Variation in BRCA2 gene linked to lung cancer, doubles a smoker's risk

New research confirms a vulnerability to lung cancer can be inherited and implicates the BRCA2 gene as harboring one of the involved genetic mutations. An international consortium of scientists used integrated results from the 1000 Genomes Project with genetic studies of lung cancer to complete the investigation

The study, published in Nature Genetics (2014; doi:10.1038/ng.3002), scanned the genomes of more than 11,000 people of European descent to look for common variations associated with non-small cell carcinoma, a common form of lung cancer.

The analysis showed that variations in the BRCA2 and CHEK2 genes can significantly increase a person's risk for lung cancer. A smoker's chances of developing lung cancer may be doubled if he or she carries the BRCA2 variation. In addition, the TP63 gene, which previously was only associated with lung cancer risk in Asian populations, was associated with risk for adenocarcinoma, a form of non-small cell carcinoma, in those of European descent.

The study used four genome-wide association studies. Scientists used imputation, a statistical form of inference, in which data from a reference set of people whose genes have been sequenced is used to fill in missing values on the genome for the study participants. The study validated the use of this approach in finding common genetic variations between multiple sets of data and by extensively genotyping additional participants.

"This variant confers one of the strongest associations found to date for cancer among those identified by genome-wide association studies, and identifies a subset of people who are particularly susceptible to harm associated with smoking," said senior author Chris Amos, PhD, director of the Center for Genomic Medicine at Dartmouth College in Hanover, New Hampshire.

The BRCA2 gene codes for a very large protein that functions primarily for coordinating activities of many different genes involved in DNA repair. Cells accumulate DNA damage as a result of environmental toxins such as those contained in tobacco smoke. Mutations in BRCA2 may affect the ability of cells to respond to DNA damage, increasing the chance that a cell will become a cancer.

"Our study showed that mutations to two genes, BRCA2 and CHEK2, have a very large effect on lung cancer risk in the context of smoking. Mutated BRCA2 in particular seems to increase risk by around 1.8 times," said study leader Richard Houlston, MD, PhD, of The Institute of Cancer Research (ICR) in London, United Kingdom. "Smokers in general have nearly a 15% chance of developing lung cancer, far higher than non-smokers. Our results show that some smokers with BRCA2 mutations are at an enormous risk of lung cancer—somewhere in the region of 25% over their lifetime."

The results of this study may influence how people are screened and treated for lung cancer. Those with genetic mutations who smoke may be candidates for lung cancer screening with low-dose CT scans. Since persons with germline mutations of BRCA1 or BRCA2 respond to the specific chemotherapy PARP inhibitors, it is possible that people with this BRCA2 mutation and lung cancer may similarly respond more favorably to PARP inhibition than other lung cancer cases.

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