Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma

Sep 24, 2026

Uploaded by Rowan

Aging is a major risk factor for many cancers, including lung adenocarcinoma (LUAD). To clarify how aging-related changes in gene regulation influence LUAD risk and survival, the study builds person-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data. PANDA/LIONESS networks are constructed for GTEx normal lung and TCGA LUAD samples. Results link age with proliferative and immune pathways, show age-accelerated targeting in younger LUAD, and identify network-informed aging signatures associated with survival and chemotherapy response. Tobacco smoking further accelerates these regulatory shifts and CLUErep highlights candidate geroprotective repurposed small molecules.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages49

Reading Time2 h 3 min

AccessFree to download

Abstract

Introduction

Lung cancer burden and age dependence

Individual-specific gene regulatory networks and study aims

bioRxiv preprint doi: [https://doi.org/10.1101/2024.07.02.601689](https://doi.org/10.1101/2024.07.02.601689); this version posted July 3, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma Enakshi Saha 1, Marouen Ben Guebila 1, Viola Fanfani 1, Katherine H. Shutta 1,2, Dawn L. DeMeo2,3, John Quackenbush1,2,4, Camila M. Lopes-Ramos1,2,3 1 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA 2 Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA 02115 3 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA 4 Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02115, USA Corresponding Author: Camila M Lopes-Ramos Email: [nhclr@channing.harvard.edu](nhclr@channing.harvard.edu) bioRxiv preprint doi: [https://doi.org/10.1101/2024.07.02.601689](https://doi.org/10.1101/2024.07.02.601689); this version posted July 3, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. bioRxiv preprint doi: [https://doi.org/10.1101/2024.07.02.601689](https://doi.org/10.1101/2024.07.02.601689); this version posted July 3, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract Aging is the primary risk factor for many individual cancer types, including lung adenocarcinoma (LUAD) . To understand how aging-related alterations in the regulation of key cellular processes might affect LUAD risk and survival outcomes, we built individual (person)-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data, using PANDA/LIONESS algorithms, for both non-cancerous lung tissue samples from the Genotype Tissue Expression (GTEx) project and LUAD samples from The Cancer Genome Atlas (TCGA) . In GTEx, we found that pathways involved in cell proliferation and immune response are increasingly targeted by regulatory transcription factors with age; these aging-associated alterations are accelerated by tobacco smoking and resemble oncogenic shifts in the regulatory landscape observed in LUAD and suggests that dysregulation of aging pathways might be associated with an increased risk of LUAD. Comparing normal adjacent samples from individuals with LUAD with healthy lung tissue samples from those without LUAD, we found that aging-associated genes show greater aging-biased targeting patterns in younger individuals with LUAD compared to their healthy counterparts of similar age, a pattern suggestive of age acceleration. This implies that an accelerated aging process may be responsible for tumor incidence in younger individuals. Using drug repurposing tool CLUEreg, we found small molecule drugs with potential geroprotective effects that may alter the accelerating aging profiles we found. We also observed that, in contrast to chronological age, a network-informed aging signature was associated with survival and response to chemotherapy in LUAD. bioRxiv preprint doi: [https://doi.org/10.1101/2024.07.02.601689](https://doi.org/10.1101/2024.07.02.601689); this version posted July 3, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the prepri

FAQs

How does the study model aging effects on LUAD at the gene regulation level?

It builds person-specific gene regulatory networks using gene expression data and transcription factor protein-protein interaction and sequence motif information, using PANDA/LIONESS algorithms.

What regulatory pathways are linked to aging in non-cancerous and LUAD contexts?

In GTEx normal lung, pathways related to cell proliferation and immune response become increasingly targeted by regulatory transcription factors with age.

How is the network-informed aging signature related to clinical outcomes in LUAD?

Unlike chronological age, the network-informed aging signature is associated with survival and response to chemotherapy in LUAD.

Sep 24, 2026

Uploaded by Rowan