New links between genes and lung cancer have been uncovered by a team at Baylor College of Medicine. The largest genome-wide association study to date in a diverse population, it revealed five new susceptibility genes and 10 new variant associations from known risk genes. The team also further validated another 24 associations in different populations.
The findings appeared this week in Nature Genetics.
“Lung cancer risk affects all populations. Risk factors in European descent populations have been widely studied, but there has been less progress in identifying genetic risk factors that also affect populations of African and Asian descent,” said Chris Amos, corresponding author of the study, director of the Institute of Clinical and Translational Medicine and professor of medicine and interim section chief of epidemiology and population sciences at Baylor.
“By studying diverse populations, we can better understand risk factors that vary among populations and how risk factors that are shared across populations may impact different people in different ways,” he added.
Lung cancer is one of the most common cancers and, according to the American Cancer Society, “by far the leading cause of cancer death.” But there has been significant progress in establishing personalized regimens for patients based on genetic biomarkers. For example, in June of this year the LUNGevity Foundation announced the launch of its Rare Mutations and Fusions Lung Cancer Patient Gateway, which will provide patients with non-small cell lung cancer and their caregivers with information on optimal treatment options.
This Baylor-led team analyzed data from more than 61,000 lung cancer patients and nearly 1 million study controls that included Europeans, Africans, and East Asians. They reported that rare-variant associations tended to be specific to populations. Even some commonly known risk factors such as CYP2A6 and CHRNA5genes—part of the nicotinic receptor subunit gene cluster—showed population specificity.
They found susceptibility candidate genes were frequently linked to biological pathways involving immune and cellular stress response. One susceptibility gene candidate the team identified is IRF4, which is known to cause melanoma. This study was the first in which it was linked to lung cancer risk.
“In the future, the results of our study could help with identification of people who are at highest risk for developing lung cancer,” said Jinyoung Byun co-first author of the study and assistant professor of medicine—epidemiology and population sciences at Baylor. “We want to better understand how genetic information can help people change their behaviors to reduce their risk for lung cancer.”
The researchers also performed functional assays on the susceptibility genes in lung fibroblast cells and found that many of these genes, including IRF4, promote DNA damage when upregulated.
“Genes that promote DNA damage may be good target candidates for PARP inhibitor therapy, which prevents cancer cells from repairing certain types of DNA damage,” said Jun Xia, co-first author of the study and postdoctoral associate at Baylor at the time of research. “These genes may also be important in studying response to immunotherapy, which tends to work best in tumors with high mutation burden.”