Error-prone DNA polymerase and oxidative stress increase the incidences of A to G mutations in tumors.
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ABSTRACT:
SUBMITTER: Lin J
PROVIDER: S-EPMC5542174 | BioStudies | 2017-01-01
REPOSITORIES: biostudies
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Project description:Follicular cell-derived thyroid cancers are heterogenous and morphological classification is a complex and highly specialized task. Hence, identification of somatic alterations could provide insights to tumor biology and serve as an add-on diagnostic tool. Furthermore, results from these add-on tools could point in the direction of a more personalized treatment strategy. In the present study we set out to identify and validate the somatic mutation profile in a sample-set of follicular cell-derived thyroid neoplasia. One-hundred-and-one archived formalin fixed paraffin embedded (FFPE) tissue samples from patients diagnosed with follicular cell-derived thyroid neoplasia were included, and upon DNA-extraction and qualitative measurements 99 samples were eligible for amplicon-based next-generation-sequencing. Libraries were generated using the TruSeq Amplicon Cancer Panel, followed by sequencing using a MiSeq. Upon data processing and variant filtering all variants were manually assessed to exclude false positive mutations in the final curated list. Moreover, hot-spot mutations were validated using an independent platform from Agilent. Each diagnostic group were correlated to mutation burden and individual mutations were classified according to recent guidelines for somatic mutation classification. Close to 100% of the archived FFPE samples were eligible for DNA-library preparation and amplicon sequencing based on DNA quality criterion. The distribution of mutations in the specific diagnostic groups resulted in a higher mutation frequency among the most dedifferentiated than in the groups with a more differentiated cell profile. Based on the distribution mutations across the samples and using hierarchical clustering, we generated four tentative mutational signatures; highly mutated tumors; tumors with mainly NRAS and TP53 mutations; BRAF mutated tumors and tumors with none or single sporadic mutations. Future studies including more samples and follow-up data may amend these signatures, however our results imply that morphological classification of follicular cell derived thyroid neoplasia could be supplemented with a somatic mutational signature. Taken together, broad screening of the somatic alterations in FFPE tissue of thyroid neoplasia is comprehensible and essential for future identification of possible treatment targets and personalized medicine.
2020-01-01 | S-EPMC7105679 | BioStudies
Project description:The aim of our investigation was to evaluate the clinicopathological characteristics and mutation patterns in newly diagnosed cases of thyroid cancer in the federal state of Salzburg, Austria, in the year 2013.The medical records of all patients newly diagnosed with thyroid cancer in 2013 in the federal state of Salzburg were retrospectively reviewed. The clinicopathological characteristics and mutations of thyroid cancers were analyzed.63 patients (mean age: 51.0 years, range: 21-81 years; female 75%, male 25%) were identified. 53 patients had papillary (12 follicular variant), 4 patients follicular (1 oxyphilic variant), 3 patients medullary, and 3 patients anaplastic thyroid cancer. T1 tumors were found in 34 patients (pT1a, 20 patients; pT1b, 14 patients), T2 tumors in 10 patients, T3 tumors in 16 patients, and T4 tumors in 3 patients. Lymph node involvement was seen in 15 patients and metastatic disease in 1 patient. Mutations of BRAF (B-type Raf kinase) were detected in 23 and mutation of NRAS (Neuroblastoma RAS Viral Oncogene Homolog) in 2 papillary thyroid cancers. No concomitant mutations of BRAF and NRAS were found.Females accounted for 75% of the patients with newly diagnosed thyroid cancer and the incidence peaked at a younger age than in males. Papillary thyroid cancer was the most frequent tumor type, accounting for 84% of the cases. A high frequency of T1 tumors and cancers with no lymph node involvement was found. Males had a higher proportion of large tumors and more aggressive forms of thyroid cancer than females. Mutations (mostly of BRAF) were found in 47% of the cases. Neither mutations of KRAS (Kirsten rat sarcoma viral oncogene homologue) nor concomitant mutations of BRAF and NRAS were found.
