Between 200 and 225 years ago, someone or several someones from the British Isles had a gene mutation that caused lung cancer. They traveled to America, settled in Southern Appalachia and transmitted the cancer gene to their descendants and their descendants’ descendants.
Today that lung cancer gene, known as EGFR T790M, is found largely in residents of the United States and mostly in Southern Appalachia, especially Tennessee and Alabama. It makes lung cancer 62 times as likely in those who have never smoked and 10 times as likely in smokers.
The gene is one of the most powerful, if not the most powerful, cancer-risk mutations ever found, said Alexander Gusev, a geneticist at Dana-Farber Cancer Institute and an author of the paper.
Those are among the stunning findings of a new report, published on Thursday in Science by researchers at Dana-Farber and 23andMe Research.
Unlike other cancer genes that can cause cancer in a variety of organs, this gene is associated only with lung cancer. Researchers expect their discovery can help unlock secrets about the development of the disease.
For those with the gene, the hope is for early detection and treatment or even cancer prevention, said Dr. Raymond DuBois, the director of the Medical University of South Carolina’s Hollings Cancer Center, who was not associated with the work.
“This is a great story,” Dr. DuBois said, adding that he “read the paper like a novel.”
The variant was discovered in 2005, but because it is so rare, researchers were limited to studying families in which several members had the gene and got lung cancer. Studies like that could not reveal how much the gene increased risk.
Investigators did learn, though, that the variant was unusual. Lung cancer patients often have mutations in the EGFR gene, but those mutations arose by random bad luck later in life. If those mutations arise in embryos, they kill the embryos. But not the EGFR T790M mutation. People are born with it, and it is not lethal. It causes only lung cancer, but decades later.
Dr. Jaclyn LoPiccolo and Dr. Pasi A. Jänne, lung cancer experts at Dana-Farber, realized that 23andMe’s data might hold the key to figuring out how dangerous EGFR T790M is. Other databases had too few people — less than a million participants, only a handful of whom had the mutation. But 23andMe, a direct-to-consumer recreational databank that many use to find ancestors, was huge.
The database had more than 10 million people who had consented to participate in research, including the 3.37 million who had provided both genetic data and information on whether they had lung cancer. There were 641 who had the mutation.
Those data allowed the investigators to trace the origin of the mutation to the settler or settlers from the British Isles, to determine the cancer risk the mutation conferred and to discover that the gene was associated only with lung cancer.
They also found that about one in 15,000 people in the United States had the gene, but one in 2,000 in Southern Appalachia had it.
For those who have the gene, it can confer a grim legacy.
Caroline Blanchard, a 35-year-old nurse practitioner from New Orleans, said her story began about 15 years ago, when her very healthy aunt, who had never smoked, got lung cancer and died within a year, at age 45. “We didn’t question it,” Ms. Blanchard said. “Her doctors said it was just sort of random.”
Then, four years ago, her grandmother got lung cancer, at age 80. Her doctors, at MD Anderson Cancer Center, suggested genetic testing. Ms. Blanchard’s grandmother had the EGFR T790M mutation.
After learning that, Ms. Blanchard’s “very healthy” mother decided to get a lung scan. It revealed nodules in both lungs: She also had the mutation.
Next it was her turn, Ms. Blanchard said. She found out she had the mutation and nodules in both lungs.
“I’m so glad my grandmother lived to be 80,” she said. If she had died in her 70s, Ms. Blanchard added, no one would have thought to test for that cancer gene.
Dr. Jänne, a senior author of the report, said lung cancer could be found early with CT scans, but guidelines reserved them for smokers and former smokers over 50. The new findings raise important questions: Should doctors screen people with the mutation earlier? Or at least more often?
He would also like to understand why the mutation affects only lung cells.
“There’s a lot to learn here,” Dr. Jänne said.
All in all, “it’s a very cool story,” said Dr. Stephen Chanock, director of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, who wrote a perspective accompanying the article.
“We always thought this gene was causing cancer,” he noted. But, he added, only now it is clear how powerful it is.
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