Combined Mutational and Clonality Analyses Support the Existence of Intra-Tumor Heterogeneity in Papillary Thyroid Cancer.
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ABSTRACT:
SUBMITTER: Muzza M
PROVIDER: S-EPMC8234519 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Papillary thyroid carcinoma (PTC) is the most common adult thyroid malignancy and often presents with multiple anatomically distinct foci within the thyroid, known as multifocal papillary thyroid carcinoma (MPTC). The widespread application of the next-generation sequencing technologies in cancer genomics research provides novel insights into determining the clonal relationship between multiple tumours within the same thyroid gland. For eight MPTC patients, we performed whole-exome sequencing and targeted region sequencing to identify the non-synonymous point mutations and gene rearrangements of distinct and spatially separated tumour foci. Among these eight MPTCs, completely discordant mutational spectra were observed in the distinct cancerous nodules of patients MPTC1 and 5, suggesting that these nodules originated from independent precursors. In another three cases (MPTC2, 6, and 8), the distinct MPTC foci of these patients had no other shared mutations except BRAF V600E, also indicating likely independent origins. Two patients (MPTC3 and 4) shared almost identical mutational spectra amongst their separate tumour nodules, suggesting a common clonal origin. MPTC patient 7 had seven cancer foci, of which two foci shared 66.7% of mutations, while the remaining cancer foci displayed no common non-synonymous mutations, indicating that MPTC7 has multiple independent origins accompanied by intraglandular disease dissemination. In this study, we found that 75% of MPTC cases arose as independent tumours, which supports the field cancerization hypothesis describing multiple malignant lesions. MPTC may also arise from intrathyroidal metastases from a single malignant clone, as well as multiple independent origins accompanied by intrathyroidal metastasis.
| S-EPMC5706659 | biostudies-literature
Project description:Intratumoral heterogeneity (ITH) refers to a subclonal genetic diversity observed within a tumor. ITH is the consequence of genetic instability and accumulation of genetic alterations, two mechanisms involved in the progression from an early tumor stage to a more aggressive cancer. While this process is widely accepted, the ITH of early stage papillary thyroid carcinoma (PTC) is debated. By different genetic analysis, several authors reported the frequent occurrence of PTCs composed of both tumor cells with and without RET/PTC or BRAFV600E genetic alterations. While these data, and the report of discrepancies in the genetic pattern between metastases and the primary tumor, demonstrate the existence of ITH in PTC, its extension and biological significance is debated. The ITH takes on a great significance when involves oncogenes, such as RET rearrangements and BRAFV600E as it calls into question their role of driver genes. ITH is also predicted to play a major clinical role as it could have a significant impact on prognosis and on the response to targeted therapy. In this review, we analyzed several data indicating that ITH is not a marginal event, occurring in PTC at any step of development, and suggesting the existence of unknown genetic or epigenetic alterations that still need to be identified.
| S-EPMC7072350 | biostudies-literature
Project description:BACKGROUND:Whereas 40 % to 70 % of papillary thyroid carcinomas (PTCs) are characterized by a BRAF mutation (BRAFmut), unified biomarkers for the genetically heterogeneous group of BRAF wild type (BRAFwt) PTCs are not established yet. Using state-of-the-art technology we compared RNA expression profiles between conventional BRAFwt and BRAFmut PTCs. METHODS:Microarrays covering 36,079 reference sequences were used to generate whole transcript expression profiles in 11 BRAFwt PTCs including five micro PTCs, 14 BRAFmut PTCs, and 7 normal thyroid specimens. A p-value with a false discovery rate (FDR) < 0.05 and a fold change > 2 were used as a threshold of significance for differential expression. Network and pathway utilities were employed to interpret significance of expression data. BRAF mutational status was established by direct sequencing the hotspot region of exon 15. RESULTS:We identified 237 annotated genes that were significantly differentially expressed between BRAFwt and BRAFmut PTCs. Of these, 110 genes were down- and 127 were upregulated in BRAFwt compared to BRAFmut PTCs. A number of molecules involved in thyroid hormone metabolism including thyroid peroxidase (TPO) were differentially expressed between both groups. Among cancer-associated molecules were ERBB3 that was downregulated and ERBB4 that was upregulated in BRAFwt PTCs. Two microRNAs were significantly differentially expressed of which miR492 bears predicted functions relevant to thyroid-specific molecules. The protein kinase A (PKA) and the G protein-coupled receptor pathways were identified as significantly related signaling cascades to the gene set of 237 genes. Furthermore, a network of interacting molecules was predicted on basis of the differentially expressed gene set. CONCLUSIONS:The expression study focusing on affected genes that are differentially expressed between BRAFwt and BRAFmut conventional PTCs identified a number of molecules which are connected in a network and affect important canonical pathways. The identified gene set adds to our understanding of the tumor biology of BRAFwt and BRAFmut PTCs and contains genes/biomarkers of interest.
