Researchers Map Potential Genetic Origins, Pathways of Lung Cancer in Never-smokers

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Findings from a small study on potential gene mutations and pathway alterations that could lead to lung cancer in never-smokers were presented in a poster at the American Association for Cancer Research–International Association for the Study of Lung Cancer Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine, held recently in San Diego, California. Timothy G. Whitsett, PhD, Senior Postdoctoral Fellow in the Cancer and Cell Biology Division at the Translational Genomics Research Institute (TGen), was lead author.1

Never-smokers account for 10% of lung cancer cases. “This is a very important subset of patients with lung cancer, and our research looks to identify pathways and genes that are potentially driving this form of cancer,” Dr. Whitsett said.

Study Details

Dr. Whitsett and his colleagues looked at three female patients with adenocarcinoma: one never-smoker with early-stage disease, one never-smoker with late-stage disease, and, as a comparison, one smoker with early-stage disease. The team performed whole genome sequencing and whole transcriptome sequencing on each patient to identify gene mutations and pathway alterations that could have led to the development and progression of their specific lung cancers.

“In the never-smoker with early-stage cancer, there were very few mutations in the genome, but when we looked at the whole transcriptome, we saw differences in gene expression,” Dr. Whitsett said.

In the never-smoker with late-stage disease, the researchers found mutations in “classic tumor-suppressor genes,” Dr. Whitsett said. He and his colleagues hypothesized that mutations of the tumor-suppressor genes might be a factor in late-stage lung cancer in never-smokers.

Genetic Profiles

Whitsett and his colleagues reported that these never-smokers’ tumors lacked alterations in common genes associated with lung cancer such as EGFR, KRAS, and EML/ALK translocations. This finding makes these patients ideal cases for the discovery of new mutations that may drive lung adenocarcinomas in never-smokers, according to the researchers.

Using whole genome sequencing and whole transcriptome sequencing to identify cancer origins “has become a way to really dive down into an individual tumor to try to understand the pathways that may be driving that tumor and identify what therapeutic interventions may be possible,” Dr. Whitsett said

The researchers are now validating these findings in about 30 never-smokers with lung adenocarcinoma and about 60 clinically matched smokers with lung adenocarcinoma. ■


1. Whitsett TG, Sinari S, Sheff S, et al: Identification of key tumorigenic pathways in never-smoker lung adenocarcinoma patients using massively parallel DNA and RNA sequencing. AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer. Poster A43. Presented January 9, 2012.