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Significantly Higher Risk Of Developing Lung Cancer In People Who Have Never Smoked Linked To Gene Variation

An article published Online First in The Lancet Oncology reports that variations in a gene called GPC5 have been identified. They might contribute to a significantly higher risk of developing lung cancer in people who have never smoked. The findings from the largest effort to determine the genetic changes involved in lung cancer in never smokers (LCINS) suggest that GPC5 might be a new target for investigation and drug development. Furthermore, this could be used to identify high-risk individuals.

People who have never smoked are defined as those who have smoked less than one hundred cigarettes in their lifetime. Lung cancer in those people is an increasing public-health problem. It is responsible for a quarter of all lung cancer cases worldwide. Regardless of numerous attempts to identify the responsible specific genetic mechanisms, the causes of lung cancer in never-smokers remain unclear. Recent studies have identified several candidate genes that have a moderate effect on the risk of lung cancer. However, no study has identified the genetic basis of lung cancer in never smokers.

Ping Yang from the Mayo Clinic College of Medicine, Rochester, USA, led an international team of researchers. They conducted a four-stage study to try and identify genetic variations responsible for increasing the risk of LCINS. The researchers began by examining DNA samples from 754 never smokers. Then they analyzed 331,918 DNA variants known as single nucleotide polymorphisms (SNPs) in 377 matched case-control pairs. This was carried out in order to find the genetic variations most likely to alter the risk of lung cancer in never smokers. Community residents who had never smoked were selected as controls and matched to patients according to age, sex, and ethnic background.

The Mayo genome-wide association study used conditional logistical regression which is a type of statistical analysis. The researchers worked to identify associations between SNPs and lung cancer risk while controlling for history of chronic obstructive pulmonary disease (COPD), exposure to second-hand smoke, and family history of lung cancer. Two specific genetic markers or SNPs (rs2352028 and rs235209) emerged as significant.

To validate their findings, the researchers took the 44 most frequently occurring genetic alterations from the Mayo study. They assessed them in two additional independent groups of never smokers:

• The first group of 735 people (from which 328 were patients and 407 were healthy controls) from the MD Anderson Cancer Center in Houston study
• The second groups of 253 people (from which 92 were patients and 161 were healthy controls) from the Harvard University in Boston study.

The two SNPs remained significant in both these replication sets.

An additional replication of rs2352028 was done in 530 never smokers in the University of California in Los Angeles (UCLA) study. The authors estimate that more than 10 percent of lung cancer cases in never smokers could be attributed to genetic variations at this locus.

Ultimately, a series of statistical analysis and examination of gene-expression levels were carried out. This provided additional explanation of the causal relationship between the two validated SNPs and the risk of LCINS. The results strongly indicated that the top two SNPs were connected with LCINS through their regulation of GPC5 expression.

Additional tests showed that GPC5 expression levels were 50 percent lower in adenocarcinoma which is the most common form of lung cancer than in matched normal lung tissue. This indicates that reduced GPC5 expression could be specific for adenocarcinoma in never smokers.

The authors write in conclusion: “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 associated statement, Ramaswamy Govindan warns that: “Even though this study reports a two-fold reduction in 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.”


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