Study Identified 25 Genetic Variants Linked with Lung Cancer Risk

April 1, 2021
Jared Kaltwasser

Although smoking is the predominate risk factor for lung cancer, about 1 in 5 cases cases are believed to be linked to genetic factors.

A new study is helping to clarify the links between genetic factors and the risk of lung cancer, identifying 25 new variants that appear to correlate with an increased susceptibility to the disease.

In a new paper, published in NPJ Precision Oncology, corresponding author Chris Amos, M.S., Ph.D., of the Institute for Clinical and Translational Research at Baylor University, explained what his team found when they performed whole exome and targeted sequencing of germline DNA on 1,045 samples from patients with lung cancer who risk for the disease seemed likely to be genetic rather from environmental exposure such as smoking. The patients included those with a family history and with ealy onset forms of the disease. Amos and his colleages compared those cases with 885 controls.

"We were looking for variants that have a relatively high impact on risk but occur at relatively low frequency," Amos said, in a press release.

Researchers have, of course, been investigating genetic susceptibility to lung cancer for some time now, Amos and his co-authors noted. Sometimes the connections are not direct; for instance, certain genetic variants appear to be correlated with a greater difficulty quitting smoking, which in turn can increase a patient’s risk of lung cancer.

Overall, lung cancer heritability is believed to be about 18%, and Amos and colleagues said rare variants are likely to account for a significant portion of those cases.

The sequencing analysis found 25 new pathogenic variants linked with lung cancer susceptibility, of which the investigators validated 5 variants. Two of the validated variants, ATM and MPZL2, were related to genes previously linked with lung cancer risk, ATM and MPZL2. The remaining 3 involved novel links to lung cancer risk: POMC, STAU2, and MLNR.

Yanhong Liu, Ph.D., a co-author on the study and member of the Dan L. Duncan Comprehensive Cancer Center at Baylor, said in the press release that one notable finding of the study was the impacts of insertions and deletions of DNA sections.

"Mutations of DNA where sections are either inserted or deleted have been understudied compared to single nucleotide variants, but they are also very important because they can result in truncated proteins," Liu said. Two-thirds of the candidate variants in the study were insertions or deletions, according to Liu.

The investigators next applied endogenous DNA damage assays in hopes of better understanding how the variants affect cancer risk. They wondered whether an increased level of endogenous DNA damage leads to genomic instability and ultimately cancer. They found that POMC, MLNR, and ATM variants were associated with increased levels of DNA damage. Amos and colleagues noted that ATM is believed to be a “first responder” to DNA damage, and variants in ATM have been linked with increased risk of multiple cancers.

Amos told Managed Healthcare Executive® that, as with other cancers, a particular person’s cancer risk is based on a variety of factors, including lifestyle, environmental, and genetic factors. With lung cancer in particular, 85% of cancers occur in people who have smoked or currently smoked. However, Amos said that still leaves a significant number of people for whom genetic variants might be a key contributing factor.

“[G]enetic factors do contribute and can also be a very important factor for some individuals,” he said. “...These factors may have relevance at an individual level and also become relevant for screening as genetic sequencing becomes more commonly applied.”