2017-01-01 | S-EPMC5552837 | BioStudies
Project description:Whole exome sequencing (WES) recently identified frequent mutations in the genes of GPCR-mediated PI3K pathway (LPAR4, PIK3CA, and PTEN) in a Chinese population with papillary thyroid cancers (PTCs). The study found LPAR4 mutations as novel gene mutations in adult population with differentiated thyroid cancer (DTC). Here, we determine the prevalence of somatic mutations in this pathway (LPAR4 (exon 1), PIK3CA (exons 9 and 20) and PTEN (exons 5, 6, 7 and 8) in 323 thyroid samples consisting of 17 multinodular goiters (MNG), 89 pediatric DTCs, 204 adult DTCs, and 13 aggressive thyroid cancers including 10 poorly differentiated (PDTC) and 3 anaplastic thyroid cancer (ATC) from another ethnic population. We found 3.37% and 2.45% (includes Q214H, a novel PTEN mutation) in GPCR-mediated PI3K pathway of pediatric and adult DTCs, respectively. Analyses of 507 DTCs from thyroid Cancer Genome Atlas data (TCGA) revealed a low prevalence of mutations in this pathway (1.18%). In 13 cases with PDTC and ATC, we found no mutation in genes of this pathway. By contrast, analyses of 117 aggressive thyroid cancers (PDTC and ATC) from TCGA showed 13% of mutations in this pathway. Moreover, analyses of 1080 pan-cancer cell lines and 9020 solid tumors of TCGA data revealed high rates of mutations in this pathway (cell lines, 24.8%; tumors, 24.8%). In addition, PIK3CA + PTEN (p = <0.001) and LPAR4 + PIK3CA (p = 0.003) significantly co-occurred. Our study reveals a low prevalence of GPCR-mediated PI3K pathway mutations both in pediatric and adult DTCs corroborating the TCGA data and suggests a significant role of this pathway only in a small portion of DTCs. The high prevalence of mutations in this pathway in other solid malignancies suggests an important role in their pathogenesis making it an attractive target for therapeutic intervention both in a small subset of DTCs and other solid cancers.
2019-01-01 | S-EPMC6609254 | BioStudies
Project description:Papillary thyroid carcinoma (PTC) is the most common type of endocrine malignancy and accounts for ~80% of thyroid carcinomas in adults and 90% in children. Risk stratification is important for identifying patients at higher risk and, for this reason, recent advances in molecular genetics of thyroid cancer can be applied to provide novel biomarkers useful in understanding tumor behavior. B-Raf proto-oncogene, serine/threonine kinase (BRAF) and rat sarcoma (RAS) mutations have been widely studied and appear to have an important role in thyroid tumorigenesis. Somatic telomerase reverse transcriptase (TERT) promoter mutations have been recently identified in several types of malignant tumors, including thyroid neoplasia; however, the actual role of TERT mutations in thyroid tumorigenesis is still under debate. In the present study, the mutational status of BRAF, RAS and TERT was analyzed in order to elucidate the roles of these genes in thyroid tumorigenesis. The TERT mutational analysis was also correlated with an immunohistochemical study of TERT protein expression. According to the literature, our data provide evidence of the BRAF and RAS roles in thyroid tumorigenesis, supporting an association between BRAF (V600E) mutations and the more aggressive clinical and pathological features of thyroid tumors. By contrast, TERT mutations were not significantly associated with any clinical parameters; therefore, its role in initial tumorigenesis should be further investigated.
2018-01-01 | S-EPMC5778878 | BioStudies
Project description:Thyroid cancer 1 (TC1, C8orf4) plays important roles in tumors. The aim of this study was to examine the protein expression levels, methylation status, and mutational status of TC1 (C8orf4) in lung cancers, and investigate the correlation between TC1, other members of the Wnt signaling pathway, and lung cancer. TC1 expression levels were assessed via immunohistochemical staining in 179 cases of lung cancer. ?-catenin, TCF4, Axin, Disabled-2, Chibby, and DNA methyltransferase-1 (DNMT1) expressions were also examined. Bisulfite sequencing PCR analysis was used to examine the methylation status of the C8orf4 locus, while PCR analysis and direct sequencing were used to determine its mutational status. We found high TC1 expression correlated with poor differentiation, advanced TNM stage, lymphatic metastasis, and poor prognosis in lung cancer patients. TC1 expression also correlated with ?-catenin and DNMT1 expressions. No mutations in C8orf4 were detected. However, methylation levels of C8orf4 in lung cancers were lower than in corresponding normal lung tissues. In conclusion, high TC1 expression is implicated in lung cancer progression and correlates with poor prognosis in lung cancer. Reduced methylation levels might be responsible for the elevated TC1 expression levels. TC1, ?-catenin, and DNMT1 can synergistically activate Wnt/?-catenin signaling in lung cancers.
