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- Title
Discriminating Interpatient Variabilities of RAS Gene Variants for Precision Detection of Thyroid Cancer.
- Authors
Fu, Guodong; Chazen, Ronald S.; MacMillan, Christina; Witterick, Ian J.
- Abstract
Key Points: Question: Is discrimination of interpatient variabilities of RAS gene variants associated with improved accuracy in malignancy diagnosis among thyroid nodules? Findings: This diagnostic study of 620 patients, including 438 surgically resected thyroid tumor tissues and 249 thyroid nodule fine-needle aspiration biopsies, delineated interpatient differences in RAS variants at the variant allele fraction (VAF) levels, ranging from 0.15% to 51.53%. While RAS variants alone, regardless of the extent of variation, were associated with low-risk thyroid cancer in 88.8% of tumor samples, they did not definitively distinguish malignancy of an unknown tumor; however, detection of interpatient variabilities of RAS, BRAF, and TERT promoter variants in combination could assist in classifying indeterminate thyroid nodules. Meaning: These findings suggest that discrimination of interpatient differences in genomic variants could facilitate precision cancer detection, including preoperative malignancy diagnosis and stratification of low-risk tumors from high-risk ones, among patients with indeterminate thyroid nodules. This diagnostic study assesses interpatient differences in RAS variants and their utility in malignancy detection among patients with thyroid nodules. Importance: Interpatient variabilities in genomic variants may reflect differences in tumor statuses among individuals. Objectives: To delineate interpatient variabilities in RAS variants in thyroid tumors based on the fifth World Health Organization classification of thyroid neoplasms and assess their diagnostic significance in cancer detection among patients with thyroid nodules. Design, Setting, and Participants: This prospective diagnostic study analyzed surgically resected thyroid tumors obtained from February 2016 to April 2022 and residual thyroid fine-needle aspiration (FNA) biopsies obtained from January 2020 to March 2021, at Mount Sinai Hospital, Toronto, Ontario, Canada. Data were analyzed from June 20, 2022, to October 15, 2023. Exposures: Quantitative detection of interpatient disparities of RAS variants (ie, NRAS, HRAS, and KRAS) was performed along with assessment of BRAF V600E and TERT promoter variants (C228T and C250T) by detecting their variant allele fractions (VAFs) using digital polymerase chain reaction assays. Main Outcomes and Measures: Interpatient differences in RAS, BRAF V600E, and TERT promoter variants were analyzed and compared with surgical histopathologic diagnoses. Malignancy rates, sensitivity, specificity, positive predictive values, and negative predictive values were calculated. Results: A total of 438 surgically resected thyroid tumor tissues and 249 thyroid nodule FNA biopsies were obtained from 620 patients (470 [75.8%] female; mean [SD] age, 50.7 [15.9] years). Median (IQR) follow-up for patients who underwent FNA biopsy analysis and subsequent resection was 88 (50-156) days. Of 438 tumors, 89 (20.3%) were identified with the presence of RAS variants, including 51 (11.6%) with NRAS, 29 (6.6%) with HRAS, and 9 (2.1%) with KRAS. The interpatient differences in these variants were discriminated at VAF levels ranging from 0.15% to 51.53%. The mean (SD) VAF of RAS variants exhibited no significant differences among benign nodules (39.2% [11.2%]), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) (25.4% [14.3%]), and malignant neoplasms (33.4% [13.8%]) (P =.28), although their distribution was found in 41.7% of NIFTPs and 50.7% of invasive encapsulated follicular variant papillary thyroid carcinomas (P <.001). RAS variants alone, regardless of a low or high VAF, were significantly associated with neoplasms at low risk of tumor recurrence (60.7% of RAS variants vs 26.9% of samples negative for RAS variants; P <.001). Compared with the sensitivity of 54.2% (95% CI, 48.8%-59.4%) and specificity of 100% (95% CI, 94.8%-100%) for BRAF V600E and TERT promoter variant assays, the inclusion of RAS variants into BRAF and TERT promoter variant assays improved sensitivity to 70.5% (95% CI, 65.4%-75.2%), albeit with a reduction in specificity to 88.8% (95% CI, 79.8%-94.1%) in distinguishing malignant neoplasms from benign and NIFTP tumors. Furthermore, interpatient differences in 5 gene variants (NRAS, HRAS, KRAS, BRAF, and TERT) were discriminated in 54 of 126 indeterminate FNAs (42.9%) and 18 of 76 nondiagnostic FNAs (23.7%), and all tumors with follow-up surgical pathology confirmed malignancy. Conclusions and Relevance: This diagnostic study delineated interpatient differences in RAS variants present in thyroid tumors with a variety of histopathological diagnoses. Discrimination of interpatient variabilities in RAS in combination with BRAF V600E and TERT promoter variants could facilitate cytology examinations in preoperative precision malignancy diagnosis among patients with thyroid nodules.
- Subjects
ONTARIO; PREDICTIVE tests; THYROID gland tumors; GENOMICS; T-test (Statistics); RESEARCH funding; POLYMERASE chain reaction; FISHER exact test; DESCRIPTIVE statistics; CHI-squared test; LONGITUDINAL method; ONCOGENES; ONE-way analysis of variance; GENETIC mutation; CONFIDENCE intervals; DATA analysis software; GENETIC testing; SENSITIVITY &; specificity (Statistics)
- Publication
JAMA Network Open, 2024, Vol 7, Issue 5, pe2411919
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2024.11919