Aging-related transcriptomic signatures associated with recurrence following resection of stage I lung adenocarcinoma
Abstract Age is an independent prognostic factor in early-stage non-small cell lung cancer, yet age-associated molecular differences and their association with cancer recurrence remain poorly understood. We investigated transcriptomic differences associated with aging and recurrence in stage I lung adenocarcinoma (LUAD). Bulk RNA sequencing was performed on tumor and adjacent normal lung tissue (NAT) from 126 patients with resected stage I LUAD. Differential expression, pathway enrichment, and multiscale embedded gene co-expression network analysis (MEGENA) were used to identify age- and recurrence-associated transcriptional differences. External confirmation was performed using TCGA and TRACERx cohorts. Older patients ( > 70 years) with recurrence demonstrated marked upregulation of cancer-associated, inflammatory, and extracellular matrix (ECM) pathways in tumors compared with older patients without recurrence. In NAT samples, older patients with recurrence showed upregulation of inflammatory and immune-related pathways, including IL-17, IL-6, and Th2 signaling, whereas these pathways were absent or downregulated in younger patients. MEGENA identified a larger number of recurrence-associated co-expression modules in older versus younger patients. These findings were partially supported in external cohorts, particularly in tumor tissue. Our findings suggest that aging in LUAD is associated with distinct inflammatory and cancer-related transcriptomic alterations associated with recurrence.
Authors
- Leopoldo N. Segal (ORCID: https://orcid.org/0000-0003-3559-9431)
- Christian V. Forst (ORCID: https://orcid.org/0000-0003-0229-9459)
- Yaa Kyeremateng
- Aristotelis Tsirigos (ORCID: https://orcid.org/0000-0002-7512-8477)
- Xianxiao Zhou (ORCID: https://orcid.org/0000-0001-9350-4467)
- Rosemary Schluger
- Ray Pillai (ORCID: https://orcid.org/0000-0002-8335-3463)
- Çiğdem Sevim Bayrak (ORCID: https://orcid.org/0000-0002-3883-5535)
- Fares Darawshy (ORCID: https://orcid.org/0000-0003-0177-908X)
- Imran Sulaiman (ORCID: https://orcid.org/0000-0003-1992-0280)
- Alena Lukovnikova
- Gregory David (ORCID: https://orcid.org/0000-0002-3371-4558)
- Michelle Fridman
- Daniel Sterman
- Sofia Roldan
- Matthew Blaisdsell
- Harvey Pass
- Marcus D. Goncalves (ORCID: https://orcid.org/0000-0002-0784-9248)
- Jun-Chieh J. Tsay (ORCID: https://orcid.org/0000-0002-2282-2510)
- Chandra Goparaju
- Kendrew Wong
- Anil Vachani
- Matthias C. Kugler
- Cecilia Chung
- Benjamin Kwok
- Destiny Collazo
- Yonghua Li
- Alexander Bain
- Bin Zhang
- Benjamin G. Wu
Institutions
- Royal College of Surgeons in Ireland (IE)
- Hebrew University of Jerusalem (IL)
- Hadassah Medical Center (IL)
- VA NY Harbor Healthcare System (US)
- Beaumont Hospital (IE)
- NYU Langone Health (US)
- New York University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- npj Aging
- Published
- 2026-08-27
- DOI
- https://doi.org/10.1038/s41514-026-00470-x
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Hadassah Medical Organization
- Royal College of Surgeons in Ireland
- York University
- Hebrew University of Jerusalem
- National Institutes of Health
- School of Medicine, New York University
- NYU Grossman School of Medicine
- National Institute on Aging
- National Cancer Institute
- National Institute of General Medical Sciences
- National Center for Advancing Translational Sciences