Public Release:  Defects in critical gene lead to accelerated lung tumor growth

University of North Carolina Health Care

CHAPEL HILL - Cancer causing mutations occur in our bodies every day - but luckily, we have specific genes that recognize these malignant events and keep cells from growing out of control. Only a few of these genes - called tumor suppressors - are currently known.

Now scientists at the University of North Carolina at Chapel Hill School of Medicine and Harvard Medical School have added to the list another powerful tumor suppressor, a gene called LKB1. Their research indicates that this gene is mutated in almost a quarter of all human lung cancers. In mice, these mutations result in tumors that are more aggressive and more likely to spread throughout the body.

"Defects in this gene appear to result in a much nastier form of lung cancer, a disease that is bad to begin with," said Dr. Norman Sharpless, an assistant professor of medicine and genetics in the UNC School of Medicine, a member of the UNC Lineberger Comprehensive Cancer Center and a senior author of the study. This finding is expected to help doctors better assign a prognosis to their patients, as well as giving them a new target for future therapies, Sharpless said.

The study, published online Aug. 5 in the journal Nature, also presents the first mouse model of the most lethal malignancy in man, a form of lung cancer called squamous cell carcinoma. Lung cancer kills more Americans each year than breast, prostate and colorectal cancers combined. Of the different types of lung cancer, squamous is strongly associated with tobacco use and is the most common worldwide.

Mice genetically engineered to have defects in the LKB1 gene in the lung develop cancer at a much faster rate than those with defects in other tumor suppressors commonly mutated in lung cancer. These mice develop cancers of not just one lung cancer subtype, but exhibit all three forms of non-small cell lung cancer: adenocarcinomas, squamous cell carcinomas and large cell carcinomas. In addition, these cancers are more likely to metastasize, or spread to other organs.

"Clearly mice with lung cancers harboring LKB1 mutations do much worse than those with other types of cancers; however, we still do not know what this gene does," Sharpless said. "This mouse model will enable us to determine how this gene is important for lung cancer and to develop therapies targeted in a way that can help human patients."

To determine whether the model mirrors the genetic events of human lung cancer, the researchers analyzed DNA from 144 non-small cell lung cancer patients treated at UNC and affiliated hospitals. Defects in LKB1 appeared in 34 percent of human lung adenocarcinomas, 19 percent of squamous cell carcinomas and 10 percent of large cell carcinomas.

"Based on this study and ones like it we should be able to sort patients into groups based on exactly what genetic lesion is causing their cancer," said Dr. Neil Hayes, an assistant professor of medicine in UNC's School of Medicine, a member of UNC Lineberger and co-author of the study. "Then we can make better treatment decisions depending on which therapy is most likely to target that defect."

Currently, Hayes and his colleagues are looking at cancer progression in patients from this study to see how specific LKB1 mutations correlate with clinical outcomes.

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The research was funded in part by grants from the National Institutes of Health, the Sidney Kimmel Foundation for Cancer Research, the Joan Scarangello Foundation to Conquer Lung Cancer, the Flight Attendant Medical Research Institute, Waxman Foundation and Harvard Stem Cell Institute.

Study co-authors at UNC include Matthew Ramsey, Cheng Fan, Chad Torrice and Janakiraman Krishnamurthy.

Drs. Kwok-Kin Wong of Dana-Farber Cancer Institute and Nabeel Bardeesy at Massachusetts General Hospital contributed equally to this work.

Note: Sharpless can be reached at (919) 966-1185 or nes@med.unc.edu

School of Medicine contacts: Les Lang, (919) 843-9687 or llang @med.unc.edu and Stephanie Crayton, (919) 966-2860 or scrayton@unch.unc.edu
Lineberger Center contact: Dianne Shaw, (919) 966-7834 or dgs@med.unc.edu News Services contact: Clinton Colmenares, (919) 843-1991 or clinton_colmenares@unc.edu

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