A group of researchers say they have found a genetic variation that is associated with lung cancer development in nonsmokers. In their study, 30% of patients who had never smoked had the same uncommon allele residing in the GPC5 gene, which reduced GPC5 expression compared to normal lung tissue. The findings suggest that the gene has a tumor suppressor-like function and that insufficient function can promote lung cancer development.
The results are detailed in the March 22 online issue of The Lancet Oncology in a paper titled “Genetic variants and risk of lung cancer in never smokers: a genome-wide association study.” The study was performed by researchers at the Mayo Clinic, Harvard University, University of California at Los Angeles (UCLA), and The University of Texas M. D. Anderson Cancer Center.
The teams scanned and analyzed the genomes of 2,272 participants who had never smoked, nearly 900 of whom were lung cancer patients. A never-smoker is defined as a person who has smoked fewer than 100 cigarettes in his or her lifetime. It took 12 years to identify and enroll these participants.
“It has been very hard to do this research because never smokers have been mingled with smokers in past studies, and what usually pops up are genes related to nicotine dependence,” notes the study's lead investigator, Ping Yang, M.D., Ph.D., Mayo Clinic genetic epidemiologist. “Our suspicion all along is that this is a distinct disease, and that is why we undertook this study. Findings from this study concern pure lung cancer that is not caused by smoking, and it gives us some wonderful new avenues to explore.”
Little is known about the GPC5 gene except that it can be overexpressed 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 types of disease development and progression,” Dr. Yang says.
The research took two years and involved four steps. In the first step, conducted at Mayo Clinic a genome-wide association study (GWAS) was performed on 377 never- smokers with lung cancer matched with 377 participants without lung cancer. They found 44 areas on the genome that were substantially different between the two groups.
To validate their findings, the scientists conducted two more GWAS scans in independent populations: 328 never-smoker lung cancer patients and 407 controls at M. D. Anderson Cancer Center; and 92 never-smoker lung cancer patients and 161 controls at Harvard University. From this, the search was narrowed to just two genomic regions that were adjacent to each other on the same gene. This was subsequently identified as a variant of GPC5.
In the third stage of the study, the researchers used a different genotyping method to look at the difference between 91 never-smoker lung cancer patients and 439 controls at UCLA. “We confirmed the variant lung cancer association again,” Dr. Yang reports.
The final stage of the study involved understanding the function of the gene. “We had to understand whether these hits really represented the functional aspect of the gene, so we tested expression level of GPC5 and found it was significantly reduced,” Dr. Yang explains.
They found that the GPC5 transcription level was twofold lower in adenocarcinoma compared to normal lung tissue. “Interestingly, this reduced transcript expression level was not found in lung carcinoid tumors,” according to Dr. Yang.
Then the researchers looked to see if this reduced expression led to tumor development, which it did in laboratory culture. “If reduction of expression of this gene leads to development of lung cancer, it suggests that this gene is normally a tumor suppressor," Dr. Yang says. "We believe it helps control the cell proliferation and division, but we need to prove its function in animal models.”
They calculated that about one-third of never-smoker lung cancer patients in this study had the same variation of the underperforming GPC5 gene. “We hypothesize that this is an important cancer trigger in these patients, and that something else is going on in the remaining two-thirds of never-smokers,” Dr. Yang says. “We don't know what that is, but we now have 42 other hits to explore.”