Evolution and Impact of Subclonal Mutations in Papillary Thyroid Cancer.
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ABSTRACT:
SUBMITTER: Masoodi T
PROVIDER: S-EPMC6849094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.
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Project description:The vast majority of mutations in the exome of cancer cells are passengers, which do not affect the reproductive rate of the cell. Passengers can provide important information about the evolutionary history of an individual cancer, and serve as a molecular clock. Passengers can also become targets for immunotherapy or confer resistance to treatment. We study the stochastic expansion of a population of cancer cells describing the growth of primary tumors or metastatic lesions. We first analyze the process by looking forward in time and calculate the fixation probabilities and frequencies of successive passenger mutations ordered by their time of appearance. We compute the likelihood of specific evolutionary trees, thereby informing the phylogenetic reconstruction of cancer evolution in individual patients. Next, we derive results looking backward in time: for a given subclonal mutation we estimate the number of cancer cells that were present at the time when that mutation arose. We derive exact formulas for the expected numbers of subclonal mutations of any frequency. Fitting this formula to cancer sequencing data leads to an estimate for the ratio of birth and death rates of cancer cells during the early stages of clonal expansion.
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Project description:Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.
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Project description:Label-free proteomics profiling of 37 paired tumor-normal tissues of papillary thyroid cancer
2024-02-08 | PXD044900 | Pride
Project description:BackgroundAlthough the most thyroid carcinoma patients have good prognosis, around 20% of papillary thyroid carcinoma (PTC) patients have a high rate of metastasis and recurrence after routine treatment, which causes high lethality with these patients. Tumor proliferation, metastasis, and invasion are important predictors of PTC invasiveness and are key factors in cancer-related death. Angiopoietin-like 2 (ANGPTL2), a secreted protein which belongs to the angiopoietin (ANGPTL) family, was reported to be involved in the regulation of several different type of cancer cell proliferation and metastasis. However, whether ANGPTL2 plays a role in the progression of PTC, particularly in metastasis and recurrence of PTC, remains unclear. Hence, the purpose of this study was to evaluate the level of ANGPTL2 in PTC and normal thyroid, as well as para-cancerous tissue. Furthermore, the impact of ANGPTL2 on PTC cell proliferation, metastasis, recurrence and invasion was assessed to investigate the possibility whether ANGPTL2 may become a novel target for PTC therapy and cancer prognosis.Materials and methodsThe level of ANGPTL2 in PTC and para-cancerous tissue was assessed by immunohistochemistry. The biological effect of ANGPTL2 on thyroid cancer cell proliferation and metastasis was investigated by the Cell Counting Kit-8 (CCK8) assay, cell scratch test, and transwell assay. Correlations of ANGPTL2 expression levels with proliferation, migration, and metastasis of thyroid cancer were assessed with the TCGA data set and analyzed by gene set enrichment analysis. Receiver operating characteristic analysis was used to evaluate the utility of ANGPTL2 as a biomarker for prediction of thyroid cancer. Survival analysis was performed using the thyroid cancer database in K-M Plotter to detect correlations between survival time and ANGPTL2 levels.ResultsCurrent study revealed that: (1) ANGPTL2 was highly expressed in thyroid cancer in comparison with adjacent normal thyroid tissue; (2) ANGPTL2 expression was increased with thyroid tumor progression; (3) ANGPTL2 increased proliferation of thyroid cancer cells; (4) ANGPTL2 promoted migration and invasion of thyroid cancer cells; (5) high level of ANGPTL2 in thyroid cancer patients were significantly associated with a poor prognosis. The patients showed a higher metastasis and recurrence rate.ConclusionANGPTL2 promoted and enhanced proliferation, metastasis, and invasion of thyroid cancer cells. ANGPTL2 may be considered as a potential biomarker for diagnosis and prognosis of thyroid cancer patients. Further evaluation needs to be done to analyze the possibility of taking ANGPTL2 as a prognostic marker and therapeutic target for papillary thyroid cancer.
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Project description:BackgroundBrain metastasis is extremely rare but predicts dismal prognosis in papillary thyroid cancer (PTC). Dynamic evaluation of stepwise metastatic lesions was barely conducted to identify the longitudinal genomic evolution of brain metastasis in PTC.MethodChronologically resected specimen was analyzed by whole exome sequencing, including four metastatic lymph nodes (lyn 1-4) and brain metastasis lesion (BM). Phylogenetic tree was reconstructed to infer the metastatic pattern and the potential functional mutations.ResultsContrasting with lyn1, ipsilateral metastatic lesions (lyn2-4 and BM) with shared biallelic mutations of TSC2 indicated different genetic originations from multifocal tumors. Lyn 3/4, particularly lyn4 exhibited high genetic similarity with BM. Besides the similar mutational compositions and signatures, shared functional mutations (CDK4 R24C , TP53R342*) were observed in lyn3/4 and BM. Frequencies of these mutations gradually increase along with the metastasis progression. Consistently, TP53 knockout and CDK4 R24C introduction in PTC cells significantly decreased radioiodine uptake and increased metastatic ability.ConclusionGenomic mutations in CDK4 and TP53 during the tumor evolution may contribute to the lymph node and brain metastasis of PTC.
