---
title: "Genomic and transcriptomic features of STAS in stage 1 lung adenocarcinoma"
id: "british-journal-of-cancer-0-genomic-and-transcriptomic-landscape-of-spread-through-air-spaces-in-stage-1"
canonical_url: "https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-genomic-and-transcriptomic-landscape-of-spread-through-air-spaces-in-stage-1"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "British Journal of Cancer"
source_url: "https://www.nature.com/articles/s41416-026-03622-8"
published_at: "2026-09-19T06:53:16.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Genomic and transcriptomic features of STAS in stage 1 lung adenocarcinoma
## Provenance & Clinical Metadata
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- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** British Journal of Cancer
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41416-026-03622-8)
- **Published At:** 2026-09-19T06:53:16.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Spread through air spaces (**STAS**) is a histologic marker of poor prognosis in early-stage lung adenocarcinoma (**LUAD**) and has been proposed as a descriptor in the ninth edition TNM staging. - In a stage 1 LUAD cohort (n=378), 54.2% of tumours were **STAS** positive, with similar incidence between **EGFR**-mutant and **EGFR**-wildtype tumours. - **STAS+** status correlated with stage 1B, lymphovascular invasion, higher histologic grade, micropapillary/solid predominant subtypes and PD-L1 TPS ≥1%. - **STAS+** remained independently associated with worse **disease-free survival** after multivariable adjustment (hazard ratio 2.32, 95% CI 1.16–4.63; p = 0.017). - Integrated molecular profiling (whole-exome and RNA sequencing) identified enrichment of **TP53** co-mutations, whole genome doubling and non-TRU transcriptomic subtypes among **STAS+** tumours. - Transcriptomic analysis showed upregulation of **cell cycle–related pathways** in **STAS+** tumours; these molecular features were directionally consistent across **EGFR**-mutant and **EGFR**-wildtype subsets. - Methods included WES at mean coverage ~400× for tumours and 100× for matched normals, RNA sequencing targeting ~50 million paired-end reads, PD-L1 IHC by SP263, and transcriptomic subtyping as TRU/PP/PI. - The study reports that **STAS+** disease is characterised by genomic instability and cell cycle dysregulation, supporting its association with a more aggressive biological phenotype and potential implications for risk stratification and adjuvant therapy selection. - Additional methodological details and supplementary analyses were provided in the article appendix; some prior studies reported variable associations between **STAS** and **EGFR** status, motivating this stage 1–restricted, integrated genomic-transcriptomic analysis.
## Clinical Analysis & Structured Key Points
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[nature](https://www.nature.com/) 2. [british journal of cancer](https://www.nature.com/bjc) 3. [articles](https://www.nature.com/bjc/articles?type=article) 4. article Genomic and transcriptomic landscape of spread through air spaces in stage 1 lung adenocarcinoma [ Download PDF ](https://www.nature.com/articles/s41416-026-03622-8.pdf) [ Download PDF ](https://www.nature.com/articles/s41416-026-03622-8.pdf) * Article * [Open access](https://www.springernature.com/gp/open-science/about/the-fundamentals-of-open-access-and-open-research) * Published: 19 September 2026 Molecular Diagnostics # Genomic and transcriptomic landscape of spread through air spaces in stage 1 lung adenocarcinoma * [Stephanie P. L. Saw](https://www.nature.com/articles/s41416-026-03622-8#auth-Stephanie_P__L_-Saw-Aff1) [ORCID: orcid.org/0000-0003-3520-9464](https://orcid.org/0000-0003-3520-9464)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Mengyuan Pang](https://www.nature.com/articles/s41416-026-03622-8#auth-Mengyuan-Pang-Aff2)[2](https://www.nature.com/articles/s41416-026-03622-8#Aff2), * [Clare Patteri](https://www.nature.com/articles/s41416-026-03622-8#auth-Clare-Patteri-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Angela Takano](https://www.nature.com/articles/s41416-026-03622-8#auth-Angela-Takano-Aff3)[3](https://www.nature.com/articles/s41416-026-03622-8#Aff3), * [Jia Chi Yeo](https://www.nature.com/articles/s41416-026-03622-8#auth-Jia_Chi-Yeo-Aff2)[2](https://www.nature.com/articles/s41416-026-03622-8#Aff2), * [Ngak