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New Lung Cancer Susceptibility Loci Discovered in GWAS

NEW YORK (GenomeWeb) – A large genome-wide association study has uncovered 10 new loci linked to lung cancer susceptibility, including risk loci that appear to vary depending on lung cancer subtype.

In a paper appearing in Nature Genetics today, researchers from Dartmouth College, the World Health Organization, the University of Toronto, and many other institutions presented findings from a GWAS involving more than 14,800 individuals with lung cancer and nearly 12,300 unaffected controls. When the researchers considered genotypes from those cases and controls alongside existing lung cancer GWAS data, they identified eight known risk loci and 10 loci that had not been implicated in lung cancer in the past.

The team went on to analyze variants at these loci in the context of different cancer subtypes and gene expression profiles for more than 1,400 normal lung tissue samples, leading to subtype-related susceptibility loci and quantitative trait loci.

"The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma," corresponding author Christopher Amos, a professor of biomedical data science at Dartmouth's Geisel School of Medicine, and his co-authors wrote.

Tobacco smoking remains the primary risk factor for lung cancer development, the team noted. But research suggests that the disease also has a heritable component, and prior GWAS have led to risk loci for lung cancer that range from mutations in BRCA2 or CHEK1 to alterations affecting human leukocyte antigen (HLA) genes or genes such as TERT, CHRNA2, and CHRNA5.

In an effort to find new susceptibility loci — and to get a better look at those described already — the researchers used the OncoArray platform to assess more than half a million SNPs in samples from 14,803 lung cancer cases and 12,262 controls, all of European descent.

Along with comparisons of genotyped and imputed SNPs in those cases and controls, the investigators brought in data for another 29,266 individuals with lung cancer and 56,450 without, who were profiled for past GWAS. They also considered profiles found in individuals with different lung cancer subtypes and in lung cancer patients with a history of smoking and in those who never smoked.

All told, 18 loci showed genome-wide significant ties to lung cancer, the researchers reported, including four new loci on chromosomes 1, 6, 8, and 15 that were associated with overall lung cancer risk and half a dozen previously unidentified loci that appeared to be specifically linked to lung adenocarcinoma risk.

With the help of gene expression profiles for 1,425 normal lung tissue samples, the team linked variants at a subset of the loci to expression quantitative trait loci in and around genes such as RNASET2, SECISBP2L, and NRG1.

"We expect that further exploration of the related target genes of these susceptibility loci will continue to provide insights into the etiology of lung cancer," the authors concluded.