| S-EPMC4315163 | biostudies-literature
Project description:BackgroundA growing number of studies have found a close association between thyroid hormones and thyrotrophin (TSH), and they also have prognostic significance in some cancer types; this study aimed to investigate the prognostic value of free triiodothyronine (fT3), free thyroxine (fT4), fT3/fT4, TSH, and their combination in patients with papillary thyroid carcinoma (PTC).MethodsThis study retrospectively analyzed the relevant data of 726 newly diagnosed PTC patients. Both univariate and multivariate analyses were used to predict the recurrence rate, and a risk score was established. In addition, with the use of a random survival forest, a random forest (RF) score was constructed. After calculating the area under the curve (AUC), the diagnostic efficacy of risk score, RF score, and four indicators was compared.ResultsfT3, fT4, fT3/fT4, and TSH were strongly associated with some invasive clinicopathological features and postoperative recurrence. Patients with high expression of fT4 and TSH have a high risk of recurrence. By contrast, patients with high expression of fT3 and fT3/fT4 have a low risk of recurrence. At the same time, the combined use of various indicators is more helpful for establishing an accurate diagnosis. By comparison, we found that the RF score was better than the risk score in terms of predicting the recurrence of PTC.ConclusionThe diagnostic accuracy of a combination of fT3, fT4, fT3/fT4, and TSH can help improve our clinical estimate of the risk of recurrent PTC, thus allowing the development of a more effective treatment plan for patients.
| S-EPMC9279971 | biostudies-literature
Project description:Synchronous parathyroid and papillary thyroid carcinoma are extremely rare. To our knowledge, only 15 cases have been reported in the last four decades. We describe a 50-year-old female without significant past medical or family history and no previous trauma presented with left heel pain that prompted her to seek medical attention. Physical examination was notable for a painless nodule at the left thyroid lobe. Laboratory evaluation showed a serum calcium level of 14.3?mg/dL (8.6-10.3?mg/dL) and intact parathyroid hormone level of 1160?pg/mL (12-88?pg/mL). 99Tc-sestamibi dual-phase with single-photon emission computed tomography fused images showed increased uptake at the left-sided inferior parathyroid gland. Neck ultrasound showed a 1.4?cm heterogeneous nodule in the middle-third of the left thyroid gland and a solitary 1.9?cm vascularized and hypoechoic oval nodule that was considered likely to represent a parathyroid adenoma. Due to its clinical context (severe hypercalcemia and very high levels of PTH), parathyroid carcinoma (PC) was suspected although imaging studies were not characteristic. The patient underwent en bloc resection of the parathyroid mass and left thyroid lobe and central neck compartment dissection. Pathology analysis revealed classical papillary thyroid carcinoma of classical subtype and parathyroid carcinoma. Immunohistochemical staining was positive for cyclidin D1 and negative for parafibromin. High clinical suspicion is required for parathyroid carcinoma diagnosis in the presence of very high level of parathyroid hormone, marked hypercalcemia, and the existence of any thyroid nodule should be approached and the coexistence of other carcinomas should be considered.
| S-EPMC7150727 | biostudies-literature
Project description:Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) to observe the differences in their molecular properties. Mutations in H/K/NRAS, DICER1, EIF1AX, IDH1, PTEN, SOS1, and SPOP were identified in miFTC or FA. We identified a low frequency of fusion genes in miFTC (only one, PAX8-PPARG), but a high frequency of that in PTC (17.60%). The frequencies of BRAFV600E and H/K/NRAS mutations were substantially different in miFTC and cPTC, and those of FVPTC were intermediate between miFTC and cPTC. Gene expression analysis demonstrated three molecular subtypes regardless of their histological features, including Non-BRAF-Non-RAS (NBNR), as well as BRAF-like and RAS-like. The novel molecular subtype, NBNR, was associated with DICER1, EIF1AX, IDH1, PTEN, SOS1, SPOP, and PAX8-PPARG. The transcriptome of miFTC or encapsulated FVPTC was indistinguishable from that of FA, providing a molecular explanation for the similarly indolent behavior of these tumors. We identified upregulation of genes that are related to mitochondrial biogenesis including ESRRA and PPARGC1A in oncocytic follicular thyroid neoplasm. Arm-level copy number variations were correlated to histological and molecular characteristics. These results expanded the current molecular understanding of thyroid cancer and may lead to new diagnostic and therapeutic approaches to the disease.
| S-EPMC4975456 | biostudies-literature
Project description:Standard surgery followed by radioactive iodine (131I, RAI) therapy are not curative for 5−20% of papillary thyroid carcinoma (PTC) patients with RAI refractory disease. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. Whole-exome sequencing was performed (at median depth 198x) on 66 RAI-refractory and 92 RAI-avid PTCs with patient-matched germline. RAI-refractory tumors were significantly associated with distinct aggressive clinicopathological features, including positive surgical margins (p = 0.016) and the presence of lymph node metastases at primary diagnosis (p = 0.012); higher nonsilent tumor mutation burden (p = 0.011); TERT promoter (TERTp) mutation (p < 0.0001); and the enrichment of the APOBEC-related single-base substitution (SBS) COSMIC mutational signatures 2 (p = 0.030) and 13 (p < 0.001). Notably, SBS13 (odds ratio [OR] 30.4, 95% confidence intervals [CI] 1.43−647.22) and TERTp mutation (OR 41.3, 95% CI 4.35−391.60) were revealed to be independent predictors of RAI refractoriness in PTC (p = 0.029 and 0.001, respectively). Although SBS13 and TERTp mutations alone highly predicted RAI refractoriness, when combined, they significantly increased the likelihood of predicting RAI refractoriness in PTC. This study highlights the APOBEC SBS13 mutational signature as a novel independent predictor of RAI refractoriness in a distinct subgroup of PTC.
