Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 129
Filtrar
1.
Acta Neuropathol Commun ; 7(1): 136, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434573

RESUMO

The authors have retracted this article [1] because a line was omitted from the data sheet; this was due to a bug in the analysis scripts.

2.
J Mol Diagn ; 21(5): 790-795, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158525

RESUMO

The tumor content of a biopsy and the average depth of coverage are two essential aspects when performing DNA sequencing using next-generation sequencing technologies. The heterogeneous nature of cancer necessitates the identification of distinct clonal cell populations to better understand and treat cancer. Deep sequencing enables researchers to identify these populations, but no consensus on an optimal depth exists for identifying clonal populations. Data from eight deep-sequenced oral squamous cell carcinoma biopsies obtained from three stage IV patients, with various degrees of tumor content, were used to randomly down sample the depth before being subjected to cluster analysis. An increase in coverage resulted in an increase in resolution for clusters of mutations, enabling the identification of distinct clonal cell populations and clonal events. From a depth of 800×, limited gain in resolution can be achieved; and from a depth of 1200×, the resolution stabilizes. Overall, researchers should aim for an average depth of 1000× to 1200× when performing deep sequencing. The tumor content will, however, dictate the resolution and fidelity of the analysis, as an increase in tumor complexity increases the need for higher tumor content.

3.
Acta Neuropathol Commun ; 7(1): 58, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023379

RESUMO

The heterogeneity of multiple sclerosis is reflected by dynamic changes of different lesion types in the brain white matter (WM). To identify potential drivers of this process, we RNA-sequenced 73 WM areas from patients with progressive MS (PMS) and 25 control WM. Lesion endophenotypes were described by a computational systems medicine analysis combined with RNAscope, immunohistochemistry, and immunofluorescence. The signature of the normal-appearing WM (NAWM) was more similar to control WM than to lesions: one of the six upregulated genes in NAWM was CD26/DPP4 expressed by microglia. Chronic active lesions that become prominent in PMS had a signature that were different from all other lesion types, and were differentiated from them by two clusters of 62 differentially expressed genes (DEGs). An upcoming MS biomarker, CHI3L1 was among the top ten upregulated genes in chronic active lesions expressed by astrocytes in the rim. TGFß-R2 was the central hub in a remyelination-related protein interaction network, and was expressed there by astrocytes. We used de novo networks enriched by unique DEGs to determine lesion-specific pathway regulation, i.e. cellular trafficking and activation in active lesions; healing and immune responses in remyelinating lesions characterized by the most heterogeneous immunoglobulin gene expression; coagulation and ion balance in inactive lesions; and metabolic changes in chronic active lesions. Because we found inverse differential regulation of particular genes among different lesion types, our data emphasize that omics related to MS lesions should be interpreted in the context of lesion pathology. Our data indicate that the impact of molecular pathways is substantially changing as different lesions develop. This was also reflected by the high number of unique DEGs that were more common than shared signatures. A special microglia subset characterized by CD26 may play a role in early lesion development, while astrocyte-derived TGFß-R2 and TGFß pathways may be drivers of repair in contrast to chronic tissue damage. The highly specific mechanistic signature of chronic active lesions indicates that as these lesions develop in PMS, the molecular changes are substantially skewed: the unique mitochondrial/metabolic changes and specific downregulation of molecules involved in tissue repair may reflect a stage of exhaustion.

4.
Ugeskr Laeger ; 181(7A)2019 Apr 01.
Artigo em Dinamarquês | MEDLINE | ID: mdl-30950381

RESUMO

In this review, we discuss the management of genomic medicine, which is based on very large data sets with up to billions of data points when analysing the whole genome. By using artificial intelligence (AI) it is possible to find patterns in such data sets and thereby identify subgroups of patients differing clinically, or to extract informative data points and construct models, which will predict disease risk, prognosis or treatment response most often in a process including training and testing (machine learning). Future clinical decision making will increasingly be based on patterns and models obtained by AI analysis of many parameters.

5.
Oncogene ; 38(23): 4560-4573, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30755730

RESUMO

Breast cancer is a heterogeneous genetic disease driven by the accumulation of individual mutations per tumor. Whole-genome sequencing approaches have identified numerous genes with recurrent mutations in primary tumors. Although mutations in well characterized tumor suppressors and oncogenes are overrepresented in these sets, the majority of the genetically altered genes have so far unknown roles in breast cancer progression. To improve the basic understanding of the complex disease breast cancer and to potentially identify novel drug targets or regulators of known cancer-driving pathways, we analyzed 86 wild-type genes and 94 mutated variants for their effect on cell growth using a serially constructed panel of MCF7 cell lines. We demonstrate in subsequent experiments that the metal cation transporter CNNM4 regulates growth by induction of apoptosis and identified a tumor suppressive role of complement factor properdin (CFP) in vitro and in vivo. CFP appears to induce the intracellular upregulation of the pro-apoptotic transcription factor DDIT3 which is associated with endoplasmic reticulum-stress response.

