Performance of multigene testing in cytologically indeterminate thyroid nodules and molecular risk stratification

Yuanyuan Zhou; Xinping Wu; Yuzhi Zhang; Zhiqiang Li; Xia Ge; Hao Chen; Yuan Mao; Wenbo Ding

doi:10.7717/peerj.16054

Performance of multigene testing in cytologically indeterminate thyroid nodules and molecular risk stratification

PeerJ. 2023 Sep 18:11:e16054. doi: 10.7717/peerj.16054. eCollection 2023.

Authors

Yuanyuan Zhou¹, Xinping Wu², Yuzhi Zhang², Zhiqiang Li¹, Xia Ge³, Hao Chen¹, Yuan Mao¹, Wenbo Ding²

Affiliations

¹ Genome Center, KingMed Center for Clinical Laboratory Co., Ltd, Hefei, Anhui Province, China.
² Department of Ultrasound, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.
³ Department of Pathological Diagnosis, KingMed Center for Clinical Laboratory Co., Ltd, Hefei, Anhui Province, China.

Abstract

Objective: Thyroid cancer is the third most prevalent cancer among females. Genetic testing based on next-generation sequencing may provide an auxiliary diagnosis to reduce cytologically diagnostic uncertainty. However, commercial multigene tests are not widely available and are not well-tested in the Chinese population.

Methods: In this study, we designed a multigene testing panel and evaluated its performance in 529 cytologically indeterminate thyroid nodules (Bethesda III, IV and V). The molecular data of the DNA mutations and RNA fusions of fine needle aspiration samples were reviewed in conjunction with a clinical diagnosis, pathological reports, and definitive surgery for retrospective analysis. Then, the molecular risk stratification was investigated for its accuracy in malignant risk prediction.

Results: The overall combined consistency revealed substantial agreement (Kappa = 0.726) with the sensitivity, specificity, positive predictive value, and negative predictive values of 97.80%, 82.14%, 98.99%, and 67.65%, respectively. The most common aberration was BRAF^V600E (82.59%), followed by NRAS mutants (4.07%), RET fusions (3.70%), and KRAS mutants (3.15%). Two cases (0.44%) were categorized into a high-risk group, 426 cases (94.67%) were categorized into a BRAF-like group with totally histopathologic papillary patterned tumors, and 22 cases (4.89%) were categorized into a RAS-like group with 14 papillary and eight follicular patterned tumors when the cohort concurrent aberrations were excluded. Potentially aggressive features may be related to concurrent molecular alterations of BRAF^V600E with TERT^Q302R, and AKT1^L52R, NRAS^G12C, NRAS^Q61R, and CCDC6-RET fusions.

Conclusions: This study provided a multigene panel for identifying benign nodules from cytologically indeterminate thyroid nodules to avoid unnecessary surgery. We provide further evidence for using molecular risk stratification as a promising predictor of disease outcomes. The results of this study may be limited by the extremely high prevalence of cancer in the cohort for clinical reference.

Keywords: Indeterminate cytology; Molecular risk stratification; Molecular testing; Next-generation sequencing; Thyroid nodule.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Female
Humans
Proto-Oncogene Proteins B-raf
Retrospective Studies
Risk Assessment
Thyroid Neoplasms* / diagnosis
Thyroid Nodule* / diagnosis

Substances

Proto-Oncogene Proteins B-raf

Grants and funding

This project was funded by the Medical Scientific Research Foundation of Jiangsu Province of China (Grant No. M2020102), the Jiangsu Provincial Key Research and Development Program (Grant No. BE2020726) and the Thyroid Research Project of Young and Middle-Aged Doctors of China International Medical Exchange Foundation (Grant No. BQE-JZX-202115). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.