Clinical Significance of Thyroid-Stimulating Hormone Receptor Gene Mutations and/or Sodium-Iodine Symporter Gene Overexpression in Indeterminate Thyroid Fine Needle Biopsies

Guan, Haixia; Matonis, Danielle; Toraldo, Gianluca; Lee, Stephanie L.

doi:10.3389/fendo.2018.00566

Cited by 13 publications

(36 citation statements)

References 53 publications

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“…NRAS and HRAS variants were primarily observed in Bethesda III/IV FNAs that were GSC Suspicious, while BRAF V600E was predominantly present in Bethesda V/VI FNAs. TSHR and SPOP variants were most frequently observed in GSC Benign FNAs (Figure 3), which is consistent with other observations (11, 40).…”

Section: Resultssupporting

confidence: 92%

Analytical and Clinical Validation of Expressed Variants and Fusions From the Whole Transcriptome of Thyroid FNA Samples

et al. 2019

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Introduction: The Afirma® Xpression Atlas (XA) detects gene variants and fusions in thyroid nodule FNA samples from a curated panel of 511 genes using whole-transcriptome RNA-sequencing. Its intended use is among cytologically indeterminate nodules that are Afirma GSC suspicious, Bethesda V/VI nodules, or known thyroid metastases. Here we report its analytical and clinical validation.Methods: DNA and RNA were purified from the same sample across 943 blinded FNAs and compared by multiple methodologies, including whole-transcriptome RNA-seq, targeted RNA-seq, and targeted DNA-seq. An additional 695 blinded FNAs were used to define performance for fusions between whole-transcriptome RNA-seq and targeted RNA-seq. We quantified the reproducibility of the whole-transcriptome RNA-seq assay across laboratories and reagent lots. Finally, variants and fusions were compared to histopathology results.Results: Of variants detected in DNA at 5 or 20% variant allele frequency, 74 and 88% were also detected by XA, respectively. XA variant detection was 89% when compared to an alternative RNA-based detection method. Low levels of expression of the DNA allele carrying the variant, compared with the wild-type allele, was found in some variants not detected by XA. 82% of gene fusions detected in a targeted RNA fusion assay were detected by XA. Conversely, nearly all variants or fusions detected by XA were confirmed by an alternative method. Analytical validation studies demonstrated high intra-plate reproducibility (89%-94%), inter-plate reproducibility (86–91%), and inter-lab accuracy (90%). Multiple variants and fusions previously described across the spectrum of thyroid cancers were identified by XA, including some with approved or investigational targeted therapies. Among 190 Bethesda III/IV nodules, the sensitivity of XA as a standalone test was 49%.Conclusion: When the Afirma Genomic Sequencing Classifier (GSC) is used first among Bethesda III/IV nodules as a rule-out test, XA supplements genomic insight among those that are GSC suspicious. Our data clinically and analytically validate XA for use among GSC suspicious, or Bethesda V/VI nodules. Genomic information provided by XA may inform clinical decision-making with precision medicine insights across a broad range of FNA sample types encountered in the care of patients with thyroid nodules and thyroid cancer.

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Section: Resultssupporting

confidence: 92%

Analytical and Clinical Validation of Expressed Variants and Fusions From the Whole Transcriptome of Thyroid FNA Samples

et al. 2019

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“…23 Gene-specific, eg, TSHR, cutoffs were detailed previously. 13,15 Statistical Analysis A t test was used for comparison of continuous variables, and a χ 2 chi-square test or Fisher exact test for comparison of categorical variables. A P value of <.05 was considered statistically significant.…”

Section: Molecular Analysismentioning

confidence: 99%

“…Specifically, mutations of thyroid-stimulating hormone receptor (TSHR), guanine nucleotide-binding protein G subunit alpha (GNAS), or enhancer of zeste 1 polycomb repressive complex 2 subunit (EZH1), sometimes with overexpression of solute carrier family 5 member 5 (SLC5A5)/sodium (Na)iodide symporter (NIS) were identified in the majority of AFTNs. [12][13][14][15][16][17] Other genetic differences between oncocytic and nononcocytic thyroid neoplasms have been established. 4 For instance, oncocytic thyroid neoplasms typically lack BRAF V600E mutations and BRAF-like alterations (eg, RET/PTC rearrangements).…”

Section: Introductionmentioning

confidence: 99%

Impact of molecular testing on detecting mimics of oncocytic neoplasms in thyroid fine‐needle aspirates diagnosed as follicular neoplasm of Hürthle cell (oncocytic) type