6.
J Gastroenterol ; 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30242476

RESUMO

The applicability of liquid biopsies is studied intensively in all types of cancer and analysis of circulating tumor DNA (ctDNA) has recently been implemented clinically for mutation detection in lung cancer. ctDNA may provide information about tumor quantity and mutations present in the tumor, and as such have many potential applications in diagnosis and treatment of cancer. It has been suggested that ctDNA analysis may overcome the issue of intra-tumor heterogeneity faced by tissue biopsies and serve as an additional diagnostic tool. Furthermore, liquid biopsies are potentially helpful for monitoring of treatment response as well as detection of minimal residual disease and relapse. Gastroesophageal cancers (GEC) have high mortality rates and the majority of patients present with advanced stage at diagnosis or succumb due to disease recurrence even after radical resection of the primary tumor. Biomarkers that can help optimize treatment strategy are thus highly desirable. The present study is a review of published data on ctDNA in GEC patients. We identified 25 studies in which tumor-specific genetic aberrations were investigated in plasma or serum and discuss these in relation to the methods applied for ctDNA analysis. The methods used for ctDNA detection greatly influence the sensitivity of the analysis and, therefore, the potential clinical applications. We found that studies of ctDNA in GEC, although limited in number, are promising for several applications such as genetic profiling of tumors and monitoring of disease progression. However, more studies are needed to establish if and how this analysis can be clinically implemented.

7.
Surg Oncol ; 27(2): 208-215, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29937173

RESUMO

INTRODUCTION: Cancer surgery may represent a potential risk of enhanced growth and metastatic ability of residual cancer cells due to post-operative immune dysfunction. This study identifies changes in transcription of genes involved in immune surveillance, immune suppression and carcinogenesis in the post-operative period of laparoscopic colon-cancer surgery within an ERAS regime. METHODS: Patients undergoing elective, curatively intended laparoscopic surgery for colon cancer stage I-III UICC were included in the study. Patients followed standard of care in an ERAS setting. Whole blood gene expression profiling (WBGP) was performed on the day prior to surgery and 1, 2, 3 and 10-14 days after surgery. Samples were collected in Paxgene tubes and Labeled cDNA was fragmented and hybridized to Affymetrix GeneChip™ 2.0. Results were corrected for multiple hypothesis testing using the false discovery rate. Pathway analysis was performed through the Molecular Signature Database. Paired fold changes of gene expression were calculated for post-operative compared to pre-operative samples. A mixed effect model was used to test differential gene expression by repeated-measures ANOVA. RESULTS: WBGP of 33,804 genes at five timepoints in six patients showed 302 significantly differentially expressed genes between samples from the day prior to surgery and the day after surgery. Pathway gene enrichment analysis showed a downregulation of immunologically relevant pathways. There was a significant downregulation of genes involved in T-cell receptor signaling, antigen presentation and NK-cell activity after surgery. Furthermore, there was an upregulation of cytokines related to metastatic ability, growth and angiogenesis. CONCLUSION: Whole blood gene expression profiling revealed dysregulation of genes involved in immune surveillance, inflammation and carcinogenesis, after laparoscopic colon cancer surgery.


Assuntos
Biomarcadores Tumorais/genética , Carcinogênese/genética , Neoplasias do Colo/sangue , Neoplasias do Colo/genética , Perfilação da Expressão Gênica , Vigilância Imunológica/genética , Inflamação/genética , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/cirurgia , Feminino , Humanos , Laparoscopia , Masculino , Prognóstico
8.
Cancer Med ; 7(8): 3571-3581, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29932310

RESUMO

Interferon-α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation-mediated toxicity, leading to treatment discontinuation in 10-30% of patients. Ruxolitinib, a potent anti-inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon-α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon-α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low-/intermediate-1-risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon-α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow-up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty-seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon-α2 and ruxolitinib is efficacious in patients with low-/intermediate-1-risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients.