Leng Sim](https://www.nature.com/articles/s41416-026-03622-8#auth-Ngak_Leng-Sim-Aff2)[2](https://www.nature.com/articles/s41416-026-03622-8#Aff2), * [Gillianne G. Y. Lai](https://www.nature.com/articles/s41416-026-03622-8#auth-Gillianne_G__Y_-Lai-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Darren W. T. Lim](https://www.nature.com/articles/s41416-026-03622-8#auth-Darren_W__T_-Lim-Aff1) [ORCID: orcid.org/0000-0002-4655-0206](https://orcid.org/0000-0002-4655-0206)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Mei-Kim Ang](https://www.nature.com/articles/s41416-026-03622-8#auth-Mei_Kim-Ang-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Ravindran Kanesvaran](https://www.nature.com/articles/s41416-026-03622-8#auth-Ravindran-Kanesvaran-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Quan Sing Ng](https://www.nature.com/articles/s41416-026-03622-8#auth-Quan_Sing-Ng-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Amit Jain](https://www.nature.com/articles/s41416-026-03622-8#auth-Amit-Jain-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Wan Ling Tan](https://www.nature.com/articles/s41416-026-03622-8#auth-Wan_Ling-Tan-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Aaron C. Tan](https://www.nature.com/articles/s41416-026-03622-8#auth-Aaron_C_-Tan-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Wei Chong Tan](https://www.nature.com/articles/s41416-026-03622-8#auth-Wei_Chong-Tan-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Amanda O. L. Seet](https://www.nature.com/articles/s41416-026-03622-8#auth-Amanda_O__L_-Seet-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1), * [Boon-Hean Ong](https://www.nature.com/articles/s41416-026-03622-8#auth-Boon_Hean-Ong-Aff4)[4](https://www.nature.com/articles/s41416-026-03622-8#Aff4), * [Tony K. H. Lim](https://www.nature.com/articles/s41416-026-03622-8#auth-Tony_K__H_-Lim-Aff3)[3](https://www.nature.com/articles/s41416-026-03622-8#Aff3), * [Anders Jacobsen Skanderup](https://www.nature.com/articles/s41416-026-03622-8#auth-Anders_Jacobsen-Skanderup-Aff2)[2](https://www.nature.com/articles/s41416-026-03622-8#Aff2) & * … * [Daniel S. W. Tan](https://www.nature.com/articles/s41416-026-03622-8#auth-Daniel_S__W_-Tan-Aff1)[1](https://www.nature.com/articles/s41416-026-03622-8#Aff1) Show authors [_British Journal of Cancer_](https://www.nature.com/bjc) (2026) [Cite this article](https://www.nature.com/articles/s41416-026-03622-8#citeas) [ Save article ](https://www.nature.com/articles/s41416-026-03622-8/save-research?_csrf=JzyimnpQiJROwyxJxPsxME6ywKTKBR3d) [ View saved research ](https://www.nature.com/saved-research) ## Abstract ### Introduction Spread through air spaces (STAS) is an adverse histologic feature in early-stage lung adenocarcinoma (LUAD) incorporated into the ninth edition TNM staging. Despite its clinical significance, the molecular features underlying STAS in stage 1 LUAD remain incompletely characterised. ### Methods Patients with stage 1 LUAD and known STAS status were identified. Whole exome and RNA sequencing were performed on tumour samples with matched normal controls. Disease-free survival (DFS) was analysed using the Kaplan–Meier method and Cox regression. ### Results Among 378 patients, 54.2% had STAS+ tumours, with similar incidence between _EGFR_ -mutant and _EGFR_ -wildtype LUAD. STAS+ tumours were significantly associated with stage 1B disease, lymphovascular invasion, higher histological grade, micropapillary or solid predominant adenocarcinoma subtype and PD-L1 tumour proportion score ≥1%. STAS+ remained independently associated with inferior DFS after multivariable adjustment (hazard ratio 2.32, 95% CI 1.16–4.63; _p_ = 0.017). At the molecular level, STAS+ tumours were enriched for _TP53_ co-mutations, whole genome doubling, non-TRU transcriptomic subtypes and upregulation of cell cycle–related pathways, with directionally consistent findings across _EGFR_ -mutant and _EGFR_ -wildtype tumours. ### Conclusions STAS+ in stage 1 LUAD is associated with a distinct molecular phenotype characterised by genomic instability and cell cycle dysregulation, consistent with a more aggressive biological phenotype with implications for risk stratification and adjuvant therapy selection. ### Explore related subjects Discover the latest articles and news in related subjects. * [Cancer genetics](https://www.nature.com/subjects/cancer-genetics) * [Lung cancer](https://www.nature.com/subjects/lung-cancer) ## Introduction Spread through air spaces (STAS) was first defined in 2015 as the identification of lung cancer tumour cells microscopically beyond the edge of the main tumour in the adjacent alveolar parenchyma, appearing as micropapillary clusters, solid nests or single cells [[1](https://www.nature.com/articles/s41416-026-03622-8#ref-CR1 "Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10:1243–60. https://doi.org/10.1097/JTO.0000000000000630 .")]