The Profile of Genetic Mutations in Papillary Thyroid Cancer Detected by Whole Exome Sequencing

Fang, Yi; Ma, Xiao; Zeng, Jing; Jin, Yu; Hu, Yong; Wang, Jinjing; Liu, Ran; Cao, Chunmei

doi:10.1159/000493966

Cited by 12 publications

(5 citation statements)

References 38 publications

(38 reference statements)

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“…The driver gene list includes the genes in the COSMIC cancer gene census (v.87), genes identified in TCGA with q < 0.05 and previous large-scale studies. 36,[47][48][49][50][51] Any variant present in these genes underwent classification based on the following criteria. If the gene was classified as tumor suppressor by COSMIC and the variant was found to be deleterious (stop-gain or predicted deleterious in two of the three computational tools-Sift, PolyPhen, and MutationTaster), the specific variant was classified as a driver.…”

Section: Driver Mutation Classificationmentioning

confidence: 99%

Evolution and Impact of Subclonal Mutations in Papillary Thyroid Cancer

Masoodi

Siraj

et al. 2019

The American Journal of Human Genetics

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Unlike many cancers, the pattern of tumor evolution in papillary thyroid cancer (PTC) and its potential role in relapse have not been elucidated. In this study, multi-region whole-exome sequencing (WES) was performed on early-stage PTC tumors (n ¼ 257 tumor regions) from 79 individuals, including 17 who had developed relapse, to understand the temporal and spatial framework within which subclonal mutations catalyze tumor evolution and its potential clinical relevance. Paired primary-relapse tumor tissues were also available for a subset of individuals. The resulting catalog of variants was analyzed to explore evolutionary histories, define clonal and subclonal events, and assess the relationship between intra-tumor heterogeneity and relapse-free survival. The multi-region WES approach was key in correctly classifying subclonal mutations, 40% of which would have otherwise been erroneously considered clonal. We observed both linear and branching evolution patterns in our PTC cohort. A higher burden of subclonal mutations was significantly associated with increased risk of relapse. We conclude that relapse in PTC, while generally rare, does not follow a predictable evolutionary path and that subclonal mutation burden may serve as a prognostic factor. Larger studies utilizing multi-region sequencing in relapsed PTC case subjects with matching primary tissues are needed to confirm these observations.

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Section: Driver Mutation Classificationmentioning

confidence: 99%

Evolution and Impact of Subclonal Mutations in Papillary Thyroid Cancer

Masoodi

Siraj

et al. 2019

The American Journal of Human Genetics

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“…[ 22 , 23 ] Fang et al . [ 6 ] reported that T:A>C:G was observed in nearly one-half of their subjects with papillary thyroid cancer (PTC), whereas the C>T/G>A substitution was the most common pattern in somatic mutations as shown by WES results for PTC. [ 25 ]…”

Section: Discussionmentioning

confidence: 99%

Profile of genetic variations in severely calcified carotid plaques by whole-exome sequencing

Katano

Nishikawa

Yamada

et al. 2020

Surgical Neurology International

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Background: The precise mechanisms of carotid calcification and its clinical significance have not been established. Methods: We classified ten plaques from carotid endarterectomy patients into high- and low-calcified plaques based on the Agatston calcium scores. We performed whole-exome sequencing for genetic profiles with single nucleotide variations (SNVs), insertions, and deletions. Bioinformatic data mining was then conducted to disclose specific gene variations to either high- or low-calcified carotid plaques. Results: In the carotid plaques, G:C>A:T/C:G>T:A transitions as SNVs, insT after C/insC after A as insertions, and delA after G/delT after C as deletions were most frequently observed, but no significant difference was observed between the high- and low-calcified plaque groups in their proportion of base-pair substitution types. In the bioinformatic analysis, SNVs of ATP binding cassette subfamily C member 6 (ADCC6) were more commonly found in high-calcified plaques and SNVs of KLKB1 were more commonly found in low-calcified plaques compared to the other group. No new genetic variants related to calcification or atherosclerosis among those not registered in dbSNP was detected. Conclusion: Our findings clarified the features of base-pair substitutions in carotid plaques, showing no relation to calcification. However, genetic variants in ADCC6 relating to vascular calcification for high-calcified plaques, and in KLKB1 encoding kallikrein associated with vascular regulation of atherosclerosis for low-calcified plaques were more specifically extracted. These results contribute to a better understanding of the genetic basis of molecular activity and calcium formation in carotid plaques.