9.
Acta Haematol ; 139(3): 195-198, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29719285

RESUMO

OBJECTIVE: Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases characterized by clonal hyperproliferation of immature and mature cells of the myeloid lineage. Genetic differences have been proposed to play a role in the development of MPNs. Monozygotic twin pairs with MPNs have been reported in a few case reports, but the MPN concordance pattern in twins remains unknown. METHOD: All twin pairs born in the period 1900-2010 were identified in the nationwide Danish Twin Registry. Only pairs with both twins alive on January 1, 1977, and those born thereafter were included to allow identification in the Danish National Patient Registry. RESULTS: A total of 158 twin pairs were registered with an MPN diagnosis: 36 monozygotic, 104 dizygotic, and 18 pairs with unknown zygosity. MPNs were diagnosed in both twins in 4 pairs. The probandwise concordance rates for monozygotic twin pairs were higher than for dizygotic twin pairs (15 vs. 0%; p = 0.016). CONCLUSION: An estimated concordance rate of 15% (95% CI 0.059-0.31) is modest, but given the rarity of MPNs this finding is clinically relevant and provides further support for the role of genetic predisposition in the development of MPNs.

10.
Oncotarget ; 9(10): 9030-9042, 2018 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-29507672

RESUMO

Current prognostic markers allocate the majority of lymph node (LN) negative and estrogen receptor (ER) positive breast cancer patients into the high-risk group. Accordingly, most patients receive systemic treatments although approximately 40% of these patients may have been cured by surgery and radiotherapy alone. Two studies identified seven prognostic microRNAs in systemically untreated, LN negative and ER positive breast cancer patients which may allow more precise patient classification. However, six of the seven microRNAs were analyzed in both studies but only found to be prognostic in one study. To validate their prognostic potential, we analyzed microRNA expression in an independent cohort (n = 110) using a pair-matched study design minimizing dependence of classical markers. The expression of hsa-miR-548c-5p was significantly associated with abridged disease-free survival (hazard ratio [HR]:1.96, p = 0.027). Contradicting published results, high hsa-miR-516-3p expression was associated with favorable outcome (HR:0.29, p = 0.0068). The association is probably time-dependent indicating later relapse. Additionally, re-analysis of previously published expression data of two matching cohorts (n = 100, n = 255) supports an association of hsa-miR-128-3p with shortened disease-free survival (HR:2.48, p = 0.0033) and an upregulation of miR-7-5p (p = 0.0038; p = 0.039) and miR-210-3p (p = 0.031) in primary tumors of patients who experienced metastases. Further analysis may verify the prognostic potential of these microRNAs.

11.
Hum Mutat ; 39(5): 593-620, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29446198

RESUMO

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

12.
PLoS One ; 13(1): e0189887, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293529

RESUMO

Cancer results from alterations at essential genomic sites and is characterized by uncontrolled cell proliferation, invasion and metastasis. Identification of driver genes of metastatic progression is essential, as metastases, not primary tumors, are fatal. To gain insight into the mutational concordance between different steps of malignant progression we performed exome sequencing and validation with targeted deep sequencing of successive steps of malignant progression from pre-invasive stages to asynchronous distant metastases in six breast cancer patients. Using the ratio of non-synonymous to synonymous mutations, a surprisingly large number of cancer driver genes, ranging between 3 and 145, were estimated to confer a selective advantage in the studied primary tumors. We report a substantial amount of metastasis specific mutations and a number of novel putative metastasis driver genes. Most notable are the DCC, ABCA13, TIAM2, CREBBP, BCL6B and ZNF185 genes, mainly mutated exclusively in metastases and highly likely driver genes of metastatic progression. We find different genes and pathways to be affected at different steps of malignant progression. The Adherens junction pathway is affected in four of the six studied patients and this pathway most likely plays a vital role in the metastatic process.


Assuntos
Neoplasias da Mama/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Metástase Neoplásica/genética , Neoplasias da Mama/genética , Feminino , Humanos
14.
J Med Genet ; 55(1): 15-20, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28490613

RESUMO

BACKGROUND: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers. METHODS: Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. RESULTS: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83). CONCLUSION: Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação/genética , Neoplasias Ovarianas/genética , Segregação de Cromossomos , Feminino , Humanos , Fatores de Risco
15.
Platelets ; : 1-7, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29215956