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Project description:Thyroid neoplasias with oncocytic features represent a specific phenotype in non-medullary thyroid cancer, reflecting the unique biological phenomenon of mitochondrial hyperplasia in the cytoplasm. Oncocytic thyroid cells are characterized by a prominent eosinophilia (or oxyphilia) caused by mitochondrial abundance. Although disruptive mutations in the mitochondrial DNA (mtDNA) are the most significant hallmark of such tumors, oncocytomas may be envisioned as heterogeneous neoplasms, characterized by multiple nuclear and mitochondrial gene lesions. We investigated the nuclear mutational profile of oncocytic tumors to pinpoint the mutations that may trigger the early oncogenic hit.Total DNA was extracted from paraffin-embedded tissues from 45 biopsies of oncocytic tumors. High-resolution melting was used for mutation screening of mitochondrial complex I subunits genes. Specific nuclear rearrangements were investigated by RT-PCR (RET/PTC) or on isolated nuclei by interphase FISH (PAX8/PPAR?). Recurrent point mutations were analyzed by direct sequencing.In our oncocytic tumor samples, we identified rare TP53 mutations. The series of analyzed cases did not include poorly- or undifferentiated thyroid carcinomas, and none of the TP53 mutated cases had significant mitotic activity or high-grade features. Thus, the presence of disruptive TP53 mutations was completely unexpected. In addition, novel mutations in nuclear-encoded complex I genes were identified.These findings suggest that nuclear genetic lesions altering the bioenergetics competence of thyroid cells may give rise to an aberrant mitochondria-centered compensatory mechanism and ultimately to the oncocytic phenotype.
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Project description:RAS-coupled MAPK and PI3K pathways play a fundamental role in thyroid tumorigenesis, and classical genetic alterations upregulating these pathways are well characterized. We hypothesized that gene abnormality of negative modulators of these signaling pathways might be an important alternative genetic background for thyroid cancer.By examining gene expression patterns of negative modulators of RAS signaling, we attempted to identify potential tumor suppressor genes. We then analyzed the methylation and mutation patterns of the identified gene in 101 thyroid tumors and tested its functions in vitro and in vivo to establish the tumor suppressor role in thyroid cancer.Among 13 negative modulators of the RAS pathway screened, RASAL1, encoding a RAS GTPase-activating protein, was frequently hypermethylated in thyroid cancers, which was coupled to its silencing in thyroid cancer cells. We also, for the first time, identified the presence of RASAL1 mutations, with a prevalence of 4.88% (n = 2 of 41) in follicular thyroid cancer (FTC) and 16.67% (n = 5 of 30) in anaplastic thyroid cancer (ATC). RASAL1 displayed MAPK- and PI3K-suppressing and thyroid tumor-suppressing activities, which were all impaired by the mutations. Hypermethylation and mutations of RASAL1 were mutually exclusive and collectively found in zero of 20 benign thyroid tumors, 3.22% (n = 1 of 31) of papillary thyroid cancers, 31.70% (n = 13 of 41) of FTCs, and 33.33% (n = 10 of 30) of ATCs. A rate of 20.83% (n = 5 of 24) of tumors carrying RASAL1 mutation or methylation at high levels (>50%) vs 44.16% (n = 34 of 77) of tumors carrying no RASAL1 mutation or methylation at low levels (< 50%) harbored any of the classical mutations (two-sided P = .02, Fisher exact test) in RAS, BRAF, PTEN, and PIK3CA genes in the MAPK and PI3K pathways, revealing a largely mutually exclusive relationship.We identified RASAL1 as a major tumor suppressor gene that is frequently inactivated by hypermethylation and mutations, providing a new alternative genetic background for thyroid cancer, particularly FTC and ATC.
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