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Perturbed Inflammatory, Proliferation, Regulatory, And Neurodegeneration Signaling Pathways Are Associated With Trait Anxiety In Cancer Survivors

This study identifies both shared inflammatory mechanisms and distinct biological pathways associated with trait anxiety in cancer survivors compared to the general population by analyzing transcriptomic data from the Multi-Ethnic Study of Atherosclerosis.

Original authors: Nidhi Thati, Julia Trudeau, Ding Quan Ng, Esther Chavez-Iglesias, Anand Dhruva, Adam Olshen, Raymond Chan, Alexandre Chan, Kord M. Kober

Published 2026-07-17

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: Nidhi Thati, Julia Trudeau, Ding Quan Ng, Esther Chavez-Iglesias, Anand Dhruva, Adam Olshen, Raymond Chan, Alexandre Chan, Kord M. Kober

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

Imagine your body as a bustling, high-tech city. Inside this city, there are millions of tiny workers (cells) constantly talking to each other to keep everything running smoothly. They send messages through complex networks called "pathways." Some of these pathways are like the city's fire department, ready to fight off invaders (inflammation). Others are like the construction crews, building new buildings and repairing roads (proliferation). Then there are the traffic controllers in the brain's command center, making sure you feel calm or alert at the right times (neurotransmission).

Sometimes, this city gets a little stressed. You might feel a temporary worry about a test or a job interview; that's like a sudden traffic jam. But sometimes, the worry sticks around, becoming a permanent part of your personality. Scientists call this "trait anxiety." It's not just a bad day; it's a long-term tendency to feel anxious, like a city that is always on high alert, even when there's no fire. While we know stress can make people sick, we don't fully understand why some people get stuck in this anxious state. Does the city's wiring get crossed? Do the fire crews get confused? And does having a history of a major disaster, like cancer, change how the city's anxiety system works compared to a city that hasn't faced that specific crisis? This is the mystery scientists are trying to solve: looking at the biological blueprints to see what's different when anxiety becomes a permanent resident.

In this study, researchers decided to take a peek inside the biological blueprints of two groups of people: cancer survivors and people who have never had cancer. They wanted to see if the "wiring" behind their anxiety looked the same or if the cancer experience left a unique fingerprint on the system. They didn't just look at one or two genes; they looked at the entire transcriptome, which is like reading the entire instruction manual for the city's workers to see which chapters were being read too loudly or too quietly.

The team analyzed data from 1,093 participants. They split everyone into two groups based on their anxiety levels: those with "low" anxiety and those with "high" anxiety. To make a fair comparison, they created a special "matched" group of non-cancer participants who looked just like the cancer survivors in terms of age, gender, income, and other details. This way, any differences they found could be blamed on the cancer history, not just because one group was older or richer.

Here is what they found when they compared the instruction manuals:

The Shared City Problems
First, they discovered that both groups had some very similar issues. In both the cancer survivors and the general population, high anxiety was linked to disturbances in four main areas:

The Fire Department (Inflammation): Both groups showed signs that their immune systems were overactive, sending out too many "alarm signals."
The Construction Crews (Cell Growth): Pathways that control how cells grow and divide were jumbled in both groups.
The Brain's Command Center (Neurodegeneration): The networks that handle brain function and nerve signals were perturbed in both.
The City Infrastructure (Cell Structure): The way cells hold their shape and talk to their neighbors was also affected in both groups.

This suggests that the basic biological recipe for feeling anxious is largely the same, whether you've had cancer or not. The "fire" of inflammation seems to be a common thread for everyone.

The Unique Cancer Scars
However, the cancer survivors had some extra, unique problems that the general population didn't show. It's as if the cancer or its treatment left specific scars on the city's blueprint.

The Heart and Muscles: In cancer survivors, pathways related to heart muscle contraction and the regulation of the cell's internal skeleton (actin cytoskeleton) were uniquely disturbed. This might be because cancer treatments can sometimes be tough on the heart and nerves, leaving a lasting mark that influences anxiety.
Specific Neurodegeneration: While both groups had issues with brain pathways, cancer survivors had unique disturbances in pathways linked to Parkinson's and Huntington's diseases, as well as smell (olfactory transduction). This hints that cancer survivors might be experiencing a different kind of "brain aging" or stress response.
Prostate and Colon Specifics: Interestingly, some pathways related to specific cancers (like prostate and colorectal cancer) were only perturbed in the survivor group, likely reflecting the specific biological history of the patients.

What This Means
The study suggests that while the general "anxiety engine" runs on similar fuel (inflammation and stress responses) for everyone, cancer survivors have an engine that has been modified by their unique history. They share the common city-wide traffic jams of anxiety, but they also have specific, localized construction zones that need attention.

The researchers found 42 pathways disturbed in the 74 cancer survivors and 80 in the 222 matched non-cancer participants. Thirty-six of these were the same in both groups. The study doesn't claim to have cured anxiety or found a magic pill yet; it simply maps out the terrain. It suggests that future treatments for anxiety in cancer survivors might need to be more precise—targeting not just the general inflammation, but also those unique heart and nerve pathways that are specific to the cancer experience. It's a first step in understanding that while the feeling of anxiety might be universal, the biological story behind it can be very different depending on your life's journey.