RESUMO

Thrombopoietin-receptor-agonists (TPO-RA) are effective treatments of immune thrombocytopenia (ITP). Previous long-term TPO-RA clinical trials have shown that thrombotic events occurred in 6% of TPO-RA-treated ITP patients. To explore the increased risk of thrombosis, the effects of TPO-RA on markers of coagulation and P-selectin were studied. The study comprised two ITP cohorts and controls. Cohort 1 included 26 patients with sequential samples acquired before and during treatment with TPO-RA. Cohort 2 included a single sample in 18 patients on TPO-RA for more than one year. Thrombin generation (endogenous thrombin potential (ETP)) prothrombin fragments 1 + 2 (F1+2), D-dimer, and plasminogen-activator-inhibitor-1 (PAI-1) were measured as well as soluble P-selectin (sP-selectin). Sequential expression of encoding genes for P-selectin (SELP) and PAI-1 (SERPINE1) was determined in four patients in cohort 1. Significantly higher levels of F1+2, D-dimer, and PAI-1 were found in ITP patients before TPO-RA treatment and in patients on long-term TPO-RA treatment than in controls. Pre-treatment levels of sP-selectin did not differ from controls. Analysis of longitudinal trends showed an increase in platelet count, sP-selectin, and PAI-1 after initiation of TPO-RA, followed by gradual decline. Platelet count and sP-selectin remained at higher levels throughout the study, whereas PAI-1 did not. Levels of other studied parameters did not show significant changes after initiation of treatment. Expression of SELP was up-regulated after initiation of TPO-RA, while the expression of SERPINE1 showed no significant changes. In conclusion, elevated pre-treatment levels of F1+2, D-dimer and PAI-1 are compatible with ITP being an intrinsically pro-thrombotic condition. After TPO-RA treatment, there were no significant changes in markers of coagulation activation or fibrinolysis, except for an initial increase in PAI-1 and a significant increase in sP-selectin both of which may contribute to increased thrombotic risk associated with TPO-RA treatment in ITP.

16.
PLoS One ; 12(8): e0183620, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28859112

RESUMO

The chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms which ultimately may transform to acute myelogenous leukemia. Most recently, chronic inflammation has been described as an important factor for the development and progression of MPNs in the biological continuum from early cancer stage to the advanced myelofibrosis stage, the MPNs being described as "A Human Inflammation Model for Cancer Development". This novel concept has been built upon clinical, experimental, genomic, immunological and not least epidemiological studies. Only a few studies have described the development of MPNs by mathematical models, and none have addressed the role of inflammation for clonal evolution and disease progression. Herein, we aim at using mathematical modelling to substantiate the concept of chronic inflammation as an important trigger and driver of MPNs.The basics of the model describe the proliferation from stem cells to mature cells including mutations of healthy stem cells to become malignant stem cells. We include a simple inflammatory coupling coping with cell death and affecting the basic model beneath. First, we describe the system without feedbacks or regulatory interactions. Next, we introduce inflammatory feedback into the system. Finally, we include other feedbacks and regulatory interactions forming the inflammatory-MPN model. Using mathematical modeling, we add further proof to the concept that chronic inflammation may be both a trigger of clonal evolution and an important driving force for MPN disease progression. Our findings support intervention at the earliest stage of cancer development to target the malignant clone and dampen concomitant inflammation.


Assuntos
Inflamação/genética , Modelos Teóricos , Transtornos Mieloproliferativos/genética , Neoplasias/genética , Carcinogênese/genética , Evolução Clonal/genética , Progressão da Doença , Humanos , Inflamação/patologia , Janus Quinase 2/genética , Transtornos Mieloproliferativos/patologia , Neoplasias/patologia , Células-Tronco Neoplásicas/patologia , Policitemia Vera/genética , Policitemia Vera/patologia , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia
17.
Sci Rep ; 7(1): 8183, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28811542

RESUMO

Aging is a complex biological process regulated by multiple cellular pathways and molecular mechanisms including epigenetics. Using genome-wide DNA methylation data measured in a large collection of Scottish old individuals, we performed discovery association analysis to identify age-methylated CpGs and replicated them in two independent Danish cohorts. The double-replicated CpGs were characterized by distribution over gene regions and location in relation to CpG islands. The replicated CpGs were further characterized by involvement in biological pathways to study their functional implications in aging. We identified 67,604 age-associated CpG sites reaching genome-wide significance of FWER <0.05, 86% demethylated with increasing age. Double-replication resulted in 5,168 CpGs (39% age-methylated and 61% age-demethylated) which were characterized by high concentration of age-methylated CpGs at 1stExon and TSS200 and a dominant pattern of age-demethylated CpGs at other gene regions, and by overwhelming age-related methylation in CpG islands and demethylation at shore/shelf and open sea. The differential distribution patterns over gene regions for methylated and demethylated CpGs both relate to reduced gene activity during aging. Pathway analysis showed that age-dependent methylations were especially involved in cellular signalling activities while demethylations particularly linked to functions of the extracellular matrix, all implicated in the aging process and age-related disease risk.

