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Scientists Identify Gene for Lung Cancer in Never-Smokers

Variations in a gene called GPC5 have been identified which might contribute to a significantly higher risk of developing lung cancer in people who have never smoked. The findings, from genome-wide association studies to outline the genetic changes involved in lung cancer in never smokers, suggest that GPC5 might be a new target for investigation and drug development, and could be used to identify high-risk individuals. Lung cancer in people who have never smoked (defined as those who have smoked fewer than 100 cigarettes in their lifetimes) is an increasing public-health problem, responsible for 25 percent of all lung cancer cases worldwide. Despite attempts to identify the specific genetic mechanisms responsible, the causes of lung cancer in never-smokers have remained poorly understood. Recent studies have identified several candidate genes that have a moderate effect on the risk of lung cancer, but no study has identified the genetic basis of lung cancer in never smokers. "This is the first gene that has been found that is specifically associated with lung cancer in people who have never smoked," said the study's senior author, Mayo Clinic genetic epidemiologist Dr. Ping Yang. "What's more, our findings suggest GPC5 may be a critical gene in lung cancer development and genetic variations of this gene may significantly contribute to increased risk of lung cancer," she said. "This is very exciting. Findings from this study concern pure lung cancer that is not caused by smoking, and it gives us some wonderful new avenues to explore. Our suspicion all along is that this is a distinct disease, and that is why we undertook this study," Dr. Yang said.

Little is known about the GPC5 gene, except that it can be over-expressed in multiple sclerosis, and that alterations in the genome where GPC5 is located are a common event in a wide variety of human tumors.

"It may be that GPC5 holds different roles depending on the tissue type during various disease development and progression," Dr. Yang said.

The scientists found in laboratory studies that the GPC5 variation leads to greatly reduced GPC5 expression in adenocarcinoma tissue, compared to normal lung tissue. The finding suggests that the gene has an important tumor suppressor-like function and that insufficient function can promote lung cancer development. "Interestingly, this reduced transcript expression level was not found in lung carcinoid tumors," Dr. Yang said.

In an accompanying comment in The Lancet Oncology, Dr. Ramaswamy Govindan, who was not involved in the study, cautioned that "even though this study reports a two-fold reduction in GPC5 expression in adenocarcinoma tissues compared to matched normal controls, it is far from clear how reduced GPC5 expression could predispose individuals to lung cancer. More studies are needed to confirm these preliminary observations in the tumor samples from those with no history of tobacco smoking."

The new results are from studies conducted by five collaborating institutions, including the Mayo Clinic College of Medicine, the Harvard University School of Public Health, the M.D. Anderson Cancer Center., UCLA, the National Cancer Institute, and the Massachusetts General Hospital and Harvard Medical School.

The results were published online on March 22 in The Lance Oncology. [Lancet press release] [Mayo press release] [The Lancet Oncology abstract]