scholarly journals Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers

2022 ◽  
Author(s):  
Aime T. Franco ◽  
Julio C. Ricarte-Filho ◽  
Amber Isaza ◽  
Zachary Jones ◽  
Neil Jain ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Molecular Subtype ◽  
Initial Therapy ◽  
Response To Therapy ◽  
The Cancer Genome Atlas ◽  
Clinical Behavior ◽  
Subtype Classification ◽  
Pathologic Classification ◽  
Metastatic Capacity ◽  
Braf Mutant

PURPOSE In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathologic classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer (DTC) and investigate whether mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. METHODS Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant ( H-K-NRAS), BRAF-mutant ( BRAF p.V600E), and RET/ NTRK fusion ( RET, NTRK1, and NTRK3 fusions) to determine differences between subtype classification in regard to pathologic data (American Joint Committee on Cancer TNM) as well as response to therapy 1 year after initial treatment had been completed. RESULTS Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1 year. Patients with RET/ NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at 1 year than patients within RAS- or BRAF-mut subgroups. CONCLUSION Our data support that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathologic classification with patients with RET/ NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.

scholarly journals Fusion-oncogenes are associated with increased metastatic capacity and persistent disease in pediatric thyroid cancers

2021 ◽  
Author(s):  
Aime T. Franco ◽  
Julio C. Ricarte-Filho ◽  
Amber Isaza ◽  
Zachary Jones ◽  
Neil Jain ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Molecular Subtype ◽  
Initial Therapy ◽  
Response To Therapy ◽  
The Cancer Genome Atlas ◽  
Clinical Behavior ◽  
Pathological Classification ◽  
Subtype Classification ◽  
One Year ◽  
Braf Mutant

Background: In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathological classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer and investigate if mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. Methods: Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant (H-K-NRAS), BRAF-mutant (BRAF p.V600E) and RET/NTRK fusion (RET, NTRK1 and NTRK3 fusions) to determine differences between subtype classification in regard to pathological data (AJCC TNM) as well as response to therapy 1-year after initial treatment had been completed. Results: Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1-year. Patients with RET/NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at one year than patients within RAS- or BRAF-mut subgroups. Conclusions: Our data supports that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathological classification with patients with RET/NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.

ISTHMUS TOPOGRAPHY IS A RISK FACTOR FOR PERSISTENT DISEASE IN PATIENTS WITH DIFFERENTIATED THYROID CANCER

2021 ◽  
Author(s):  
Alfredo Campennì ◽  
Rosaria Maddalena Ruggeri ◽  
Massimiliano Siracusa ◽  
Giulia Giacoppo ◽  
Flavia La Torre ◽  
...  
Keyword(s):  
Risk Factor ◽  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Disease Free Survival ◽  
Initial Therapy ◽  
Response To Therapy ◽  
Rank Test ◽  
Additional Risk Factor ◽  
Persistent Disease ◽  
Incomplete Response

Aim: The risk of differentiated thyroid cancer (DTC) recurrence is widely evaluated according to the 2015 ATA Risk Stratification System. Topography of malignant nodules has been previously reported as an additional risk factor but is not included in the ATA system. Thus, our study aimed to evaluate the relationship between DTC topography and response to initial therapy. Patients and Methods: We enrolled 401 low- to intermediate-risk patients with DTC who had undergone thyroidectomy and radioiodine therapy. DTC topography was recorded and compared with the response to therapy as assessed 12 months after end of therapy. Results: Overall, 366/401 (91.3%) patients had an excellent response to initial therapy while 22/401 (5.5%) and 13/401 (3.2%) had incomplete biochemical or structural response, respectively. Incomplete response occurred in 10/36 (27.8%), 5/125 (4.0%), and 4/111 (3.6%) patients whose unifocal malignant nodules were located in the isthmus, right lobe, or left lobe. Incomplete response was also observed in 4/54 (7.4%) and 12/75 (16%) patients carrying multifocal cancers in one or both lobes, respectively. Patients with isthmic cancer more frequently demonstrated incomplete response compared with those who had cancer in other locations (p=0.00). No significant relationship was found with age, gender, maximum size of malignant nodule, Hashimoto’s thyroiditis, vascular invasion, and extrathyroidal extension (p=0.78, p=0.77, p=0.52, p=0.19, p=0.73, and p=0.26, respectively). The risk of incomplete response was about 65% higher in patients with isthmic lesions compared with other patients (odds ratio=6.725). A log-rank test demonstrated that disease-free survival (DFS) of patients with isthmic lesions was significantly shorter than that of other patients (p=0.02). Conclusion: Our data show that isthmus topography of malignant thyroid nodules is a risk factor for having both persistent disease 12 months after primary treatment and reduced DFS.

scholarly journals Is Male Sex A Prognostic Factor in Papillary Thyroid Cancer?

