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 the largest effort to outline the genetic changes involved in lung cancer in never smokers (LCINS), published in an Article Online First in The Lancet Oncology, 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 less than 100 cigarettes in their lifetime) is an increasing public-health problem, responsible for a quarter of all lung cancer cases worldwide. Despite attempts to identify the specific genetic mechanisms responsible, the causes of lung cancer in never-smokers remain 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.
Ping Yang from the Mayo Clinic College of Medicine, Rochester, USA, led an international team in 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, and analysed 331918 DNA variants known as single nucleotide polymorphisms (SNPs) in 377 matched case-control pairs* to find the genetic variations most likely to alter the risk of lung cancer in never smokers.
The Mayo genome-wide association study used conditional logistical regression, a type of statistical analysis, 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 and assessed them in two additional independent groups of never smokers: 735 (328 patients and 407 healthy controls) from the MD Anderson Cancer Centre in Houston study and 253 (92 patients and 161 healthy controls) from the Harvard University in Boston study. The two SNPs remained significant in both these replication sets.
A further 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% of lung cancer cases in never smokers could be attributed to genetic variations at this locus.
Finally, a series of statistical analyses and analyses of gene-expression levels were done to further clarify the causal relationship between the two validated SNPs and the risk of LCINS. The results strongly indicated that the top two SNPs were associated with LCINS through their regulation of GPC5 expression.
Further tests showed that GPC5 expression levels were 50% lower in adenocarcinoma (the most common form of lung cancer) than in matched normal lung tissue, indicating that reduced GPC5 expression could be specific for adenocarcinoma in never smokers.
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 cautions 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 tumour samples from those with no history of tobacco smoking."
Dr Ping Yang, Mayo Clinic College of Medicine, Rochester, USA. T) +1 507 266 5369 E) yang.ping@mayo.edu
Dr Ramaswamy Govindan, Washington University School of Medicine, St Louis, MO, USA. E) rgovinda@im.wustl.edu
For full Article and Comment, see: http://press.thelancet.com/tloyang.pdf
Notes to Editors
*Community residents who had never smoked were selected as controls and matched to patients according to age, sex, and ethnic background.
Journal
The Lancet Oncology