First Gene Linked to Lung Cancer in Nonsmokers

Janis C. Kelly

March 30, 2010

March 30, 2010 — Nonsmokers account for 10% to 15% of lung cancer cases in Europe and North America, 30% to 40% of cases in Asian countries, and 53% of all cases in women. Up to one third of these patients carry a newly identified susceptibility gene that reduces the expression of GPC5, a glypican gene that is suppressed in adenocarcinomas.

Ping Yang, PhD, and colleagues from the Mayo Clinic College of Medicine in Rochester, Minnesota, report the new cancer risk factor in the April issue of The Lancet Oncology. Dr. Yang led an international team in a 4-stage search for genetic variations that increase lung cancer risk in never smokers (defined as people who have smoked fewer than 100 cigarettes in their lifetime).

Dr. Yang told Medscape Oncology that "this study involved multiple institutions. Two had second-hand smoking information, and 2 did not. The role of the GPC5 gene in the risk for lung cancer among never smokers is independent of the effect of second-hand smoking; in other words, finding this gene did not diminish the risk for lung cancer linked to second-hand smoking. Larger studies are needed that can test the genetic effect separately in those who had been and those who had not been exposed to second-hand smoking."

Molecular oncologist Adi F. Gazdar, MBBS, who has also studied lung cancer in never smokers, was asked by Medscape Oncology to comment on the study. Dr. Gazdar, who is the W. Ray Wallace Distinguished Chair in Molecular Oncology Research at the University of Texas Southwestern Medical School in Dallas, said that "this is a good piece of work by experienced and competent scientists. It is the first large study that targets never smokers, and it identifies a previously unknown locus that may predispose to lung cancer in never smokers. A new putative tumor suppressor gene was identified."

"We know that genetic factors must predispose to lung cancer in never smokers. This study offers hope [that] those at increased risk [will be identified]," said Dr. Gazdar.

Separating Out Nonsmokers

For the current study, Dr. Yang and colleagues scanned and analyzed the genomes of 2272 participants who had never smoked, nearly 900 of whom were lung cancer patients. It took them 12 years to identify and enroll these study participants.

"It has been very hard to do this research because never smokers have been mingled with smokers in previous studies, and what usually pops up are genes related to nicotine dependence," Dr. Yang said.

The researchers began by examining DNA samples from 754 never smokers, and analyzed 331,918 DNA single-nucleotide polymorphisms (SNPs) in 377 matched case–control pairs to find the genetic variations most likely to alter the risk for lung cancer in never smokers. The scans looked at areas inside and outside genes, and at coding and noncoding regions. They turned up 44 "hits" that were substantially different between the lung cancer patients and the healthy control subjects.

The Mayo Clinic genome-wide association study used conditional logistical regression to identify associations between SNPs and lung cancer risk, while controlling for history of chronic obstructive pulmonary disease, exposure to second-hand smoke, and family history of lung cancer. SNPs rs2352028 and rs235209 were adjacent to each other on the same gene, which the researchers identified as a variant of GPC5.

"It was indeed a surprise that we found the specific gene. We believe other genes will emerge with more rigorous search and validation of the genomic hits," Dr. Yang said.

Validation in Independent Cohorts

To validate their findings, the researchers took the 44 most frequently occurring genetic alterations from the Mayo study and assessed them in 2 independent groups of never smokers: 735 people (328 patients and 407 healthy controls) from the University of Texas M.D. Anderson Cancer Center in Houston, and 253 people (92 patients and 161 healthy controls) from Harvard University in Boston, Massachusetts. The 2 SNPs remained significant in both these replication sets. Another replication of rs2352028 was done in 530 never smokers at the University of California in Los Angeles.

The authors estimate that more than 10% of lung cancer cases in never smokers could be attributed to genetic variations at this locus, and further analysis suggested that the top 2 SNPs were associated with lung cancer in never smokers through their regulation of GPC5 expression.

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 said.

The GPC5 transcription level was 2-fold lower in adenocarcinoma than in normal lung tissue. "Interestingly, this reduced transcript expression level was not found in lung carcinoid tumors," Dr. Yang said.

Reduced GPC5 expression also led to tumor development in vitro. "If reduction of expression of this gene leads to the development of lung cancer, it suggests that this gene is normally a tumor suppressor," Dr. Yang said. "We believe it helps control cell proliferation and division, but we need to prove its function in animal models."

Important Trigger in One Third of Never Smokers

The researchers calculated that about one third of never-smoker lung cancer patients in this study had the same variation of the underperforming GPC5 gene. Dr. Yang suspects 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. "We don't know what that is, but we now have 42 other hits to explore," she said.

The authors conclude: "Genetic variants at 13q31.3 alter the expression of GPC5, and are associated with susceptibility to lung cancer in never smokers. . . . Future studies are needed to investigate the regulatory effects of these SNPs (or tagged variants) and the functional role of GPC5 in lung tumorigenesis."

In an accompanying comment, Ramaswamy Govindan, MD, cautions that "even though this study reports a 2-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." Dr. Govindan is associate professor of oncology at Washington University School of Medicine in St. Louis, Missouri.

The study was supported by the US National Institutes of Health and by the Mayo Foundation. Dr. Yang and Dr. Gazdar have disclosed no relevant financial relationships. Dr. Govindan reports receiving consulting fees from Genentech and Astra-Zeneca.

Lancet Oncol. 2010;11:304-305, 321-330.

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