A genomic analysis of lung cancer in people with no history of smoking has found that a majority of these tumors arise from the accumulation of mutations caused by natural processes in the body. The international team of scientists, led by researchers at the National Cancer Institute (NCI), carried out high-coverage whole-genome sequencing (WGS) of 232 lung cancers from people who have never smoked. Their results identified, for the first time, three molecular subtypes of lung cancer in never smokers (LCINS).

The team claims the new insights will help to understand how lung cancer arises in people who have no history of smoking, and may guide the development of more precise clinical treatments. “What we’re seeing is that there are different subtypes of lung cancer in never smokers that have distinct molecular characteristics and evolutionary processes,” said epidemiologist Maria Teresa Landi, MD, PhD, of the Integrative Tumor Epidemiology Branch in NCI’s Division of Cancer Epidemiology and Genetics, who led the study. “In the future we may be able to have different treatments based on these subtypes.”

The researchers, including scientists at the National Institute of Environmental Health Sciences, and other institutions, reported on their study in Nature Genetics, in a paper titled, “Genomic and evolutionary classification of lung cancer in never smokers,” in which they conclude, “Our findings suggest developmental processes and possible new therapeutic approaches for LCINS.”

Lung cancer is the leading cause of cancer-related deaths worldwide, and every year, more than 2 million people around the world are diagnosed with the disease, the authors noted. Most people who develop lung cancer have a history of tobacco smoking, but 10–20% of people who develop lung cancer have never smoked. Lung cancer in never smokers occurs more frequently in women and at an earlier age than lung cancer in smokers. Most LCINS are lung adenocarcinomas (LUAD).

Environmental risk factors, such as exposure to second-hand tobacco smoke, radon, air pollution, and asbestos, or having had previous lung diseases, may explain some lung cancers among never smokers, but scientists still don’t know what causes the majority of these cancers. And while Several studies have profiled the genomic landscape of LUAD and the rarer carcinoid subtype, previous LUAD samples were mostly from smokers, primarily undergoing whole-exome sequencing (WES), the researchers noted. “The largest moderate to high-coverage whole-genome sequencing (WGS)-based LUAD studies cumulatively total less than 100 LCINS individuals, mostly of Asian ancestry.”

For their large epidemiologic study—part of the Sherlock-Lung study—Landi and colleagues carried out whole-genome sequencing to characterize the genomic changes in tumor tissue and matched normal tissue from 232 never smokers, predominantly of European descent, who had been diagnosed with non-small cell lung cancer (NSCLC). The tumors included 189 adenocarcinomas (the most common type of lung cancer), 36 carcinoids, and seven other tumors of various types. The patients had not yet undergone treatment for their cancer.

Illustration, lung cancer research [National Cancer Institute]

The researchers investigated the tumor genomes for mutational signatures, which are patterns of mutations associated with specific mutational processes, such as damage from natural activities in the body (for example, faulty DNA repair or oxidative stress) or from exposure to carcinogens. Mutational signatures act like a tumor’s archive of activities that led up to the accumulation of mutations, providing clues into what caused the cancer to develop. A catalogue of known mutational signatures now exists, although some signatures have no known cause. In this study, the researchers discovered that a majority of the tumor genomes of never smokers bore mutational signatures associated with damage from endogenous processes.

As expected, because the study was limited to never smokers, the researchers did not find any mutational signatures that have previously been associated with direct exposure to tobacco smoking. Nor did they find those signatures among the 62 patients who had been exposed to secondhand tobacco smoke. However, Landi cautioned that the sample size was 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.”

The genomic analyses also revealed three novel subtypes of lung cancer in never smokers, to which the researchers assigned musical names based on the level of “noise” (that is, the number of genomic changes) in the tumors. The predominant “piano” subtype had the fewest mutations; it appeared to be associated with the activation of progenitor cells, which are involved in the creation of new cells. This subtype of tumor grows extremely slowly, over many years, and is difficult to treat because it can have many different driver mutations. “The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers’ progenitor cells many years before tumor diagnosis,” the team noted. However, as they continued, “The founder cells of piano appear around a decade before diagnosis and provide an optimal time window for early detection.”

In contrast, the “mezzo-forte” subtype had specific chromosomal changes as well as mutations in the growth factor receptor gene EGFR, which is commonly altered in lung cancer, and exhibited faster tumor growth. And the “forte” subtype exhibited whole-genome doubling (WGD), a genomic change that is often seen in lung cancers in smokers. This subtype of tumor also grows quickly.

“Whereas WGD is observed in over 60% of LUADs in smokers and is considered to be a major driver of aggressive lung adenocarcinomas, it occurs in 36% of LCINS overall but in 95.7% of the forte subtype,” the team reported. “While mezzo-forte is enriched for specific chromosomal arm-level amplifications and has frequent EGFR mutations, tumors in the quiet piano have a low mutational burden, infrequent WGD, small numbers of known drivers and a larger proportion of subclonal mutations indicative of extensive intratumor heterogeneity.” The forte tumors and tumors from passive smokers also had shorter telomeres than their matched normal samples, while piano-type tumors had longer telomeres, suggesting fewer cell divisions.

“We’re starting to distinguish subtypes that could potentially have different approaches for prevention and treatment,” said Landi. So while the slow-growing piano subtype could give clinicians a window of opportunity to detect these tumors earlier when they are less difficult to treat, the mezzo-forte and forte subtypes have only a few major driver mutations, suggesting that these tumors could be identified by a single biopsy and could benefit from targeted treatments, she suggested. “These findings create avenues for personalized treatment in LCINS,” the team concluded. “Currently, treatments targeting the most recurrent genomic alterations in forte and mezzo-forte are available or are under investigation in clinical trials, namely for TP53 or MDM2-TP53 interaction and for mutations in EGFR or ERBB2, genes that conveyed the poorest survival among the RTK–Ras pathway, and even for tumors with both TP53 deficiency and RTK–Ras mutations (21% of our tumors).”

A future direction of this research will be to study people of different ethnic backgrounds and geographic locations, and whose exposure history to lung cancer risk factors is well described. “We’re at the beginning of understanding how these tumors evolve,” Landi noted. “This analysis shows that there is heterogeneity, or diversity, in lung cancers in never smokers.” Co-author Stephen J. Chanock, MD, director of NCI’s Division of Cancer Epidemiology and Genetics, further commented, “We expect this detective-style investigation of genomic tumor characteristics to unlock new avenues of discovery for multiple cancer types.”

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