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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

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.

About TGen

The Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. Research at TGen is focused on helping patients with diseases such as cancer, neurological disorders and diabetes. TGen is on the cutting edge of translational research where investigators are able to unravel the genetic components of common and complex diseases. Working with collaborators in the scientific and medical communities, TGen believes it can make a substantial contribution to the efficiency and effectiveness of the translational process. TGen is affiliated with the Van Andel Research Institute in Grand Rapids, Michigan. For more information, visit:

Press Contact:
Steve Yozwiak
TGen Senior Science Writer
About the AACR:
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes 33,000 laboratory, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowships and career development awards to young investigators, and it also funds cutting-edge research projects conducted by senior researchers. The AACR has numerous fruitful collaborations with organizations and foundations in the United States and abroad and functions as the Scientific Partner of Stand Up To Cancer, a charitable initiative that supports groundbreaking research aimed at getting new cancer treatments to patients in an accelerated time frame.

The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care, and Educational Workshops are held for the training of young cancer investigators. The AACR publishes seven major peer-reviewed journals: Cancer Discovery; Cancer Research; Clinical Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Prevention Research. In 2010, AACR journals received 20 percent of the total number of citations given to oncology journals. The AACR also publishes Cancer Today, a magazine for cancer patients, survivors and their caregivers, which provides practical knowledge and new hope for cancer survivors. A major goal of the AACR is to educate the general public and policymakers about the value of cancer research in improving public health, the vital importance of increases in sustained funding for cancer research and biomedical science, and the need for national policies that foster innovation and the acceleration of progress against the 200 diseases we call cancer.

Follow the AACR on Twitter: @aacr #aacr

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About the IASLC:

The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated to the study of lung cancer. Founded in 1974, the association's membership includes more than 3,500 lung cancer specialists in 80 countries.

IASLC members promote the study of etiology, epidemiology, prevention, diagnosis, treatment and all other aspects of lung cancer and thoracic malignancies. IASLC disseminates information about lung cancer to scientists, members of the medical community and the public and uses all available means to eliminate lung cancer as a health threat for individual patients throughout the world. Membership is open to any physician, scientist, nurse or allied health professional interested in lung cancer, including patients, survivors, caregivers and advocates.

IASLC publishes the Journal of Thoracic Oncology, a valuable resource for medical specialists and scientists who focus on the detection, prevention, diagnosis and treatment of lung cancer.

To learn more about IASLC, visit

Steve Yozwiak | EurekAlert!
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