Association of Gene Expression Alterations with Aggressive Features in Papillary Thyroid Carcinomas Harboring Low Allele Frequency BRAF V600E Mutations

Sep 30, 2026

Importance. BRAF V600E mutations are frequently linked to aggressive papillary thyroid carcinomas (PTCs), yet tumors with low allele frequency (AF) are often viewed as indolent; exceptions suggest additional determinants. Gene expression alterations (GEA) may help distinguish tumors with more aggressive molecular phenotypes. Objective. Assess whether aggressive clinicopathologic features correlate with GEA positivity in low AF BRAF V600E–mutated PTCs. Design, methods, results, and conclusion summarize this association.

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CategoryHealthcare

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Pages9

Reading Time23 min

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Abstract

Importance

Objective

Design and Setting

Participants and Exposure

Main Outcome Measures

Results

Conclusion and Relevance

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Introduction

Association of Gene Expression Alterations with Aggressive Features in Papillary Thyroid Carcinomas Harboring Low Allele Frequency BRAF V600E Mutations Journal of Otolaryngology-Head & Neck Surgery Volume 55: 1–9 © The Author(s) 2026 Article reuse guidelines: [sagepub.com/journals-permissions](sagepub.com/journals-permissions)[ ](sagepub.com/journals-permissions)[DOI: 10.1177/19160216251409738](DOI: 10.1177/19160216251409738)[ ](DOI: 10.1177/19160216251409738)[journals.sagepub.com/home/ohn](journals.sagepub.com/home/ohn) Alexandra Katz, MD, MSc 1 , Coralie Lefebvre, DCS2, Saruchi Bandargal, DCS2, Véronique-Isabelle Forest, MD, MSc3,4, Marc Philippe Pusztaszeri, MD5, and Richard J. Payne, MD, MSc3,4 Abstract Importance. BRAF V600E mutations are frequently associated with aggressive papillary thyroid carcinomas (PTCs), yet tumors with low allele frequency (AF) are often considered to be indolent. However, exceptions exist, suggesting additional factors may influence tumor behavior. Gene expression alterations (GEA) may help identify tumors with more aggressive molecular phenotypes. Objective. To evaluate whether aggressive clinicopathologic features are associated with GEA positivity in low AF BRAF V600Emutated PTCs. Design. Retrospective cohort study. Setting. Two McGill University Academic Hospitals, 2019 to 2024. Participants. Patients with PTC harboring BRAF V600E (AF ≤ 25%) who underwent preoperative testing. Intervention or Exposure. Low AF BRAF V600E mutation ( ≤25%) characterized using ThyroSeq v3 genomic classifier. Main Outcome Measures. The primary outcome was GEA status. Tumor aggressiveness (defined by extrathyroidal extension, lymph node metastasis, lymphovascular invasion, high-risk histology, or aggressive variants), Bethesda classification, and AF were evaluated as predictors of GEA using logistic regression. Stratified analysis was performed based on AF ( ≤ 10% vs. > 10%). Results. Among 49 patients identified (mean age 49 ± 14 years; 86% female; mean AF 11% ± 8%), 73%(36/49) had aggressive features and 61%(30/49) had GEA-positive tumors. Among GEA-positive tumors, 80%(24/30) were classified as aggressive and had a significantly-higher median AF (16.5%) than GEA-negative tumors (P = .0003). Stratified analysis showed that Bethesda VI nodules significantly predicted GEA positivity in tumors with AF > 10%(P = .03). Conclusion. In low AF BRAF V600E-mutated PTCs, GEA positivity is associated with high-risk cytology, higher AF, and aggressive tumor features. Relevance. GEA may be a useful molecular marker of aggressive tumor biology in low AF PTCs and holds potential as a complementary tool for preoperative risk stratification. Keywords papillary thyroid carcinoma, BRAF V600E mutation, allele frequency, gene expression alterations, head and neck oncology, Thyroseq v3, molecular testing, surgical management Received July 19, 2025; accepted October 28, 2025. Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ([https://creativecommons.org/licenses/by-nc/4.0/](https://creativecommons.org/licenses/by-nc/4.0/)) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ([https://us.sagepub.com/en-us/nam/open-access-at-sage](https://us.sagepub.com/en-us/nam/open-access-at-sage)). Graphical Abstract 1 Faculty of Medicine, Université de Montréal, QC, Canada 2Faculty of Medicine, McGill University, Montreal, QC, Canada 3Department of Otolaryngology-Head and Neck Surgery, McGill University, Royal Victoria Hospital, Montreal, QC, Canada 4Department of Otolaryngology-Head and Neck Surgery, McGill University, Jewish General Hospital, Montreal, QC, Canada 5Department of Pathology, McGill University, Jewish General Hospital, Montreal, QC, Canada Current affi

FAQs

What study question does the paper address?

It evaluates whether aggressive clinicopathologic features are associated with gene expression alterations (GEA) positivity in PTCs harboring low allele frequency BRAF V600E mutations.

How were patients with low allele frequency BRAF V600E selected?

Patients with PTC containing BRAF V600E with allele frequency (AF) ≤ 25% who underwent preoperative testing were included, and the low AF mutation was characterized using ThyroSeq v3.

What factors were found to predict GEA positivity?

Among low AF BRAF V600E–mutated PTCs, GEA-positive tumors showed higher aggressive characteristics and higher median AF; in stratified analysis, Bethesda VI cytology significantly predicted GEA positivity for tumors with AF > 10%.

Sep 30, 2026

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