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Exome Study Uncovers Low-Frequency Risk Variants for Lung Cancer in China

NEW YORK (GenomeWeb) – A study appearing online today in the American Journal of Human Genetics highlighted low-frequency, protein-coding variants on chromosomes 6 and 20 that seem to notch up the chance of developing lung cancer in Chinese individuals.

Researchers from China and the US used exome chips to assess protein-coding sequence patterns in samples from more than 1,300 individuals with lung cancer and almost 2,000 unaffected controls. In the lung cancer patients, they found an over-representation of three low-frequency variants in and around the chromosome 6 genes BAT2 and FKBPL, and the BPIFB1 gene on chromosome 2 — results they verified in more than 9,600 additional cases and controls.

Consistent with a potential role for these genes in lung cancer development or progression, the team saw distinct levels of BAT2, FKBPL, and BPIFB1 in its analyses of existing expression data for more than 100 lung cancer tumors and matched normal tissues.

"Our results highlight the important role low-frequency variants play in lung cancer susceptibility," corresponding author Hongbing Shen, an epidemiology, biostatistics, and personalized medicine researcher at Nanjing Medical University, and colleagues wrote.

Environmental factors — particularly tobacco smoking — are well known for contributing to lung cancer development, the team noted. But inherited genetic factors also influence individuals' propensity for the disease, a top cause of cancer deaths globally.

To complement results from past genome-wide association studies that have linked common genetic variants to enhanced or diminished lung cancer risk, the researchers embarked on a search for rare or low-frequency alterations associated with lung cancer.

Using Illumina's HumanExome Beadchip, they looked at protein-coding patterns in 1,348 Han Chinese individuals with lung cancer and 1,998 unaffected individuals from the same population.

Based on patterns found in the discovery stage of the study, the team attempted to replicate lung cancer associations for 21 low-frequency variants in another 1,115 cases and 1,246 controls resembling those in the discovery set. Four variants carried forward from that replication group were then tested in 3,584 cases and 3,669 controls from northern China.

Following the second round of validation as well as an analysis of all of the cases and controls together, the researchers were left with three low-frequency, missense variants that were still significantly associated with lung cancer near BAT2, FKBPL, and BPIFB1.

A fourth variant, near another chromosome 6 gene called HIST1H1E, showed more tenuous ties to the disease.

At the variant level, the team noted that a protective change in BAT2 was linked to later age at lung cancer diagnosis, while the BPIFB1 glitch coincided with early disease onset. And the group's gene-based analysis underscored potential contributions by the FKBPL gene in lung cancer pathogenesis. 

Moreover, all three genes at sites with significant lung cancer associations appeared to be present at different levels in lung tumors, based on patterns in 107 matched tumor-normal samples previously subjected to lung cancer profiling by the Cancer Genome Atlas project.