Landau

Nikiforov

Ohori

et al. 2021

Cancer Cytopathology

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BACKGROUND: Some thyroid nodules cytologically presenting as follicular neoplasm, Hürthle cell (Oncocytic) type (FNHCT), are not oncocytic tumors and represent autonomously functioning thyroid nodules (AFTNs) with TSHR, GNAS, and EZH1 mutations or oncocytic metaplasia. A to be defined subset of FNHCT harbors genome haploidisationtype DNA copy number alterations (GH-CNA). Molecular profiling of FNHCT may distinguish oncocytic neoplasms from its mimics. METHODS: Consecutive fine-needle aspirates of 180 thyroid nodules over 37 months diagnosed as FNHCT and tested by ThyroSeq v3 were identified. Histologic follow-up was available for 79 of 180 nodules (44%). RESULTS:No molecular alterations were found in 76 of 180 nodules (42%), of which 15 were resected (oncocytic metaplasia, n = 7; follicular oncocytic adenoma, n = 8). Of nodules followed without surgery, 17 of 101 (17%) showed TSHR, EZH1, and GNAS mutations of AFTNs. Papillary thyroid carcinoma was identified by BRAF V600E (n = 2) and hyalinizing trabecular adenoma by PAX8-GLIS3 (n = 1). GH-CNA alone was detected in 42 of 180 FNHCT nodules (23%), of which 29 were resected and histologically diagnosed as follicular oncocytic neoplasms. All remaining resected nodules were histologically proven oncocytic neoplasms: 1) RAS-like alterations without GH-CNA (n = 25) and 2) TERT and/or TP53 mutations co-occurring with GH-CNA (n = 6), including anaplastic thyroid carcinoma arising from follicular oncocytic carcinoma with TP53, TERT mutations with GH-CNA (n = 2). CONCLUSIONS: A proportion of FNHCT nodules are AFTNs and oncocytic metaplasias, which can be suspected based on characteristic mutations or lack of alterations on molecular testing. Among resected FNHCTs, GH-CNAs characterize approximately half of histologically confirmed follicular oncocytic neoplasms.

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“…{ One study (32) combined data for patients run on either 7-gene or 14gene panel. { Nodules from certain publications (33)(34)(35)(36)38) were tested by 7-or 14-gene panels but only reported data on a subset of genes, variants, and/or fusions. x One publication (37) analyzed nodules and reported data on two different panels.…”

Section: Inclusion/exclusion Criteriamentioning

confidence: 99%

“…1; Supplementary Table S1; Supplementary Data S2). Some publications involving larger gene panels only reported data on a subset of genes/variants/fusions (e.g., tested samples by full 14-gene panel but only reported on TSHR findings) (33)(34)(35)(36)38), limiting the interpretation of the full panel.…”

Section: Panels Usedmentioning

confidence: 99%

Molecular Variants and Their Risks for Malignancy in Cytologically Indeterminate Thyroid Nodules

Goldner

Angell

McAdoo

et al. 2019

Thyroid

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Background: Gene panels are routinely used to assess predisposition to hereditary cancers by simultaneously testing multiple susceptibility genes and/or variants. More recently, genetic panels have been implemented as part of solid tumor malignancy testing assessing somatic alterations. One example is targeted variant panels for thyroid nodules that are not conclusively malignant or benign upon fine-needle aspiration (FNA). We systematically reviewed published studies from 2009 to 2018 that contained genetic data from preoperative FNA specimens on cytologically indeterminate thyroid nodules (ITNs) that subsequently underwent surgical resection. Pooled prevalence estimates per gene and variant, along with their respective positive predictive values (PPVs) for malignancy, were calculated. Summary: Our systematic search identified 540 studies that were supplemented by 18 studies from bibliographies or personal files. Sixty-one studies met all inclusion criteria and included >4600 ITNs. Overall, 26% of nodules contained at least 1 variant or fusion. However, half of them did not include details on the specific gene, variant, and/or complete fusion pair reported for inclusion toward PPV calculations. The PPVs of genomic alterations reported at least 10 times were limited to BRAF V600E (98%, 95% confidence interval [CI 96-99%]), PAX8/ PPARG (55% [CI 34-78%]), HRAS Q61R (45% [CI 22-72%]), BRAF K601E (42% [CI 19-68%]), and NRAS Q61R (38% [CI 23-55%]). Excluding BRAF V600E , the pooled PPV for all other specified variants and fusions was 47%. Multiple variants within the same nodule were identified in *1% of ITN and carried a cumulative PPV of 77%. Conclusions: The chance that a genomic alteration predicts malignancy depends on the individual variant or fusion detected. Only five alterations were reported at least 10 times; BRAF V600E had a PPV of 98%, while the remaining four had individual PPVs ranging from 38% to 55%. The small sample size of most variants and fusion pairs found among ITNs, however, limits confidence in their individual PPV point estimates. Better specific reporting of genomic alterations with cytological category, histological subtype, and cancer staging would facilitate better understanding of cancer prediction, and the independent contribution of the genomic profile to prognosis.

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Clinical Significance of Thyroid-Stimulating Hormone Receptor Gene Mutations and/or Sodium-Iodine Symporter Gene Overexpression in Indeterminate Thyroid Fine Needle Biopsies

Cited by 13 publications

References 53 publications

Analytical and Clinical Validation of Expressed Variants and Fusions From the Whole Transcriptome of Thyroid FNA Samples

Analytical and Clinical Validation of Expressed Variants and Fusions From the Whole Transcriptome of Thyroid FNA Samples

Impact of molecular testing on detecting mimics of oncocytic neoplasms in thyroid fine‐needle aspirates diagnosed as follicular neoplasm of Hürthle cell (oncocytic) type

Molecular Variants and Their Risks for Malignancy in Cytologically Indeterminate Thyroid Nodules

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