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NIOSH Respiratory Diseases Research Program

Evidence Package for the National Academies' Review 2006-2007

NIOSH Programs > Respiratory Diseases > Evidence Package > 5. Respiratory Malignancies

5.5 Lung Cancer Diagnostic Tools

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Issue

The overall five-year relative survival rate for lung cancer is only 15 percent. For cases detected when the disease is still localized, the five-year survival rate lung cancer is 49 percent.  However, only 16 percent of all lung cancers are discovered before the disease spreads. These data, all from the NCI’s Surveillance Epidemiology and End Results Program154 indicate the potential usefulness of new tools for accurate early detection and staging of lung cancer.

Approach

Human carcinogenesis results from adverse changes that occur in the DNA of normal cells. Comparative genomic hybridization and spectral karyotyping are new methods of interrogating the genetic code of tumors and comparing it with normal tissue to determine what chromosomal changes have occurred in the tumor cells. Certain chromosomal changes are the hallmarks of specific tumor types, and some of these changes are markers for a tumor’s aggressiveness (for example, invasion or metastasis).

RDRP scientists have used spectral karyotyping and comparative genomic hybridization to identify genetic changes that occur during the lung cancer process. They have further developed a Cooperative Research and Development Agreement with Spectral Genomics, Inc. Together they have designed a syntenic genomic chip (a comparative genomic hybridization array) which will allow the comparison of common changes that occur in lung cancers that can be experimentally induced in mice with those that occur in humans. This should increase the pace of research progress, as the mouse model for lung adenocarcinoma is currently the only experimentally manipulable model for human lung adenocarcinoma. The comparative genomic hybridization array chip also has the potential to improve the accuracy and speed of staging of adenocarcinoma of the lung.

The DLC-1 gene, a newly determined human lung cancer tumor suppressor gene, was found to be significantly down-regulated in 20 of 21 (> 95 percent) primary non-small cell lung carcinomas, making it the most common genetic change observed in human lung adenocarcinoma. Furthermore, DLC-1 down-regulation appears to be an early event in lung tumor development.

Re-expression of DLC-1 in human non-small cell lung carcinomas cell lines which exhibit down-regulated expression of DLC-1 results in significant in vitro growth inhibition as demonstrated by either a colony formation assay and/or a cell proliferation assay as well as suppression of in vivo tumorigenicity in nude mice, suggesting that DLC-1 is a potential target for intervention into the disease process. The extremely high percentage (> 95 percent) of DLC-1 down-regulation in human lung adenocarcinoma also suggests that DLC-1 may serve as a useful biomarker for early detection of human lung adenocarcinoma. Similar chromosomal linkage groups were found to be altered in both human and mouse lung adenocarcinoma, implying that the mouse is a valid genetic model for the study of human lung adenocarcinoma. Chromosomal regions containing mouse lung adenocarcinoma susceptibility genes linked to tumor size were frequently amplified, whereas chromosomal regions linked to tumor multiplicity were frequently deleted, suggesting that many lung cancer susceptibility genes function in a manner analogous to oncogenes or tumor suppressor genes. These data provided the first insight into the mechanism(s) of how lung cancer susceptibility genes function in the genesis of lung cancer.

Outputs and Transfer

A key report of this research was published in 2004 and has already received some recognition through literature citations (18, A5-42). A second report has also been published (19, A5-43).

Through the Cooperative Research and Development Agreement with Spectral Genomics, Inc., a syntenic genomic chip has been developed and a patent is pending (#2004-025124). This mouse-human chip will be used to allow direct comparisons between mouse and human lung adenocarcinomas.

Intermediate Outcome

This RDRP research has lead to generalizable knowledge concerning lung cancer mechanisms that is valuable to other lung cancer researchers. The syntenic chip is the fore-runner of a human chip that will be used in the diagnosis and staging of lung adenocarcinomas in humans.

What’s Ahead

The objective of this research is to isolate genes of importance in the carcinogenesis process and develop biomarkers. Future aims of this RDRP research are to:

  • Analyze the changes in gene expression and gene copy number that occur in development of lung adenocarcinoma in humans and mice
  • Identify the specific changes which will aid in the early detection, diagnosis, staging and intervention of lung adenocarcinoma

This research is intended to further validate the mouse model as a viable research tool to examine the development and progression of lung adenocarcinoma. The comparative genomic hybridization arrays we will utilize are high resolution and will provide a level of detail not previously available to the research community. By utilizing these arrays in conjunction with follow-up validation with fluorescent in situ hybridization and Polymerase Chain Reaction (PCR), we expect to identify a set of gene alterations that are common to both human and mouse lung adenocarcinomas. It is our contention that common alterations across species are more likely to be important in the initiation and development of adenocarcinoma than are those occurring in only a single species. Results from the mouse and human studies will be used to establish biomarkers for occupational exposure to lung carcinogens and the early detection and staging of lung cancer. The Cooperative Research and Development Agreement established with Spectral Genomics Inc. will assess the applicability of the observed gene expression and gene copy number changes detected in our studies to aid in the early detection, diagnosis, and staging of lung cancer.

 

154. NCI [2006] Surveillance Epidemiology and End Results (SEER) Cancer State Fact Sheets: Cancer of the Lung and Bronchus. [seer.cancer.gov/statfacts/html/lungb.html].