| S-EPMC8946015 | biostudies-literature
Project description:BackgroundPapillary thyroid carcinoma (PTC) is the most common malignant endocrine tumour, and its incidence and prevalence are increasing considerably. Cellular heterogeneity in the tumour microenvironment is important for PTC prognosis. Spatial transcriptomics is a powerful technique for cellular heterogeneity study.MethodsIn conjunction with a clinical pathologist identification method, spatial transcriptomics was employed to characterise the spatial location and RNA profiles of PTC-associated cells within the tissue sections. The spatial RNA-clinical signature genes for each cell type were extracted and applied to outlining the distribution regions of specific cells on the entire section. The cellular heterogeneity of each cell type was further revealed by ContourPlot analysis, monocle analysis, trajectory analysis, ligand-receptor analysis and Gene Ontology enrichment analysis.ResultsThe spatial distribution region of tumour cells, typical and atypical follicular cells (FCs and AFCs) and immune cells were accurately and comprehensively identified in all five PTC tissue sections. AFCs were identified as a transitional state between FCs and tumour cells, exhibiting a higher resemblance to the latter. Three tumour foci were shared among all patients out of the 13 observed. Notably, tumour foci No. 2 displayed elevated expression levels of genes associated with lower relapse-free survival in PTC patients. We discovered key ligand-receptor interactions, including LAMB3-ITGA2, FN1-ITGA3 and FN1-SDC4, involved in the transition of PTC cells from FCs to AFCs and eventually to tumour cells. High expression of these patterns correlated with reduced relapse-free survival. In the tumour immune microenvironment, reduced interaction between myeloid-derived TGFB1 and TGFBR1 in tumour focus No. 2 contributed to tumourigenesis and increased heterogeneity. The spatial RNA-clinical analysis method developed here revealed prognosis-associated cellular heterogeneity in the PTC microenvironment.ConclusionsThe occurrence of tumour foci No. 2 and three enhanced ligand-receptor interactions in the AFC area/tumour foci reduced the relapse-free survival of PTC patients, potentially leading to improved prognostic strategies and targeted therapies for PTC patients.
| S-EPMC10905537 | biostudies-literature
Project description:BackgroundThe tumor microenvironment (TME) plays a pivotal role in cancer progression in papillary thyroid carcinoma (PTC), yet the composition and the phenotype of cells within the TME in bilateral PTC are poorly understood.MethodsWe performed unbiased transcriptome-wide single-cell RNA sequencing (scRNA-seq) analysis on 29,561 cells from 3 pairs of bilateral PTC and 1 non-tumor thyroid sample. The results of the analysis were validated by a large-scale bulk transcriptomic dataset deposited in The Cancer Genome Atlas (TCGA) database.ResultsOur integrative analysis of thyroid follicular cells revealed 42 signaling pathways enriched in malignant follicular cells, including cytokine-cytokine receptor interaction, PI3K/Akt signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, and tumor necrosis factor (TNF) signaling pathway. A 6-gene signature (CXCL3, CXCL1, IL1A, CCL5, TNFRSF12A, and IL18) in the cytokine-cytokine receptor interaction pathway was constructed to predict the prognosis of patients with PTC, with high risk scores being associated with decreased overall survival [hazard ratio (HR) = 3.863, 95% CI = 2.233-6.682, p < 0.001]. Gene set variation analysis (GSVA) indicated that the pathways enriched in bilateral PTC were significantly different, indicating great heterogeneity in bilateral PTC, even with the same BRAF V600E mutation. Comprehensive analysis of T cells revealed that the proportion of CD8+ tissue-resident memory T cells expressing IFNG decreased in tumor samples with advanced N stage. Within the myeloid compartment, the ratio of suppressive M2-like to pro-inflammatory M1-like macrophages increased with advanced disease stage, which was confirmed in the bulk dataset using transcriptomic profiles. In addition, we also identified numerous biologically critical interactions among myeloid cells, T cells, and follicular cells, which were related to T-cell recruitment, M2-like macrophage polarization, malignant follicular cell progression, and T-cell inhibitory signaling.ConclusionOur integrative analyses revealed great inter-tumor heterogeneity within the TME in bilateral PTC, which will offer assistance for precise diagnosis and treatment.
| S-EPMC9065345 | biostudies-literature
Project description:Label-free proteomics profiling of 37 paired tumor-normal tissues of papillary thyroid cancer
2024-02-08 | PXD044900 | Pride