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Lung Cancers in Non-Smokers Fall Into Informative Molecular Subtypes

NEW YORK – An international team led by investigators at the National Cancer Institute's cancer epidemiology and genetics division has defined three somatic copy number-based subtypes of lung cancers that occur in individuals with no smoking history, along with alterations linked to better or worse survival outcomes in non-smoker lung cancer patients.

"Our findings suggest developmental processes and possible new therapeutic approaches for [lung cancer in never smokers (LCINS)]," co-senior and corresponding author Maria Teresa Landi, with NCI's Division of Cancer Epidemiology and Genetics, and her colleagues wrote in a paper published on Monday in Nature Genetics.

The researchers did whole-genome sequencing on tumor and matched normal samples from 232 individuals with untreated LCINS (including 226 individuals of European descent, four individuals with Asian ancestry and two individuals with African ancestry), comparing the sequences with those from 38 lung adenocarcinomas in smokers. The results revealed copy number alteration-based subtypes dubbed piano, forte, and mezzo-forte.

The mezzo-forte subtype included tumors with EGFR mutations and chromosome-arm amplifications involving chromosomes 1, 5, 7, or 8, for example, whereas the team saw an overrepresentation of whole-genome duplications in the forte tumors. In contrast, tumors in the piano subtype tended to show fewer mutations, with relatively infrequent chromosomal shifts or genome duplications, but that did contain recurrent RET gene fusions, germline mutations in RET, and mutations affecting a RET regulator-coding gene called NKX2.

"While mezzo-forte is enriched for specific chromosomal arm-level amplifications and has frequent EGFR mutations, tumors in the quiet piano [tumors] have a low mutational burden, infrequent [whole-genome duplication], small numbers of known drivers and a larger proportion of sub-clonal mutations indicative of extensive intratumor heterogeneity," the authors reported.

The team noted that the forte subtype — marked by whole genome duplication, focal duplications, increased tumor mutational burden, and other molecular alterations — was common in lung adenocarcinomas from smokers, while non-smokers were far more likely to have tumors classified in the piano subtype.

Almost half of the LCINS tumors fell into the piano subtype, including 78 lung adenocarcinomas and three dozen carcinoid tumors, the investigators reported, noting that that subtype appeared to coincide with enhanced overall survival.

Although more than one-quarter of the LCINS participants reported a history of secondhand tobacco exposure, the researchers did not see the mutational signatures linked to smoking history. On the other hand, they did detect an APOBEC mutational signature and other mutational signatures. The tumors in tobacco-exposed individuals often had shorter telomeres, they added, as did tumors in the forte subtype, consistent with more rampant cell division.

When it came to alterations linked to LCINS outcomes, meanwhile, the team found that TP53-mutated tumors, tumors with MDM2 amplifications, EGFR mutations, or CHEK2 loss-of-homozygosity were linked to shorter-than-usual survival times, as were cases involving chromosome 15 or 22 losses. Mortality risk roughly doubled when such mutations turned up in LCINS tumors, the authors reported.

"A risk score calculated as the mutational burden of these five independent genomic alterations showed an increment of mortality risk for each genomic alteration of approximately 1.9," they wrote.

The researchers noted that overall survival times appeared to contract in cases involving ERBB2 mutations, though that pattern was made murkier by the presence of survival-related TP53 mutations in more than half of the tumors marked by ERBB2 changes. Likewise, tumors with KRAS mutations or ALK fusions showed tenuous ties to poor survival, while tumors with MET gene changes tended toward improved survival outcomes relative to tumors that lacked RTK-Ras pathway mutations.

"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," the authors wrote, adding that the potentially prognostically beneficial piano subtype "has a scarcity of driver mutations, offering limited targets for therapeutic intervention."