. It is well-established as a poor prognostic factor, particularly among lung adenocarcinoma (LUAD), and various studies have consistently reported the association between STAS and higher recurrence rates, especially following limited surgical resection in early-stage disease [[2](https://www.nature.com/articles/s41416-026-03622-8#ref-CR2 "Han YB, Kim H, Mino-Kenudson M, Cho S, Kwon HJ, Lee KR, et al. Tumor spread through air spaces \(STAS\): prognostic significance of grading in non-small cell lung cancer. Mod Pathol. 2021;34:549–61. https://doi.org/10.1038/s41379-020-00709-2 ."), [3](https://www.nature.com/articles/s41416-026-03622-8#ref-CR3 "Jia M, Yu S, Yu J, Li Y, Gao H, Sun PL. Comprehensive analysis of spread through air spaces in lung adenocarcinoma and squamous cell carcinoma using the 8th edition AJCC/UICC staging system. BMC Cancer. 2020;20:705. https://doi.org/10.1186/s12885-020-07200-w .")]. Reflecting its prognostic relevance, the International Association for the Study of Lung Cancer (IASLC) has recently recommended that STAS be incorporated as a histologic descriptor in the proposed ninth edition of the TNM classification [[4](https://www.nature.com/articles/s41416-026-03622-8#ref-CR4 "Travis WD, Eisele M, Nishimura KK, Aly RG, Bertoglio P, Chou TY, et al. The International Association for the Study of Lung Cancer \(IASLC\) staging project for lung cancer: recommendation to introduce spread through air spaces as a histologic descriptor in the ninth edition of the TNM classification of lung cancer. Analysis of 4061 pathologic stage I NSCLC. J Thorac Oncol. 2024;19:1028–51. https://doi.org/10.1016/j.jtho.2024.03.015 .")]. In this study comprising 4061 stage 1 NSCLC, STAS was reported to be significantly associated with worse survival outcomes regardless of histologic type after adjusting for age, sex, grade and lymphovascular invasion (LVI). STAS was also found to be independent of visceral pleural invasion (VPI), the latter of which upstages T1 lung cancers to T2a [[4](https://www.nature.com/articles/s41416-026-03622-8#ref-CR4 "Travis WD, Eisele M, Nishimura KK, Aly RG, Bertoglio P, Chou TY, et al. The International Association for the Study of Lung Cancer \(IASLC\) staging project for lung cancer: recommendation to introduce spread through air spaces as a histologic descriptor in the ninth edition of the TNM classification of lung cancer. Analysis of 4061 pathologic stage I NSCLC. J Thorac Oncol. 2024;19:1028–51. https://doi.org/10.1016/j.jtho.2024.03.015 ."), [5](https://www.nature.com/articles/s41416-026-03622-8#ref-CR5 "Detterbeck FC, Woodard GA, Bader AS, Dacic S, Grant MJ, Park HS, et al. The Proposed Ninth Edition TNM classification of lung cancer. Chest. 2024;166:882–95. https://doi.org/10.1016/j.chest.2024.05.026 .")]. Notably, molecular data were not available in this study. Despite its established prognostic significance, the molecular correlates of STAS, particularly within specific oncogene subsets, remain incompletely characterised. A large Chinese cohort of 442 stage I-III surgically resected LUAD with panel-based next-generation sequencing (NGS) data comprising 68 lung cancer genes identified a higher proportion of _TP53_ alterations in STAS-positive (STAS + ) versus STAS-negative (STAS − ) tumours (49.8% vs 34.8%, _p_ = 0.002) and more frequent _EGFR_ L858R missense mutations (19.5% vs 37.6%, _p_ < 0.001) in STAS − [[6](https://www.nature.com/articles/s41416-026-03622-8#ref-CR6 "Ye R, Yu Y, Zhao R, Han Y, Lu S. Comprehensive molecular characterizations of stage I–III lung adenocarcinoma with tumor spread through air spaces. Front Genet \[Internet\]. 2023;14-2023. Available from: https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1101443 .")]