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Medicineworld.org: Gene linked to lung cancer in never-smokers

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Gene linked to lung cancer in never-smokers




A five-center collaborative study that scanned the genomes of thousands of "never smokers" diagnosed with lung cancer as well as healthy never smokers has found a gene they say could be responsible for a significant number of those cancers.



Gene linked to lung cancer in never-smokers

In the March 22 on line issue of Lancet Oncology, the scientists reported that about 30 percent of patients who never smoked and who developed lung cancer had the same uncommon variant, or allele, residing in a gene known as GPC5. The research was co-led by researchers at the Mayo Clinic campus in Minnesota, Harvard University, University of California at Los Angeles (UCLA), and MD Anderson Cancer Center. Scientists found in laboratory studies that this allele leads to greatly reduced GPC5 expression, in comparison 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.

"This is the first gene that has been observed that is specifically linked to lung cancer in people who have never smoked," says the study's lead investigator, Ping Yang, M.D., Ph.D., Mayo Clinic genetic epidemiologist.

"What's more, our findings suggest GPC5 appears to be a critical gene in lung cancer development and genetic variations of this gene may significantly contribute to increased risk of lung cancer," she says. "This is very exciting".

The research teams scanned and analyzed the genomes of 2,272 participants who have never smoked, nearly 900 of whom were patients with lung cancer. It took scientists 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 past studies, and what commonly pops up are genes correlation to nicotine dependence," Dr. Yang says.

"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 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 appears to be that GPC5 holds different roles depending on the tissue type during various disease development and progression," Dr. Yang says.

A never smoker is defined as a person who has smoked fewer than 100 cigarettes in his or her lifetime, and that describes 15 percent of men and 53 percent of women who develop lung cancer -- accounting for 25 percent of all lung cancers worldwide, as per Dr. Yang. In the Western countries, between 10 and 15 percent of lung cancers occur among never smokers, but in Asian countries, 30 to 40 percent of lung cancers are never smokers, she says. "Our suspicion all along is that this is a distinct disease, and that is why we undertook this study," 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) waccording toformed on 377 never smokers with lung cancer, matched with 377 participants without lung cancer, the "control" population. This was the first GWAS ever conducted solely among never smokers, and it involved scanning the entire genome of every participant, looking for differences among 300,000 markers or so-called single-nucleotide polymorphisms (SNPs). The scan looks at everything -- inside and outside genes, coding and noncoding regions, Dr. Yang says. They found 44 "hits" -- hinting 44 areas on the genome that were substantially different between the patients with lung cancer and healthy control population.

Then, to rigorously validate their findings in other populations, scientists launched stage 2. That involved using data from two more GWAS scans in independent populations -- 328 never smoker patients with lung cancer and 407 controls at MD Anderson Cancer Center, and 92 never smoker patients with lung cancer and 161 controls at Harvard University. From this, the search was narrowed to just two hits.

Both of these hits were adjacent to each other on the same gene, which the scientists then identified as a variant of GPC5.

In the third stage of the study, the scientists used a different method to perform genotyping from the method used in stages 1 and 2 to look at the difference between 91 never smoker patients with lung cancer and 439 controls at UCLA. "We confirmed the variant-lung cancer association again," Dr. Yang says.

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 says. They observed that the GPC5 transcription level was twofold lower in adenocarcinoma in comparison to normal lung tissue. "Interestingly, this reduced transcript expression level was not found in lung carcinoid tumors," Dr. Yang says.

Then the scientists 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 patients with lung cancer 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," she says.

"We don't know what that is, but we now have 42 other hits to explore," Dr. Yang says.


Posted by: Scott    Source




Did you know?
A five-center collaborative study that scanned the genomes of thousands of "never smokers" diagnosed with lung cancer as well as healthy never smokers has found a gene they say could be responsible for a significant number of those cancers. In the March 22 on line issue of Lancet Oncology, the scientists reported that about 30 percent of patients who never smoked and who developed lung cancer had the same uncommon variant, or allele, residing in a gene known as GPC5. The research was co-led by researchers at the Mayo Clinic campus in Minnesota, Harvard University, University of California at Los Angeles (UCLA), and MD Anderson Cancer Center. Scientists found in laboratory studies that this allele leads to greatly reduced GPC5 expression, in comparison 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.

Medicineworld.org: Gene linked to lung cancer in never-smokers

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