Germline Genetic Variants in ATM and Lung Cancer Susceptibility

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An international consortium of researchers has identified a mutation involved in a person’s susceptibility to lung cancer. This variant could help identify certain populations at greater risk for lung cancer, according to results reported by Ji et al in Nature Communications.

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ATM Variant

Their combined efforts identified a genetic variant that changes the protein sequence of the ATM gene, which is involved in repair of DNA damage. The ATM gene has been implicated in a rare syndrome that includes cancer susceptibility, but susceptibility to lung cancer has never been clearly recognized as a part of its effects until this genetic variant was identified.

“We know that ATM genetic variants are involved with susceptibility to different types of cancer—breast cancer being the most studies—but it was really unexpected to see such a strong genetic effect in lung cancer. There’s something unusual about this genetic variant and how it acts,” said senior study author Chris Amos, PhD, Associate Director of Quantitative Science at the Dan L Duncan Comprehensive Cancer Center and Director for the Institute for Clinical and Translational Medicine at Baylor College of Medicine.

Since the research involved studies from countries across the world, the researchers were able to trace the population origins of this variant. It was found almost exclusively in individuals of Ashkenazi Jewish decent.

“That the variant is found mostly in one population is consistent with something geneticists call a founder effect,” said first study author Xuemei Ji, MD, PhD, an instructor at Dartmouth College at the time of the research. “Founder effect variants are used in breast cancer screening programs, particularly in Ashkenazi Jewish populations. This ATM variant has a similar prevalence to those. There’s been a lot of progress in techniques for lung cancer screening over recent years, so this finding might be really useful for targeted lung screening. Understanding the biological processes in which this ATM variant acts may also lead to new therapeutic options.”

The expansive nature of this study also allowed the researchers to consider how this variant influences the subtypes of lung cancer. The researchers found this variant seemed involved in patients with lung cancer that did not have a history of tobacco smoking, in women and in those afflicted with a particular subtype of lung cancer, lung adenocarcinoma.

“Most lung cancers occur in smokers but, unfortunately, it does occur rarely in never-smokers and, for reasons that aren’t entirely clear, disproportionately in never-smoking women with this type of lung cancer," said lead study author James McKay, PhD, Head of the Genetic Cancer Susceptibility Group at the International Agency for Research on Cancer. “Hopefully, this finding might help us to understand that enigma a little more.”

The researchers concluded, “Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.”

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