2021 ◽  
Vol 10 (11) ◽  
pp. 2438
Author(s):  
Aleksandra Gajowiec ◽  
Anna Chromik ◽  
Kinga Furga ◽  
Alicja Skuza ◽  
Danuta Gąsior-Perczak ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Predictive Factor ◽  
Disease Status ◽  
Initial Therapy ◽  
Clinicopathological Features ◽  
Response To Therapy ◽  
Papillary Thyroid ◽  
Male Sex

Identifying risk factors is crucial for predicting papillary thyroid cancer (PTC) with severe course, which causes a clinical problem. The purpose of this study was to assess whether male sex can be such a predictive factor and to verify whether including it as a predictive factor of high initial risk of recurrence/persistence would help to enhance the value of the American Thyroid Association initial risk stratification system (ATA). We retrospectively analyzed 1547 PTC patients (1358 females and 189 males), treated from 1986 to 2018. The relationship between sex and clinicopathological features, response to therapy, and disease status was assessed. Men with PTC showed some adverse clinicopathological features more often than women, including angioinvasion, lymph node metastases, and tumor size > 40 mm. There were sex-related disparities with respect to response to initial therapy and final follow-up. Male sex is associated with some unfavorable clinicopathological features of PTC, which may affect response to initial therapy or final disease status. In our study, modification of the ATA system by including male sex as a risk factor does not enhance its value. Thus, further studies are needed to assess whether males require treatment modalities or oncological follow-up protocols that are different from those of females.

Characterization of Subtypes of BRAF-Mutant Papillary Thyroid Cancer Defined by Their Thyroid Differentiation Score

2021 ◽  
Author(s):  
Laura Boucai ◽  
Venkatraman Seshan ◽  
Michelle Williams ◽  
Jeffrey A Knauf ◽  
Mahesh Saqcena ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Transforming Growth Factor ◽  
Clinical Stage ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Molecular Characteristics ◽  
Papillary Thyroid ◽  
Smad Pathway ◽  
Braf Mutant

Abstract Context The BRAFV600E mutation has been associated with more advanced clinical stage in papillary thyroid cancer (PTC) and decreased responsiveness to radioiodine (RAI). However, some BRAF mutant PTCs respond to RAI and have an indolent clinical behavior suggesting the presence of different subtypes of BRAF mutant tumors with distinct prognosis. Objective To characterize the molecular and clinical features of 2 subtypes of BRAF-mutant PTCs defined by their degree of expression of iodine metabolism genes. Design 227 BRAF-mutant PTCs from the Cancer Genome Atlas Thyroid Cancer study were divided into 2 subgroups based on their thyroid differentiation score (TDS): BRAF-TDShi and BRAF-TDSlo. Demographic, clinico-pathological, and molecular characteristics of the 2 subgroups were compared. Results Compared to BRAF-TDShi tumors (17%), BRAF-TDSlo tumors (83%) were more frequent in blacks and Hispanics (6% vs 0%, P = 0.035 and 12% vs 0%, P = 0.05, respectively), they were larger (2.95 ± 1.7 vs 2.03 ± 1.5, P = 0.002), with more tumor-involved lymph nodes (3.9 ± 5.8 vs 2.0 ± 4.2, P = 0.042), and a higher frequency of distant metastases (3% vs 0%, P = 0.043). Gene set enrichment analysis showed positive enrichment for RAS signatures in the BRAF-TDShi cohort, with corresponding reciprocal changes in the BRAF-TDSlo group. Several microRNAs (miRs) targeting nodes in the transforming growth factor β (TGFβ)-SMAD pathway, miR-204, miR-205, and miR-144, were overexpressed in the BRAF-TDShi group. In the subset with follow-up data, BRAF-TDShi tumors had higher complete responses to therapy (94% vs 57%, P < 0.01) than BRAF-TDSlo tumors. Conclusion Enrichment for RAS signatures, key genes involved in cell polarity and specific miRs targeting the TGFβ-SMAD pathway define 2 subtypes of BRAF-mutant PTCs with distinct clinical characteristics and prognosis.

scholarly journals CSIG-03. RECONCILING TUMOR HETEROGENEITY IN GLIOBLASTOMA USING A PATHWAY-BASED APPROACH

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii28-ii28
Author(s):  
Alvaro Alvarado ◽  
Kaleab Tessema ◽  
Kunal Patel ◽  
Riki Kawaguchi ◽  
Richard Everson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Patient Survival ◽  
Molecular Subtype ◽  
Gene List ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Molecular Architecture ◽  
Survival Pathways ◽  
Cancer Genome Atlas

