Table 1 |.

Somatic features reported for LCINS compared to tobacco-related lung cancers

Feature	LCINS	Tobacco-related lung cancer
Histology	NSCLC; mostly LUAD1,2	LUAD, LSCC or SCLC; strongest association with LSCC and SCLC334
Targetable driver alterations	Present in 78–92% of LUADs3–5	Present in 49.5% of LUADs (mainly KRAS mutations)7
PD-L1 expression level	Low36–8,a	Highest with current smoking; PD-L1 staining intensity is positively correlated with pack-years of smoking history136
TMB	0–3mut/Mb (refs. 3–5,9–13) (median 1.1 mut/Mb)	Up to tenfold higher than in LCINS131, with a dose–response relationship between pack-years of smoking history and TMB132
Genomic signatures	Devoid of tobacco-associated mutational signatures, including LCINS with SHS exposure3–5	SBS signature 4b (mainly C>A transversions), attributable to misrepair of DNA damage40,135; less strongly associated with indel-based signature 3c and doublet-base substitution signature 2 (ref. 335); total number of SBS nearly fivefold higher in smoking-related versus non-smoking-related LUADs (mean 12.09 vs 2.65; P = 2.7 × 10−13); total number of indels higher in smoking-related versus non-smoking-related LUADs (mean 0.39 vs 0.14; P = 7.9 × 10−14)40

LCINS, Lung cancers in individuals who have never smoked; LUAD, lung adenocarcinoma; mut/Mb, mutations per megabase; NSCLC, non-small-cell lung cancer; SBS, single-base substitution; LSCC, lung squamous cell carcinoma; SCLC, small-cell lung cancer; SHS, secondhand smoke; TMB, tumour mutational burden.

^aModerate to high levels of PD-L1 expression have been observed in LCINS with MET exon 14 mutations^14,15.

^bReliably detectable with targeted panel-based next-generation sequencing assays.

^cReliable detection restricted to whole-exome or whole-genome sequencing analyses^336,337; at present, these mutational signatures are mainly used for investigational purposes with limited use in clinical diagnostics.