeneity of potential biomarkers in advanced-stage lung cancers is limited. A finding of such heterogeneity between primary and metastatic lesions would prove valuable to determine if a metastatic lesion can be a surrogate for the primary tumor, as more biomarkers will likely be used in the future to inform treatment decisions.

METHODS:

We performed RNA sequencing to analyze intertumor heterogeneity in 30 specimens (primary tumors, intrathoracic, and extrathoracic metastatic lesions) obtained from five treatment-naïve lung cancer patients.

RESULTS:

The global unsupervised clustering analysis showed that the lesions clustered at the individual patient level rather than on the metastatic sites, suggesting that the characteristics of specific tumor cells have a greater impact on the gene expression signature than the microenvironment in which the metastasis develops. The mutational and transcriptional data highlight the presence of intertumor heterogeneity showing that the primary tumors are usually distinct from metastatic lesions. Through a comparison between metastatic lesions and the primary tumors, we observed that pathways related to cell proliferation were upregulated, whereas immune-related pathways were downregulated in metastatic lesions.

CONCLUSION:

These data not only provide insight into the evolution of lung cancers, but also imply possibilities and limitations of biomarker-based treatment in lung cancers.

KEYWORDS:

Autopsy; Biomarkers; Immune-related markers; RET fusion; RNA sequencing; Tumor heterogeneity

PMID:
29933065
PMCID:
PMC6153034
[Available on 2019-10-01]
DOI:
10.1016/j.jtho.2018.05.039
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