RAS Mutations, and RET/PTC and PAX8/PPAR-gamma Chromosomal Rearrangements Are Also Prevalent in Benign Thyroid Lesions: Implications Thereof and A Systematic Review

Najafian, Alireza; Noureldine, Salem I.; Azar, Faris; Atallah, Chady; Trinh, Gina; Schneider, Eric B.; Tufano, Ralph P.; Zeiger, Martha A.

doi:10.1089/thy.2016.0348

Cited by 35 publications

(42 citation statements)

References 80 publications

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“…Despite the high specificity of BRAFV600E and RET/PTC as markers of malignancy, 13 the clinical usefulness of the 7-gene test we used is limited by the low specificity and low positive predictive value of RAS and RAS-like mutations (PAX8/PPARg and BRAFK601E) because these mutations are also detected in such benign thyroid nodules as follicular adenomas. [14][15][16] In addition, the indolent encapsulated PTC follicular variant recently reclassified as a low-risk neoplasm (noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP]) accounts for a large proportion of RAS-mutated nodules. 17 However, it remains to be established whether mutation-positive adenomas and NIFTP are follicular-patterned in situ carcinomas and should be considered as true-positives in the evaluation of the positive predictive value of the 7-gene test.…”

Section: Discussionmentioning

confidence: 99%

Different qualifiers of AUS/FLUS thyroid FNA have distinct BRAF, RAS, RET/PTC, and PAX8/PPARg alterations

Bellevicine¹,

Sgariglia²,

Migliatico³

et al. 2018

Cancer Cytopathology

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Section: Discussionmentioning

confidence: 99%

Different qualifiers of AUS/FLUS thyroid FNA have distinct BRAF, RAS, RET/PTC, and PAX8/PPARg alterations

Bellevicine¹,

Sgariglia²,

Migliatico³

et al. 2018

Cancer Cytopathology

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“…Early studies with the 7‐gene mutation panel indicated that rat sarcoma (RAS) (a family of small guanosine triphosphate hydrolases) mutations were most common but were not highly specific for thyroid cancer, thereby limiting the PPV of the test. Recent studies have demonstrated that RAS mutations also can be identified in up to 48% of benign nodules; therefore, the type of RAS mutation and the degree of allelic frequency can be used to guide decision‐making . Similarly, many thyroid nodules with RAS and PAX8/PPARγ mutations are the histologically noninvasive encapsulated follicular variant of PTC, now reclassified as NIFTP .…”

Section: The Development Of Thyroid Molecular Testingmentioning

confidence: 99%

“…However, BRAF mutation does not appear to improve prognosis or direct treatment beyond traditional TNM classifications, and the independent use of BRAF would incorrectly upstage the majority of indolent behaving, lower stage classical PTCs. Furthermore, it has been demonstrated that certain RAS mutations have a higher likelihood of distant metastasis and increased mortality compared with BRAF mutations, but RAS mutations can also be identified in benign follicular adenomas and in the noninvasive encapsulated follicular variant of PTCs (NIFTP), now reclassified as a premalignant tumor . Two molecular markers that appear to confer an increased risk of tumor recurrence and tumor‐related mortality are tumor protein 53 (TP53) and telomerase reverse transcriptase (TERT) mutations.…”

Section: Comprehensive Tests To Improve Overall Accuracymentioning

confidence: 99%

“…Recent studies have demonstrated that RAS mutations also can be identified in up to 48% of benign nodules; therefore, the type of RAS mutation and the degree of allelic frequency can be used to guide decision-making. 24 Similarly, many thyroid nodules with RAS and PAX8/ PPARc mutations are the histologically noninvasive encapsulated follicular variant of PTC, 10 now reclassified as NIFTP. 9 The definition of NIFTP was only recently published and reclassified to highlight the limited malignant potential of these precancerous lesions.…”

Section: A "Rule-in" Test: Gene Mutation Panelmentioning

confidence: 99%

“…Furthermore, it has been demonstrated that certain RAS mutations have a higher likelihood of distant metastasis and increased mortality compared with BRAF mutations, but RAS mutations can also be identified in benign follicular adenomas and in the noninvasive encapsulated follicular variant of PTCs (NIFTP), now reclassified as a premalignant tumor. 24 Two molecular markers that appear to confer an increased risk of tumor recurrence and tumor-related mortality are tumor protein 53 (TP53) and telomerase reverse transcriptase (TERT) mutations. TP53 mutations are late events in tumor clone progression and have been known to occur mostly in poorly differentiated and anaplastic thyroid cancers, often deriving from well differentiated PTCs.…”

Section: Thyroseq Ngs Assaymentioning

confidence: 99%

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Molecular testing for thyroid nodules: Review and current state

Roth

Witt

Steward

2017

Cancer

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Thyroid nodules affect nearly two-thirds of the world population. Fine-needle biopsy with cytologic evaluation remains the diagnostic test of choice to distinguish benign from malignant thyroid nodules yet fails to discriminate as benign or malignant in up to one-third of cases. This review discusses the limitation of current cytopathologic evaluation, the development of thyroid molecular testing, and the strengths and limitations of commercially available tests. Initial cytomolecular testing sought to identify specific gene mutations associated with thyroid cancer. Although the presence of a mutation was strongly associated with cancer, the likelihood of identifying a mutation was low; therefore, the test had low sensitivity. Subsequent tests developed have sought to improve the accuracy of cytomolecular testing for thyroid fine-needle aspirations, both to reassure patients and providers when malignancy may be absent and to confirm the malignancy when present. The development of cytomolecular testing for thyroid nodules has informed and improved current understanding of thyroid nodule formation and progression. When used appropriately and with clear understanding of the advantages and disadvantages, cytomolecular testing has the potential to improve patient care in the setting of indeterminate thyroid nodules by helping to guide both the need for and the extent of thyroid surgery. Cancer 2018;124:888-98. © 2017 American Cancer Society.

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Discriminating Interpatient Variabilities of RAS Gene Variants for Precision Detection of Thyroid Cancer

Fu,

Chazen,

MacMillan

et al. 2024

JAMA Netw Open

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ImportanceInterpatient variabilities in genomic variants may reflect differences in tumor statuses among individuals.ObjectivesTo 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 ParticipantsThis 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.ExposuresQuantitative 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 MeasuresInterpatient 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.ResultsA 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 &lt; .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 &lt; .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 RelevanceThis 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.

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RAS Mutations, and RET/PTC and PAX8/PPAR-gamma Chromosomal Rearrangements Are Also Prevalent in Benign Thyroid Lesions: Implications Thereof and A Systematic Review

Cited by 35 publications

References 80 publications

Different qualifiers of AUS/FLUS thyroid FNA have distinct BRAF, RAS, RET/PTC, and PAX8/PPARg alterations

Different qualifiers of AUS/FLUS thyroid FNA have distinct BRAF, RAS, RET/PTC, and PAX8/PPARg alterations

Molecular testing for thyroid nodules: Review and current state

Discriminating Interpatient Variabilities of RAS Gene Variants for Precision Detection of Thyroid Cancer

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