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Researchers have identified unique genetic signatures of lung cancer in people who never smoked cigarettes, using whole genome sequencing to analyze tumors from this under-studied population.

The new study, published Monday in Nature Genetics, more than doubles the number of sequenced lung tumors from never-smokers and helps point the way toward developing personalized treatments distinct from those used for smokers’ cancers, the authors said.

While smokers or former smokers account for the majority of lung cancer, never-smokers — classified as those who never smoked or have tried fewer than 100 cigarettes in a lifetime — account for 10% to 25% of cases worldwide. But that proportion is growing as smoking decreases, and data show that the absolute number of cases among never-smokers may also be increasing, though it’s unclear.

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“If lung cancer in never-smokers were a separate entity, it would be in the top 10 cancers in the U.S.” for both incidence and deaths, surgeon Andrew Kaufman of Mount Sinai Hospital in New York told STAT earlier this year.

Still, most genome sequencing of lung cancer is performed on tumors from smokers. For the new paper, researchers from the National Cancer Institute and other collaborators performed whole gene sequencing on tumors from 232 patients with lung cancer who never smoked, and whose exposure to risk factors was unknown.

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“We used a detective approach,” said study author Maria Teresa Landi, a senior adviser and investigator at the National Cancer Institute. She and her team call the research their Sherlock-Lung study, after Sir Arthur Conan Doyle’s iconic detective. “By looking at the genome of the tumor, we use the changes in the tumors as a footprint to follow to infer the causes of the disease,” she said.

There were three genetic subtypes they identified, which they called piano, mezzo-forte, and forte, after the musical terms that denote variation in loudness.

The metaphorical naming was apt — the “piano” tumors were quiet, in a way, with few mutations, and less aggressive. They accounted for about half of all the tumors studied and grew dramatically slower than the other subtypes, with a median latency period of nine years of growth before becoming clinically evident. In the middle, “mezzo-forte” tumors, identified by increases in DNA in a specific arm-like region of the cell chromosome, represented one-third of the tumors and saw much shorter latency periods of around three and a half months. “Forte” tumors were the loudest, most aggressive, and most similar to lung cancer among smokers, dominated by whole-gene-doubling mutations, which create multiple unstable copies of a gene. Those tumors saw median latency periods of just one month and made up one-fifth of the studied sample.

“This is a very important finding to look at these subtypes so that we can strategize our treatment accordingly,” said Stephen Lam, a professor at the University of British Columbia and respirologist at BC Cancer not involved with the study.

Clinicians know how to treat tumors like those of the forte subtype. With many mutations, they can be targeted with immunotherapy or inhibitors for specific cancer-driving mutations.

“But if you have a quiet genome, not many mutations, very diverse — what do you do?” Landi asked about the piano subtype. “You really need to understand what causes these tumors in a completely different approach, because you can’t treat them with a normal type of treatment.”

For the piano tumors, the long latency may provide a window for early identification, but clinicians will need to know what symptoms or signs to look for in order to recommend screening. Current screening recommendations only apply to smokers.

That potential among the piano subtype for early detection is critical, said Rayjean Hung, a professor of epidemiology at the University of Toronto and head of the Prosserman Centre for Population Health Research, who was not involved with the study. “Early detection actually might be the most relevant topic for that specific type of tumor, rather than an alternate therapy,” she said.

Landi’s team found that the genetic signs point to a role for stem cells in the piano subtype.The mutations that do exist in these tumors are often related to genes that regulate stem cells. In that case, the established, aggressive treatments won’t work with stem cells in the piano subtype.

“If this is true, it changes a lot of things in the way we should think of tumorigenesis,” Landi said.

Landi and her team have more experiments ahead of them to confirm the relationship to stem cells and other potential causative factors of lung cancer in never-smokers. They’ll likely perform single-cell RNA sequencing to confirm their stem cell hypothesis.

Across the scientific literature, there have been only around 100 instances of whole gene sequencing in never-smokers, according to Landi. The broadening research will likely be useful to others in the field.

“This is actually very good background information to look at how the genome interacts with the environment,” Lam said.

The research represents a tremendous amount of work, Hung said, but she believes even more will be needed to validate its implications.

The Sherlock-Lung team’s goal is to perform whole gene sequencing on 2,000 samples from lung cancer patients who never smoked.

“Clearly we need to do more for these tumors,” Landi said. “It’s growing and it’s lethal.”

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