May 25, 2020 / 3:40 PM / 2 months ago

Higher lung cancer risk seen with two new germline mutations

NEW YORK (Reuters Health) - Two newly identified germline genetic variants are associated with an increased risk of lung cancer, researchers report.

“We were surprised by finding new variants that have not previously been associated with cancer or other diseases,” Dr. Christopher I. Amos of Baylor College of Medicine, in Houston, Texas, told Reuters Health by email.

While hereditary factors are important in lung-cancer pathogenesis, only rare germline mutations responsible for lung-cancer etiology have been reported. Still, these mutations can confer as much as an 80% lifetime risk for developing cancer and influence as many as 10% of cancers diagnosed yearly.

Dr. Amos and colleagues used data from two independent datasets comprising more than 39,000 individuals of European ancestry to identify reliable germline mutations that highly affect lung cancer risk and to discover new genes involved in the etiology of lung cancer.

They identified two variants, rs56009889 and rs150665432, that were associated with a more than two-fold increase in the odds of having lung cancer, the researchers report in Nature Communications.

The first variant maps within the ATM tumor suppression gene and results in an L2307F missense mutation in the FAT domain that regulates ATM activity. Carriers of this variant had 4.19-fold increased odds of developing lung cancer. The increased risk was significant among females (3.22-fold increased odds) and for lung adenocarcinoma (2.48-fold increased odds).

All five L2307F homozygotes in these datasets had lung adenocarcinoma.

“The L2307F variant of the ATM gene that we identified occurs fairly frequently in Ashkenazi Jews, at a little over 4% of the population carrying this variant,” Dr. Amos said.

The second variant maps within KIAA0930 and codes for Q4X, which results in the truncation of the full-length protein, whose function is unknown, from 409 to three amino acids. Carriers of Q4X had 2.59-fold increased odds of developing lung cancer, and all 29 homozygotes in the discovery set developed lung cancer.

KIAA0930 was significantly overexpressed in lung cancer cells, compared with normal lung samples, whereas ATM showed limited variability of expression. KIAA0930 was also significantly upregulated in the majority of carcinomas developing from epithelial cells, suggesting that it is a carcinoma-associated candidate gene.

“Given the high prevalence of the ATM mutation in Ashkenazi Jewish people, it is possible that tailored screening based on this and other genotypes that influence risk for this population may be warranted, just as Ashkenazi Jewish individuals have precision screening based on the higher prevalence of BRCA1 and BRCA2 mutations in this population,” Dr. Amos said.

“The KIAA0930 gene has not been well-studied, and the interpretation of our finding of a mutation that truncates its expression is novel and needs to be reproduced,” he said.

“These studies reinforce the value of large collaborative studies, which enabled us to identify a novel variant that poses higher risk to specific populations,” Dr. Amos said.

Dr. Rakesh Kumar of the Cancer Genetics Research Group, Shri Mata Vaishno Devi University, in Katra, India, who recently identified a genetic variant of TP63 associated with lung-cancer risk in a northern Indian population, told Reuters Health by email, “The elevated genetic risks associated with these variants imply potential clinical benefits in using these variants for the identification of individuals who would benefit most from screening programs, as well as suggestions for therapeutic targets.”

“The identification of the novel lung cancer-related germline mutations could greatly advance our understanding of lung-cancer etiology,” said Dr. Kumar, who wasn’t involved in the new work. “Drugs specifically targeting these mutations or their byproducts are well within reach, as there are a lot of studies where ATM inhibitors have been used in isolation or in combination with other drugs.”

The study did not have commercial funding, and the authors report no conflicts of interest.

SOURCE: go.nature.com/2ziu9q2 Nature Communications, online May 11, 2020.

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