Gene Changes Identified in Most Common Lung Cancer

NHGRI

Lung cancer is the most common cause of cancer deaths in the United States and throughout the world. Globally, it leads to more than a million deaths each year. Less than 20% of those diagnosed with lung cancer survive 5 years after their diagnosis.

The most common type of lung cancer in the U.S. is adenocarcinoma. This cancer is typically caused by smoking. However, as smoking rates decrease, a greater percentage of cases are occurring in people who’ve never smoked.

Like all cancers, lung adenocarcinoma arises from errors in DNA that lead to uncontrolled cell growth. Identifying the changes in each cancer’s complete set of DNA—its genome—may ultimately result in more targeted therapies, improved prevention, and new detection strategies.

The Cancer Genome Atlas (TCGA) Research Network is a comprehensive effort to analyze the molecular basis of cancer. With more than 150 scientists at dozens of institutions across the nation, the TCGA research network is funded by NIH’s National Cancer Institute (NCI) and National Human Genome Research Institute (NHGRI). In a new TCGA study, researchers examined tumor samples and matched normal material from 230 patients with lung adenocarcinoma. The study appeared online on July 9, 2014, in Nature.

In 143 out of 230 samples (62%), the researchers found known activating mutations (misspellings) in oncogenes—genes known to have the potential to cause cancer when mutated or expressed at high level. To identify additional alterations, the investigators looked at DNA copy number changes—changes in gene number from the deletion or multiplication (amplification) of sections of DNA. They detected amplification of 2 oncogenes, ERBB2 and MET, that are part of a signaling pathway known as RTK/RAS/RAF. These mutations cause the pathway to become stuck in the “on” state, triggering tumor cell growth and survival.

The researchers also identified mutations in other genes—including NF1 and RIT1, part of the RTK/RAS/RAF pathway—that can drive lung adenocarcinomas.

By analyzing DNA, RNA, and protein levels, the team determined that several metabolic pathways were activated in the tumor samples. Overall, 76% of the samples had mutations that activate the RTK/RAS/RAF pathway. This work may lead to refinements in how cancers are classified and could lead to more personalized diagnosis and treatment.

“Combined with the earlier TCGA analysis of squamous lung cancers, we now have a comprehensive understanding of many of the genetic pathways that lead to cancers of the lung,” says NCI Director Dr. Harold Varmus. “Based on this knowledge, we can now seek better pathway inhibitors to improve patient outcomes.”