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Vol. LXVI, No. 16
August 1, 2014

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Study Identifies Novel Genomic Changes in the Most Common Type of Lung Cancer

Researchers from The Cancer Genome Atlas (TCGA) Research Network have identified novel mutations in a well-known cancer-causing pathway in lung adenocarcinoma, the most common subtype of lung cancer. Knowledge of these genomic changes may expand the number of possible therapeutic targets for this disease and potentially identify a greater number of patients with treatable mutations because many potent cancer drugs that target these mutations already exist.

In the study, published online July 9 in the journal Nature, researchers examined the genomes, RNA and some protein from 230 lung adenocarcinoma samples. In three-quarters of the samples, the scientists ultimately identified mutations that put a cell signaling pathway known as the RTK/RAS/RAF pathway into overdrive.

“The integrated nature of TCGA analysis made these findings and their potential therapeutic implications possible,” said NIH director Dr. Francis Collins. “We hope this lays the groundwork for future work in precision medicine.”

Mutations affecting the RTK/RAS/RAF pathway can cause it to become stuck in the “on” state. As a result, signals that promote cancer cell proliferation and survival are produced continuously. However, some drugs currently available curb aberrant activity of this pathway and prompt therapeutic responses in patients.

Lung adenocarcinoma, the most common form of the disease in the United States, develops in tissues near the outer parts of the lungs and can spread widely.

NIH Study Finds Extreme Obesity May Shorten Life Expectancy Up to 14 Years

Adults with extreme obesity have increased risks of dying at a young age from cancer and many other causes including heart disease, stroke, diabetes and kidney and liver diseases, according to results of an analysis of data pooled from 20 large studies of people from 3 countries. The study, led by researchers from NCI, found that people with class III (or extreme) obesity had a dramatic reduction in life expectancy compared with people of normal weight. The findings appeared July 8 in PLOS Medicine.

“While once a relatively uncommon condition, the prevalence of class III, or extreme, obesity is on the rise. In the United States, for example, 6 percent of adults are now classified as extremely obese, which, for a person of average height, is more than 100 pounds over the recommended range for normal weight,” said Dr. Cari Kitahara of NCI’s Division of Cancer Epidemiology and Genetics and lead author of the study. “Prior to our study, little had been known about the risk of premature death associated with extreme obesity.”

The 20 studies that were analyzed included adults from the United States, Sweden and Australia. The researchers found that the risk of dying overall and from most major health causes rose continuously with increasing BMI within the class III obesity group.

NIH Scientists Identify Gene Linked to Fatal Inflammatory Disease in Children

NIAMS team members include (from l) Dr. Yan Huang, Dr. Bernadette Marrero, Dr. Adriana A. Jesus, Dr. Gina Montealegre, SAVI patient Elliot Schuman, Dr. Raphaela Goldbach-Mansky, Patricia O’Brien, Dawn Chapelle and Dr. Yin Liu.

NIAMS team members include (from l) Dr. Yan Huang, Dr. Bernadette Marrero, Dr. Adriana A. Jesus, Dr. Gina Montealegre, SAVI patient Elliot Schuman, Dr. Raphaela Goldbach-Mansky, Patricia O’Brien, Dawn Chapelle and Dr. Yin Liu.

Investigators have identified a gene that underlies a very rare but devastating autoinflammatory condition in children. Several existing drugs have shown therapeutic potential in laboratory studies and one is currently being studied in children with the disease, which the researchers named STING-associated vasculopathy with onset in infancy (SAVI). The findings appeared online July 17 in the New England Journal of Medicine. The research was done at NIAMS.

“Not only do these discoveries have profound implications for children with SAVI, but they could have a broader impact by helping us to understand other, more common inflammatory conditions,” said NIAMS director Dr. Stephen Katz. “Diseases such as lupus share some characteristics with SAVI, so this work may lead to novel insights and possibly new treatments for these debilitating conditions as well.”

The senior author of the study, Dr. Raphaela Goldbach-Mansky, and co-lead authors Dr. Yin Liu, Dr. Adriana A. Jesus and Dr. Bernadette Marrero are in the NIAMS translational autoinflammatory disease section.

In 2004, Goldbach-Mansky was called upon to advise on a patient with a baffling problem—a 10-year-old girl with signs of systemic inflammation, especially in the blood vessels, who had not responded to any of the medications her doctors had used to treat her. By 2010, Goldbach-Mansky had seen two other patients with the same symptoms. She suspected that all three had the same disease, and that it was caused by a genetic defect that arose in the children themselves, rather than having been inherited from their parents, who were not affected. Her hunch suggested a strategy for identifying the genetic defect. By comparing the DNA of an affected child with the DNA of the child’s parents, scientists would be able to spot the differences and possibly identify the disease-causing mutation.

“When mutations that cause autoinflammatory conditions hit an important pathway, the outcome for patients can be dismal,” said Goldbach-Mansky. “But because SAVI is caused by a single gene defect and interferon has such a strong role, I’m optimistic that we’ll be able to target the pathway and potentially make a huge difference in the lives of these children.”

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