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Program Number: AHNS18
Session Name: Scientific Session 4 - Cancer Biology
Session Date: Thursday, May 15, 2025
Session Time: 9:00 AM - 9:45 AM

The Epigenetic link between Psychosocial Stress and Survival of Oral Squamous Cell Carcinoma

Traeden D Wilson, MD¹; Phuong Dong, PhD²; Bac-An Luong²; Gary Yu, DrPH, MPH³; Michele Arambula²; Bradley Aouizerat, PhD⁴; Paul Walker, MD¹; Khahn Nguyen, MD¹; Nicholas Callahan, MPH, DMD, MD⁵; Carissa Thomas, MD, PhD, FACS⁶; Chi Viet, DDS, MD, PhD, FACS²; ¹Loma Linda University Department of Otolaryngology; ²Loma Linda University School of Dentistry; ³Columbia University; ⁴New York University College of Dentistry; ⁵University of Illinois Chicago College of Dentistry; ⁶University of Colorado Department of Otolaryngology

Psychological well-being predicts future physical health and mortality beyond its association with reduced stress and depression. Studies on psychological well-being in cancer have not evaluated the effect of psychosocial stressors on cancer outcomes. The objective of this study was to investigate the impact of psychosocial stressors and their resultant dysregulated epigenetic pathways on oral squamous cell carcinoma (OSCC) outcomes.

This prospective multi-institutional study enrolled 173 OSCC patients to determine prior and current psychosocial stressors (using Adverse Childhood Experience – ACE and Life Events Checklist – LEC-5), characterize cancer symptoms and quality of life disturbance (using UCSF Oral Pain Questionnaire – UCSF-OPQ, modified Brief Pain Inventory – BPI, and EORTC-QLQC30 and HN35), and collect flash-frozen cancer tissue and oral brush swabs for epigenetic analysis (with MethylCap-Seq; MC-Seq). Data was analyzed by a biostatistician using Pearson correlation, Student's t-test, one way ANOVA, Kaplan-Meier log-rank test and Cox hazard regression. Our cohort consisted of 99 males, 74 females; racial/ethnic composition included 118 White, 14 Asian, 12 Black, and 28 White-Hispanic. The mean age of the cohort was 64. Patients with high cancer pain (UCSF-OPQ) had significantly greater physical and psychological interferences (modified BPI; p<0.05). Patients with financial difficulties had worse cancer pain (UCSF-OPQ) and quality of life (EORTC), independent of their cancer stage (p<0.001). Physical interferences were significantly worse in all minorities compared to White patients (p=0.01). Patients with worse pain had disturbances in all 6 functional categories measured by EORTC-QLQC30, including physical, cognitive, social, emotional, and role functioning and global health status (p<0.0001). In terms of the effect of childhood or adult psychosocial stressors on cancer outcomes, patients with a high ACE or LEC-5 score had worse cancer symptoms (in all symptom scales including modified BPI, EORTC-QLQ, and H&N35) independent of their pathologic stage. A Cox hazard regression model showed that the H&N35 functional score (HR = 1.969, CI 95% [1.060 - 3.659]) was independent of pathologic stage (HR =1.808, CI 95% [1.244-2.628] and age (HR: 1.669, CI 95% [1.151-2.419]) in predicting survival (Fig. 1). Using machine learning-based bioinformatic analysis of MC-seq data in both flash-frozen cancer tissue and brush swab samples of OSCC patients, we determined the top epigenetically dysregulated genes in patients with high ACE or LEC-5 scores. We showed that genes/pathways with known significant roles in OSCC, such as CDKN2A (p16), JAK/STAT, cytokine binding, growth factor binding, and cadherin pathways, were epigenetically dysregulated in OSCC patients with psychosocial stress. We identified additional genes and pathways whose epigenetic regulation has not previously been associated with poor outcomes in OSCC (e.g., AP3B2, and ALOX5AP genes; retinoic acid binding pathway).

Our results demonstrate that psychosocial stressors significantly worsen cancer symptom burden, which is independently associated with worse cancer outcomes and survival. We delineate the significant epigenetic pathways that are dysregulated in patients with psychosocial stressors, which contribute to cancer outcome. This study provides an epigenetic link between behavioral health and OSCC survival. Furthermore, the use of brush swabs in lieu of tissues provide a non-invasive test for epigenetic biomarker development in OSCC.

 

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