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- Posted Monday January 9, 2012
TGen researchers map potential genetic origins, pathways of lung cancer in nonsmokers
Study presented at AACR-IASLC conference of multiple novel
mutations and pathway changes not found in patients with lung
cancer who smoked
SAN DIEGO - Jan. 9, 2012 - Researchers at the Translational
Genomics Research Institute (TGen) have begun to identify mutations
and cellular pathway changes that lead to lung cancer in
never-smokers - a first step in developing potential therapeutic
targets.
"This is the starting point. We certainly have a lot of pathways
and gene expression alterations that we're going to be very
interested in confirming and looking at in larger cohorts of
patients," said Dr. Timothy G. Whitsett, Senior Postdoctoral Fellow
in TGen's Cancer and Cell Biology Division.
Whitsett presented the findings today at the American Association
for Cancer Research (AACR) and International Association for the
Study of Lung Cancer (IASLC) Joint Conference on Molecular Origins
of Lung Cancer: Biology, Therapy and Personalized Medicine, held
Jan. 8-11, 2012, at the San Diego Marriott Marina &
Hotel.
"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 cancer," said Dr. Whitsett, who works
under Dr. Nhan Tran, head of TGen's CNS Tumor Research Lab. The
title of the abstract Dr. Whitsett presented is Identification of
key tumorigenic pathways in never-smoker lung adenocarcinoma
patients using massively parallel DNA and RNA sequencing.
Never-smokers are defined for this study as individuals who smoked
less than 100 cigarettes in their lifetime. About 10 percent of
lung cancer cases occur in this patient population, which
researchers have not examined as extensively as they have studied
patients with lung cancer who smoked.
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 (WGS) and whole transcriptome sequencing (WTS) on each
patient to identify gene mutations and pathway alterations that
could have led to the development and progression of their specific
lung cancer.
"In the never-smoker with early-stage cancer, there are very few
mutations in the genome, but when we looked at the whole
transcriptome, we see differences in gene expression," Whitsett
said.
In the never-smoker with late-stage disease, researchers found
mutations in what Whitsett called "classic tumor-suppressor genes."
He and his colleagues hypothesize that mutations of the
tumor-suppressor genes might be a factor in late-stage lung cancer
in never-smokers.
Notably, the researchers 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.
Whitsett said that using WGS and WTS 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."
The researchers are now validating these findings in about 30
never-smokers with lung adenocarcinoma and about 60 clinically
matched smokers with lung adenocarcinoma.
TGen collaborators on this project included: Center for Thoracic
and Esophageal Disease at St. Joseph's Hospital and Medical Center,
Phoenix, Ariz.; Integrated Biobank of Luxembourg, Luxembourg;
Virginia G. Piper Cancer Center Clinical Trials at Scottsdale
Healthcare, Scottsdale, Ariz.