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Project description: Not available
| S-EPMC3650490 | biostudies-literature
Project description:Mitogen-activated protein kinase kinase 1 (MAP2K1) is a dual specificity protein kinase that phosphorylates both threonine and tyrosine residues in ERK. MAP2K1 mutations have been identified in several cancers. However, their role in Middle Eastern papillary thyroid cancer (PTC) and colorectal cancer (CRC) is lacking. In this study, we evaluated the prevalence of MAP2K1 mutations in a large cohort of Middle Eastern PTC and CRC using whole-exome and Sanger sequencing technology. In the discovery cohort of 100 PTC and 100 CRC cases (comprising 50 MAPK mutant and 50 MAPK wildtype cases each), we found one MAP2K1 mutation each in PTC and CRC, both of which were MAPK wildtype. We further analyzed 286 PTC and 289 CRC MAPK wildtype cases and found three MAP2K1 mutant PTC cases and two MAP2K1 mutant CRC cases. Thus, the overall prevalence of MAP2K1 mutation in MAPK wildtype cases was 1.1% (4/336) in PTC and 0.9% (3/339) in CRC. Histopathologically, three of the four MAP2K1 mutant PTC cases were follicular variant and all four tumors were unifocal with absence of extra-thyroidal extension. All the three CRC cases harboring MAP2K1 mutation were of older age (> 50 years) and had moderately differentiated stage II/III tumors located in the left colon. In conclusion, this is the first comprehensive report of MAP2K1 somatic mutations prevalence in PTC and CRC from this ethnicity. The mutually exclusive nature of MAP2K1 and MAPK mutations suggests that each of these mutation may function as an initiating mutation driving tumorigenesis through MAPK signaling pathway.
| S-EPMC8144646 | biostudies-literature
Project description:Papillary thyroid cancer (PTC) is the second most commonly diagnosed malignancy in U.S. Latinas and in Colombian women. Studies in non-Latinos indicate that BRAF and TERT mutations are PTC prognostic markers. This study aimed to determine the prevalence and clinical associations of BRAF and TERT mutations in PTC Latino patients from Colombia. We analyzed mutations of BRAF (V600E) and TERT promoter (C228T, C250T) in tumor DNA from 141 patients (75 with classical variant PTC, CVPTC; 66 with follicular variant PTC, FVPTC) recruited through a multi-center study. Associations between mutations and clinical variables were evaluated with Fisher exact tests. Survival was evaluated with Kaplan-Meier plots. Double-mutant tumors (BRAF+/TERT+, n = 14 patients) were more common in CVPTC (P = 0.02). Relative to patients without mutations (n = 48), double mutations were more common in patients with large tumors (P = 0.03), lymph node metastasis (P = 0.01), extra-thyroid extension (P = 0.03), and advanced stage (P = 6.0 × 10-5). In older patients, TERT mutations were more frequent (mean age 51 years vs 45 years for wild type TERT, P = 0.04) and survival was lower (HR = 1.20; P = 0.017); however, given the small sample size, the decrease in survival was not statically significant between genotypes. Comparisons with published data in US whites revealed that Colombian patients had a higher prevalence of severe pathological features and of double-mutant tumors (10 vs 6%, P = 0.001). Mutations in both oncogenes show prognostic associations in Latinos from Colombia. Our study is important to advance Latino PTC precision medicine and replicates previous prognostic associations between BRAF and TERT in this population.
| S-EPMC6765322 | biostudies-literature
Project description:ContextThyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have attained menopause by age 55 yr.ObjectiveThe objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis.DesignGender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease-specific survival (DSS).Participants and settingPatients were followed in a prospective registry.Main outcome measureThe relationships between gender, age, and PTC outcomes were analyzed.ResultsThe unadjusted hazard ratio (HR) for DSS for women was 0.40 [confidence interval (CI) 0.24-0.65]. This female advantage diminished when DSS was adjusted for age at diagnosis and stage with a HR encompassing unity (HR 0.72, CI 0.44-1.19). Additional multivariate models of DSS considering gender, disease stage, and various age groupings showed that the DSS for women diagnosed at under 55 yr was improved over men (HR 0.33, CI 0.13-0.81). However, the HR for DSS increased to become similar to men for women diagnosed at 55-69 yr (HR 1.01, CI 0.42-2.37) and at 70 yr or greater (HR 1.17, CI 0.48-2.85).ConclusionsAlthough the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes. The first period is a period with better outcomes for women than men when the diagnosis occurs at younger than 55 yr; the second is a period with similar outcomes for both women and men diagnosed at ages greater than 55 yr. These data raise the question of whether an older age cutoff would improve current staging systems. We hypothesize that older age modifies the effect of gender on outcomes due to menopause-associated hormonal alterations.
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