# Genomic and evolutionary classification of lung cancer in never smokers

Source: https://onco.cc/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/  
OnCo record `paper-zhang-lung-cancer-never-smokers-nat-genet-2021` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The Sherlock-Lung study sequenced 232 lung cancers from people who never smoked and found three distinct types, none of them carrying the tobacco damage signature. One type appears to begin decades before it is diagnosed.

## Summary

Zhang, Joubert, Ansari-Pour and colleagues, with Landi as senior author, performed high-coverage whole-genome sequencing of 232 lung cancers in never smokers and defined three subtypes by copy-number aberration, named piano, mezzo-forte and forte.

The dominant piano subtype is rare in smokers' lung cancer: low mutational burden, high intratumour heterogeneity, long telomeres, frequent KRAS mutations, stem cell-like properties and slow growth, with driver progenitor cells datable to many years before diagnosis. Mezzo-forte carries specific amplifications and EGFR mutations; forte is defined by whole-genome doubling. No strong tobacco smoking signatures were detected, even in cases with secondhand smoke exposure.

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Tags: lung-evidence
- Journal: Nature Genetics
- Year: 2021
- DOI: 10.1038/s41588-021-00920-0
- Authors: Zhang T, Joubert P, Ansari-Pour N, et al.
- Findings: Three subtypes defined by copy-number aberration across 232 whole genomes: piano, mezzo-forte and forte.; The piano subtype features somatic UBA1 mutations, germline AR variants, stem cell-like properties, low mutational burden, high intratumour heterogeneity, long telomeres and frequent KRAS mutations.; Mezzo-forte is characterised by specific amplifications and EGFR mutations; forte by whole-genome doubling.; No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke.; Five genomic alterations independently doubled mortality; genes in the receptor tyrosine kinase-Ras pathway had distinct impacts on survival.
- What it means: Lung cancer in never-smokers is not smokers' lung cancer with the smoking removed; it is a different set of diseases with a different clock. The slow-growing piano subtype in particular is the argument that a screening test aimed at never-smokers would need to look for something other than what low-dose computed tomography was built to find.
- Caveats: 232 genomes, largely from tissue banks, with the referral patterns that implies; subtype frequencies are not population estimates.; Subtypes are defined by copy-number structure and have no prospective treatment implication yet.; Mutational signature analysis cannot exclude every unrecorded tobacco or environmental exposure.

## Sources

- Nat Genet 2021: https://doi.org/10.1038/s41588-021-00920-0
- PubMed: https://pubmed.ncbi.nlm.nih.gov/34493867/
- Sherlock-Lung study (NCI): https://dceg.cancer.gov/research/what-we-study/sherlock-lung

## Connected records

- key papers: [Lung adenocarcinoma promotion by air pollutants](https://onco.cc/key-papers/paper-hill-lung-adenocarcinoma-air-pollutants-nature-2023/), [Tracking the evolution of non-small-cell lung cancer](https://onco.cc/key-papers/paper-jamal-hanjani-tracerx-evolution-nsclc-nejm-2017/)
- cancers: [Adenocarcinoma of the lung](https://onco.cc/cancers/lung-adenocarcinoma/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/), [Early Detection & Screening](https://onco.cc/fronts/early-detection/)
- technologies: [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/)
- institutions: [National Cancer Institute (NIH)](https://onco.cc/institutions/nci/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/)
- bottlenecks: [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [The hardest cancers are found late](https://onco.cc/bottlenecks/b-early-detection/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- journals: [Nature Genetics](https://onco.cc/journals/nature-genetics/)
- roadmaps: [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/)
- ideas: [Treat lung cancer in never-smokers as its own disease, with its own detection programme](https://onco.cc/ideas/idea-lung-never-smoker-disease-its-own-programme/)

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