Research Identifies Mutational Signatures of Nonsmall Cell Lung Cancer Tumors in Never Smokers

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A genomic analysis of the lung cancer tumors of 232 never smokers grouped them into three categories with musical names: piano, mezzo-forte and forte.

Smoking greatly increases the risk of lung cancer yet between 10% and 25% of lung cancers occur in people who have never smoked. Research is now beginning to show that lung cancer in these “never smokers” arises from a different set of mutations than lung cancer that occurs in smokers.

One possible implication of this research is that lung cancer therapies geared to genetic differences in tumors may need to differ for never smokers.

“What we’re seeing is that there are different subtypes of lung cancer in never smokers that have distinct molecular characteristics and evolutionary processes,” Maria Teresa Landi, M.D., Ph.D., an epidemiologist of the Integrative Tumor Epidemiology Branch in the National Cancer’s Division of Cancer Epidemiology and Genetics, commented in a National Institutes of Health press release after the publication of a genomic analysis study published last week in the Nature Genetics. “In the future we may be able to have different treatments based on these subtypes.”

Landi and her colleagues used whole-genome sequencing to characterize the genomic changes in tumor tissue and matched normal tissue from 232 never smokers with nonsmall cell lung cancer who started treated.The tumors included 189 adenocarcinomas, which is the most common type of lung cancer, 36 carcinoids, and seven other tumors of various types.

As described in the press release, the researchers sifted through the sequencing data for known mutational signatures in lung cancer. They did not find any mutational signatures that have previously been associated with exposure to tobacco smoking. They also didn’t find those tobacco exposure-related signature among the 62 patients who had been exposed to secondhand tobacco smoke. But Landi cautioned in the press release that the number of people in the study was relatively small and the level of exposure highly variable. “We need a larger sample size with detailed information on exposure to really study the impact of secondhand tobacco smoking on the development of lung cancer in never smokers,” Landi said in the press release.

Landi and her colleagues grouped the never-smoker lung cancers into three mutational subtypes and labeled them with musical terms. The predominant “piano” subtype — in music, piano means to play softly — had the fewest mutations. According to the press released, it appears to be associated with the activation of progenitor cells, which are involved in the creation of new cells. Tumors in the piano subtype grow slowly but are difficult to treat with targeted therapies because they tend to have many different driver mutations.

The second subtype they dubbed “mezzo-forte,” which in music means moderately loud. Tumors in that group grow faster but have particular chromosomal changes as well as mutations in the growth factor receptor gene EGFR.

The third “forte” subtype exhibited whole-genome doubling, a genomic change that is often seen in lung cancers in smokers. This subtype of tumor also grows quickly.

“We’re starting to distinguish subtypes that could potentially have different approaches for prevention and treatment,” said Landi in the press release.

Tumors in the piano subtype could perhaps be detected earlier when they are less difficult to treat, noted the press release. The mezzo-forte and forte subtypes, although faster growing, have a relatively few major driver mutations, so they might be identified by a single biopsy and easier to match up with the appropriate targeted treatments.

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