BRCA2 Variant Linked to Lung Cancer Risk

Neil Osterweil

June 18, 2014

Genetic bad actor BRCA2 has been implicated in yet another cancer.

The gene is known to increase risk for breast and ovarian cancers.

Now, as a new genomic study shows, a rare variant of the BRCA2 gene is associated with increased risk for squamous cell lung cancer, particularly among cigarette smokers.

"This variant confers one 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 Christopher Amos, PhD, director of the Center for Genomic Medicine at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

Dr. Amos is senior author of a meta-analysis combining data from 4 genome-wide association studies (GWAS) involving more than 11,000 people with lung cancer. The results were published online June 1 in Nature Genetics.

The authors collected genomic information on people of European ancestry, including 11,348 patients with lung cancer and 15,861 control individuals. The data came from GWAS conducted at the University of Texas MD Anderson Cancer Center Institute in Houston; the Institute of Cancer Research in London, United Kingdom; the National Cancer Institute in Bethesda, Maryland; and the International Agency for Cancer Research in Lyon, France.

The investigators used a bit of statistical legerdemain known as imputation to infer the presence of missing data in the genomes of study participants by comparing data with those from a reference set of individuals whose genomes had been sequenced.

They then looked at the pooled data for single-nucleotide polymorphisms (SNPs) that appeared in association with lung cancer and calculated odds ratios (ORs) for the SNPs in relation to all lung cancers, including adenocarcinomas and squamous cell carcinomas.

A total of 9 SNPs out of 50 suspect genomic regions were identified as likely candidates. The investigators then tried to genotype the 9 SNPs in 4 additional GWAS.

They found large-effect genome-wide associations for squamous cell carcinoma of the lung in rare variants of the gene encoding for BRCA2 (rs11571833, OR = 2.47, P = 4.74 x 10-20).

"Notably, this study facilitated the identification of BRCA2 Thr9976, which is the strongest genetic association in lung cancer reported so far. For a smoker carrying this variant (2% of the population), the risk of developing lung cancer is approximately doubled, which may have implications for identifying high-risk ever-smoking subjects for lung cancer screening," they write.

The authors note that information about the genetic association between BRCA2 Thr9976 and lung cancer could be used in future studies of the effect of poly (ADP-ribose) polymerase (PARP) inhibitors in smokers with lung cancer.

They also identified in this population of European ancestry a variant in chromosomal location 3q28 (TP63, rs13314271) associated with a small increase in risk for lung adenocarcinoma (OR = 1.13, P = 7.22 x 1010) that had been previously reported only in Asians.

In contrast, a variant in CHEK2 (rs17879961) was associated with reduced risk for lung cancer (OR = 0.38, P = 1.27 x 10-13).

The work was supported by medical research agencies in the investigators' respective countries. The authors have disclosed no relevant financial relationships.

Nat Genet. Published online June 1, 2014. Abstract

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