Abstract Despite efforts to gain a deeper understanding of its molecular architecture, glioblastoma (GBM) remains uniformly fatal. While genome-based molecular subtyping has revealed that GBMs may be parsed into several molecularly distinct categories, this insight has yielded little progress towards extending patient survival. In particular, the great phenotypic heterogeneity of GBM – both inter and intratumorally – has hindered therapeutic efforts. To this end, we interrogated tumor samples using a pathway-based approach to resolve tumoral heterogeneity. Gene set enrichment analysis (GSEA) was applied to gene expression data and used to provide an overview of each sample that can be compared to other samples by generating sample clusters based on overall patterns of enrichment. The Cancer Genome Atlas (TCGA) samples were clustered using the canonical and oncogenic signatures and in both cases the clustering was distinct from the molecular subtype previously reported and clusters were informative of patient survival. We also analyzed single cell RNA sequencing datasets and uniformly found two clusters of cells enriched for cell cycle regulation and survival pathways. We have validated our approach by generating gene lists from common elements found in the top contributing genesets for a particular cluster and testing the top targets in appropriate gliomasphere patient-derived lines. Samples enriched for cell cycle related genesets showed a decrease in sphere formation capacity when E2F1, out top target, was silenced and when treated with fulvestrant and calcitriol, which were identified as potential drugs targeting this genelist. Conversely, no changes were observed in samples not enriched for this gene list. Finally, we interrogated spatial heterogeneity and found higher enrichment of the proliferative signature in contrast enhancing compared with non-enhancing regions. Our studies relate inter- and intratumoral heterogeneity to critical cellular pathways dysregulated in GBM, with the ultimate goal of establishing a pipeline for patient- and tumor-specific precision medicine.

scholarly journals Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

2014 ◽  
Vol 21 (6) ◽  
pp. 891-902 ◽  
Author(s):  
Min-Hee Kim ◽  
Ja Seong Bae ◽  
Dong-Jun Lim ◽  
Hyoungnam Lee ◽  
So Ra Jeon ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Progression ◽  
Tumour Size ◽  
External Validation ◽  
Allelic Frequency ◽  
The Cancer Genome Atlas ◽  
Braf V600e ◽  
Validation Dataset ◽  
Papillary Thyroid ◽  
Additional Information

The BRAF V600E mutation is the most common genetic alteration in thyroid cancer. However, its clinicopathological significance and clonal mutation frequency remain unclear. To clarify the inconsistent results, we investigated the association between the allelic frequency of BRAF V600E and the clinicopathological features of classic papillary thyroid carcinoma (PTC). Tumour tissues from two independent sets of patients with classic PTC were manually microdissected and analysed for the presence or absence of the BRAF mutation and the mutant allelic frequency using quantitative pyrosequencing. For external validation, the Cancer Genome Atlas (TCGA) data were analysed. The BRAF V600E mutation was found in 264 (82.2%) out of 321 classic PTCs in the training set. The presence of BRAF V600E was only associated with extrathyroidal extension and the absence of thyroiditis. In BRAF V600E-positive tumours, the mutant allelic frequency varied from 8 to 41% of the total BRAF alleles (median, 20%) and directly correlated with tumour size and the number of metastatic lymph nodes. Lymph node metastases were more frequent in PTCs with a high (≥20%) abundance of mutant alleles than in those with a low abundance of mutant alleles (P=0.010). These results were reinforced by validation dataset (n=348) analysis but were not reproduced in the TCGA dataset. In a population with prevalent BRAF mutations, quantitative analysis of the BRAF mutation could provide additional information regarding tumour behaviour, which is not reflected by qualitative analysis. Nonetheless, prospective studies are needed before the mutated allele percentage can be considered as a prognostic factor.

Phospholipase C Delta 3 inhibits apoptosis and promotes proliferation, migration, and invasion of thyroid cancer cells via Hippo pathway

2021 ◽  
Vol 53 (4) ◽  
pp. 481-491
Author(s):  
Lizhi Lin ◽  
Jialiang Wen ◽  
Bangyi Lin ◽  
Hao Chen ◽  
Adheesh Bhandari ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phospholipase C ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Hippo Pathway ◽  
Suppressive Effect ◽  
The Cancer Genome Atlas ◽  
Disease Stage ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Abstract In recent decades, the incidence of thyroid cancer (TC) has rapidly increased, leading us to explore the complex underlying mechanisms. We identified the gene Phospholipase C Delta 3 (PLCD3) as a potential oncogene in TC by conducting the whole transcriptome sequencing. Our study is to understand the oncogenic role of PLCD3 in TC. We verified the overexpression of PLCD3 in TC from The Cancer Genome Atlas, Gene Expression Omnibus databases, and a locally validated cohort. Clinical correlation analysis showed that PLCD3 expression was related to histological type, T stage, lymph node metastasis (LNM), and disease stage. The high expression of PLCD3 could be a distinguishing factor for TC and its LNM. The biological function was examined using small interfering RNA-transfected TC cell lines. Silenced PLCD3 could inhibit colony formation, migration, and invasion ability and promote apoptosis of TC cell lines. PLCD3 silencing reversed the epithelial-mesenchymal transition but induced the apoptotic progress. Further exploration revealed that PLCD3 might be associated with critical genes of the Hippo pathway. The expressions of RHOA, YAP1/TAZ, and their downstream targets were decreased significantly when PLCD3 was down-regulated. YAP1 overexpression rescued the tumor-suppressive effect caused by PLCD3 silencing. This study demonstrates that PLCD3 is an oncogene that supports tumorigenesis and progression in TC, and PLCD3 may be a potential target gene for TC treatment.

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