. Interestingly, the authors did not observe any difference in 1-year disease-free survival (DFS) comparing STAS+ vs STAS− patients. However, data specific to stage 1 patients were not available. Other studies evaluating STAS in early-stage LUAD have reported inconsistent associations with _EGFR_ mutation status and clinical outcomes, underscoring the need for more granular molecular characterisation in well-defined oncogene subsets [[3](https://www.nature.com/articles/s41416-026-03622-8#ref-CR3 "Jia M, Yu S, Yu J, Li Y, Gao H, Sun PL. Comprehensive analysis of spread through air spaces in lung adenocarcinoma and squamous cell carcinoma using the 8th edition AJCC/UICC staging system. BMC Cancer. 2020;20:705. https://doi.org/10.1186/s12885-020-07200-w ."), [7](https://www.nature.com/articles/s41416-026-03622-8#ref-CR7 "Lee JS, Kim EK, Kim M, Shim HS. Genetic and clinicopathologic characteristics of lung adenocarcinoma with tumor spread through air spaces. Lung Cancer. 2018;123:121–6. https://doi.org/10.1016/j.lungcan.2018.07.020 ."), [8](https://www.nature.com/articles/s41416-026-03622-8#ref-CR8 "Toyokawa G, Yamada Y, Tagawa T, Kozuma Y, Matsubara T, Haratake N, et al. Significance of spread through air spaces in resected pathological stage i lung adenocarcinoma. Ann Thorac Surg. 2018;105:1655–63. https://doi.org/10.1016/j.athoracsur.2018.01.037 .")]. Accordingly, we sought to define the molecular mechanisms underlying STAS through integrated whole exome and transcriptomic profiling in a stage 1 LUAD-restricted cohort, with the aim of identifying the biological basis of its adverse prognostic impact across oncogenic driver subsets. ## Methods Patients diagnosed with AJCC8 stage 1 LUAD at the National Cancer Centre Singapore with minimum 2 years of follow up after surgical resection and available _EGFR_ mutation and STAS status were identified. All included cases were histologically confirmed as adenocarcinoma on surgical resection by dedicated thoracic pathologists. STAS assessment was performed by dedicated thoracic pathologists as part of routine institutional standard of care histopathologic reporting; pathologists were not blinded to clinical information. STAS was defined according to the 2015 World Health Organization classification criteria [[1](https://www.nature.com/articles/s41416-026-03622-8#ref-CR1 "Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10:1243–60. https://doi.org/10.1097/JTO.0000000000000630 .")]. _EGFR_ mutations were prospectively confirmed by Cobas, Sanger sequencing and/or next generation sequencing on tumour tissue as per institutional standard of care. PD-L1 expression was assessed by immunohistochemistry (IHC) using the SP263 assay and reported as tumour proportion score (TPS). Fresh-frozen tumour samples with matched normal controls underwent whole-exome sequencing (WES) at a mean coverage depth of 400× for tumour and 100× for matched normal samples. RNA sequencing was performed with a target depth of 50 million paired-end reads per sample. Sequencing was prioritised for _EGFR_ -mutant tumours as part of an ongoing dedicated translational research programme, which accounts for the higher proportion of _EGFR_ -mutant cases. Further details on tissue processing, sequencing, genomic and transcriptomic analyses are provided in the Supplementary [Appendix](https://www.nature.com/articles/s41416-026-03622-8#MOESM1). Transcriptomic subtypes were assigned as terminal respiratory unit (TRU), proximal proliferative (PP), or proximal inflammatory (PI) according to previously described classifications [[9](https://www.nature.com/articles/s41416-026-03622-8#ref-CR9 "Collisson EA, Campbell JD, Brooks AN, Berger AH, Lee W, Chmielecki J, et al. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50. https://doi.org/10.1038/nature13385 .")]. Associations between categorical and continuous variables were assessed using Fisher’s exact test and Wilcoxon rank-sum test, respectively. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. DFS was defined as time from surgery until disease recurrence or death (whichever occurred first); surviving patients without recurrence were censored at their date of last follow-up. Univariable and multivariable Cox proportional hazards models were used to evaluate the association between STAS and DFS. Where binary comparisons of categorical variables with more than two levels were performed, Fisher’s exact test compared the category of interest with all remaining categories combined. A two-sided _p_ < 0.05 was considered statistically significant unless othe
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