Technical Summary: Perturbed Inflammatory, Proliferation, Regulatory, And Neurodegeneration Signaling Pathways Are Associated With Trait Anxiety In Cancer Survivors

Problem Statement
Trait anxiety, defined as a stable personality characteristic predisposing individuals to heightened anxiety, is a prevalent symptom among cancer survivors, linked to reduced quality of life and an increased risk of Generalized Anxiety Disorder (GAD). While previous research has identified biological mechanisms of anxiety in the general population—primarily focusing on inflammatory and immune processes—and specific gene biomarkers in oncology patients, there is a lack of understanding regarding the pathway-level perturbations associated with trait anxiety specifically in cancer survivors. Furthermore, it remains unclear how these biological mechanisms in cancer survivors overlap with or diverge from those in the general population. This study addresses the gap in knowledge regarding the transcriptomic landscape of trait anxiety in cancer survivors compared to a matched non-cancer cohort.

Methodology
The study utilized data from the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective longitudinal study. The analysis included 1,093 participants with complete gene expression data and trait anxiety assessments from the baseline visit (Exam 1, 2000–2002).

Cohorts: The participants were divided into a cancer survivor cohort ( $n=74$ ) and a propensity-score matched (PSM) non-cancer cohort ( $n=222$ ). The PSM matched survivors based on age, race/ethnicity, gender, employment, income, BMI, education, and marital status to ensure comparability.
Phenotyping: Trait anxiety was assessed using ten items from the Spielberger State-Trait Anxiety Inventory. Participants were stratified into "low" (<3rd quartile) and "high" (≥3rd quartile) trait anxiety groups.
Genomic Analysis: Gene expression data were derived from peripheral blood mononuclear cells (PBMCs). Differential gene expression between low and high anxiety groups was evaluated using empirical Bayes models (edgeR), adjusting for demographic and clinical covariates that differed significantly between groups.
Pathway Analysis: Pathway Impact Analysis (PIA) was employed to interpret transcriptomic data across 149 signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Significance was determined using a strict False Discovery Rate (FDR) threshold of < 0.025.

Key Contributions and Results
This study is the first to evaluate transcriptomic perturbations in signaling pathways associated with trait anxiety severity in cancer survivors against a matched non-cancer cohort. The analysis identified distinct and shared biological mechanisms:

Overall Perturbation Counts:
- Cancer Survivors: 42 pathways were significantly perturbed between high and low anxiety groups.
- Non-Cancer Cohort: 80 pathways were significantly perturbed.
- Overlap: 36 pathways were common to both cohorts. Six pathways were unique to cancer survivors.
Shared Mechanisms (Common Pathways):
Both cohorts exhibited perturbations in four primary molecular mechanisms:
- Inflammation & Immune Signaling: Pathways such as cytokine-cytokine receptor interaction, chemokine signaling, and osteoclast differentiation were perturbed in both groups, suggesting inflammation is a shared mechanism for trait anxiety.
- Cellular Growth, Cycle, & Proliferation: Shared perturbations included the PI3K-Akt, MAPK, mTOR, Hippo, and p53 signaling pathways, as well as general cell cycle and cancer pathways.
- Neurodegeneration & Neurotransmission: Common pathways included neuroactive ligand-receptor interaction, axon guidance, and Alzheimer's disease signaling.
- Cell Structure & Regulation: Shared perturbations involved ECM-receptor interaction, focal adhesion, endocytosis, and GnRH signaling.
Distinct Mechanisms (Unique to Cancer Survivors):
Six pathways were uniquely perturbed in the cancer survivor cohort, suggesting cancer-specific or treatment-related biological alterations:
- Neurodegeneration: Parkinson's disease, Huntington's disease, and olfactory transduction pathways.
- Cell Structure & Regulation: Regulation of actin cytoskeleton and cardiac muscle contraction.
- Cancer-Specific: Prostate cancer pathway.
Distinct Mechanisms (Unique to Non-Cancer Cohort):
The non-cancer cohort showed unique perturbations in various immune pathways (e.g., NOD-like receptor, Toll-like receptor, NF-kappa B signaling), apoptosis, and metabolic pathways (e.g., Type I and II diabetes, adipocytokine signaling).

Significance and Claims
The authors claim this study provides the first transcriptomic evaluation of trait anxiety in cancer survivors, identifying both shared and distinct molecular underpinnings compared to the general population.

Shared Mechanisms: The findings suggest that inflammatory and immune signaling pathways form a common biological foundation for trait anxiety across both populations. This implies that therapeutic strategies targeting inflammation may be broadly applicable.
Distinct Mechanisms: The unique perturbations in cancer survivors—specifically those related to neurodegeneration (Parkinson's, Huntington's), cytoskeleton regulation (actin), and cardiac function—suggest that systemic dysregulations caused by cancer or its treatments (e.g., chemotherapy-induced neurotoxicity or cardiotoxicity) may contribute to trait anxiety in this specific population.
Clinical Implication: By distinguishing between shared and distinct pathways, the study suggests that while general anxiety interventions may be relevant, targeted interventions addressing cancer-specific biological alterations (such as neurodegeneration or cardiac function) could be necessary for effective management of trait anxiety in cancer survivors.

The authors maintain a modest stance, noting that the small sample size of cancer survivors ( $n=74$ ) necessitates further validation. They also acknowledge limitations regarding the lack of data on specific cancer treatments, time since diagnosis, and specific stressors, which may influence the observed biological perturbations.

Technical Summary: Perturbed Inflammatory, Proliferation, Regulatory, And Neurodegeneration Signaling Pathways Are Associated With Trait Anxiety In Cancer Survivors

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