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“…WES is one of the NGS platforms that can detect variations in the protein-coding area of genes (exons), which account for approximately 3.09% of the whole genome (12). Its function and application to detect disease-causing mutations have been previously demonstrated in papillary thyroid cancer cases (13)(14)(15)(16) and other clinical studies (17,18).…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing and bioinformatic analyses revealed differences in gene mutation profiles in papillary thyroid cancer patients with and without benign thyroid goitre background

Eng

Abdullah

et al. 2023

Front. Endocrinol.

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BackgroundPapillary thyroid cancer (PTC) is the most common thyroid malignancy. Concurrent presence of cytomorphological benign thyroid goitre (BTG) and PTC lesion is often detected. Aberrant protein profiles were previously reported in patients with and without BTG cytomorphological background. This study aimed to evaluate gene mutation profiles to further understand the molecular mechanism underlying BTG, PTC without BTG background and PTC with BTG background.MethodsPatients were grouped according to the histopathological examination results: (i) BTG patients (n = 9), (ii) PTC patients without BTG background (PTCa, n = 8), and (iii) PTC patients with BTG background (PTCb, n = 5). Whole-exome sequencing (WES) was performed on genomic DNA extracted from thyroid tissue specimens. Nonsynonymous and splice-site variants with MAF of ≤ 1% in the 1000 Genomes Project were subjected to principal component analysis (PCA). PTC-specific SNVs were filtered against OncoKB and COSMIC while novel SNVs were screened through dbSNP and COSMIC databases. Functional impacts of the SNVs were predicted using PolyPhen-2 and SIFT. Protein-protein interaction (PPI) enrichment of the tumour-related genes was analysed using Metascape and MCODE algorithm.ResultsPCA plots showed distinctive SNV profiles among the three groups. OncoKB and COSMIC database screening identified 36 tumour-related genes including BRCA2 and FANCD2 in all groups. BRAF and 19 additional genes were found only in PTCa and PTCb. “Pathways in cancer”, “DNA repair” and “Fanconi anaemia pathway” were among the top networks shared by all groups. However, signalling pathways related to tyrosine kinases were the most significantly enriched in PTCa while “Jak-STAT signalling pathway” and “Notch signalling pathway” were the only significantly enriched in PTCb. Ten SNVs were PTC-specific of which two were novel; DCTN1 c.2786C>G (p.Ala929Gly) and TRRAP c.8735G>C (p.Ser2912Thr). Four out of the ten SNVs were unique to PTCa.ConclusionDistinctive gene mutation patterns detected in this study corroborated the previous protein profile findings. We hypothesised that the PTCa and PTCb subtypes differed in the underlying molecular mechanisms involving tyrosine kinase, Jak-STAT and Notch signalling pathways. The potential applications of the SNVs in differentiating the benign from the PTC subtypes requires further validation in a larger sample size.

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The Profile of Genetic Mutations in Papillary Thyroid Cancer Detected by Whole Exome Sequencing

Cited by 12 publications

References 38 publications

Evolution and Impact of Subclonal Mutations in Papillary Thyroid Cancer

Evolution and Impact of Subclonal Mutations in Papillary Thyroid Cancer

Profile of genetic variations in severely calcified carotid plaques by whole-exome sequencing

Whole-exome sequencing and bioinformatic analyses revealed differences in gene mutation profiles in papillary thyroid cancer patients with and without benign thyroid goitre background

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