Defects in critical gene lead to accelerated lung tumor growth

August 05, 2007

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.
-end-
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

University of North Carolina Health Care

Related Lung Cancer Articles from Brightsurf:

State-level lung cancer screening rates not aligned with lung cancer burden in the US
A new study reports that state-level lung cancer screening rates were not aligned with lung cancer burden.

The lung microbiome may affect lung cancer pathogenesis and prognosis
Enrichment of the lungs with oral commensal microbes was associated with advanced stage disease, worse prognosis, and tumor progression in patients with lung cancer, according to results from a study published in Cancer Discovery, a journal of the American Association for Cancer Research.

New analysis finds lung cancer screening reduces rates of lung cancer-specific death
Low-dose CT screening methods may prevent one death per 250 at-risk adults screened, according to a meta-analysis of eight randomized controlled clinical trials of lung cancer screening.

'Social smokers' face disproportionate risk of death from lung disease and lung cancer
'Social smokers' are more than twice as likely to die of lung disease and more than eight times as likely to die of lung cancer than non-smokers, according to research presented at the European Respiratory Society International Congress.

Lung cancer therapy may improve outcomes of metastatic brain cancer
A medication commonly used to treat non-small cell lung cancer that has spread, or metastasized, may have benefits for patients with metastatic brain cancers, suggests a new review and analysis led by researchers at St.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Lung transplant patients face elevated lung cancer risk
In an American Journal of Transplantation study, lung cancer risk was increased after lung transplantation, especially in the native (non-transplanted) lung of single lung transplant recipients.

Proposed cancer treatment may boost lung cancer stem cells, study warns
Epigenetic therapies -- targeting enzymes that alter what genes are turned on or off in a cell -- are of growing interest in the cancer field as a way of making a cancer less aggressive or less malignant.

Are you at risk for lung cancer?
This question isn't only for people who've smoked a lot.

Read More: Lung Cancer News and Lung Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.