18.
Exp Dermatol ; 26(10): 926-933, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28370374

RESUMO

The gene expression time-course of repeated challenge of contact allergy (CA) remains largely unknown. Therefore, using diphenylcyclopropenone (DPCP) as model allergen in healthy humans we set out to examine: (i) the monotonous and complex gene expression time-course trajectories following repeated DPCP challenges to find the predominant gene expression pattern, (ii) the time-course of cell infiltration following repeated DPCP challenges and (iii) the transcriptome of a repeated CA exposure model. We obtained punch biopsies from control and DPCP-exposed skin from ten DPCP sensitized individuals at 5-6 monthly elicitation challenges. Biopsies were used for microarray gene expression profiling, histopathology and immunohistochemical staining. Validation of microarray data by qRT-PCR was performed on 15 selected genes. Early gene expression time points were also validated in an independent data set. An increasing and decreasing trend in gene expression followed by a plateau was predominantly observed during repeated DPCP challenges. Immune responses reached a plateau after two challenges histopathologically, immunohistochemically and in the time-course gene expression analysis. Transcriptional responses over time revealed a Th1/Th17 polarization as three upstream regulators (IFN-γ, IL-1 and IL-17) activated most of the top upregulated genes. Of the latter genes, 9 of 10 were the same throughout the time course. Excellent correlations between array and PCR data were observed. The transcriptional responses to DPCP over time followed a monotonous pattern. This response pattern confirms and supports the newly reported clinical time-course observations in de novo-sensitized individuals showing a plateau response, and thus, there is concordance between clinical response, histopathology, immunohistochemistry and microarray gene expression in volunteers de novo-sensitized to DPCP.


Assuntos
Dermatite Alérgica de Contato/genética , Dermatite Alérgica de Contato/imunologia , Expressão Gênica , Pele/metabolismo , Transcriptoma , Adulto , Biópsia , Ciclopropanos , Dermatite Alérgica de Contato/etiologia , Dermatite Alérgica de Contato/patologia , Feminino , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Interferon gama/metabolismo , Interleucina-1/metabolismo , Interleucina-17/metabolismo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , Pele/patologia , Células Th1/imunologia , Células Th17/imunologia , Fatores de Tempo , Adulto Jovem
19.
Oral Oncol ; 68: 74-80, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28438297

RESUMO

OBJECTIVES: Local recurrence and the development of second primary tumors (SPT) are important factors that can influence the survival rate of oral squamous cell carcinoma (OSCC) patients. We investigate the concept of field cancerization which proposes that normal tissue adjacent to the primary tumor harbor pre-neoplastic alterations that can lead to the development of local recurrence and SPTs. MATERIALS AND METHODS: To examine the concept of field cancerization, we applied whole-exome and targeted ultra-deep sequencing on 5 freshly frozen samples from a stage III OSCC patient from three tumor sites, lymph node metastasis and blood. Lastly, we sequenced one formalin-fixed paraffin-embedded recurrence biopsy that was collected approximately a year and half later located in the same area as before. RESULTS: Sequencing identified 126 somatic mutations. We identified 24 mutations in the recurrence biopsy and 14 mutations are shared by the primary tumor. CONCLUSION: The low number of shared mutations indicates that either these mutations represent a very early clone in the primary tumor's evolution, or that these mutations represent a pre-neoplastic field, in which the primary tumor and recurrence are derived from. In both instances, the clinical recurrence is of a monoclonal origin which suggests either field cancerization by migration of mutated cells in the adjacent mucosa, or that the recurrence developed out of remaining tumor tissue.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas/genética , Variações do Número de Cópias de DNA , Humanos , Neoplasias Bucais/genética , Mutação
20.
Sci Rep ; 7: 43813, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28276460

RESUMO

A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively. The genetic concordance between different steps of malignant progression is mostly unexplored as very few studies have included cancer samples separated by both space and time. We applied whole exome sequencing and targeted deep sequencing to 26 successive samples from six patients with metastatic estrogen receptor (ER)-positive breast cancer. Our data provide support for both linear and parallel progression towards metastasis. We report for the first time evidence of metastasis-to-metastasis seeding in breast cancer. Our results point to three distinct routes of metastasis emergence. This may have profound clinical implications and provides substantial novel molecular insights into the timing and mutational evolution of breast cancer metastasis.


Assuntos
Neoplasias Ósseas/genética , Neoplasias da Mama/genética , Neoplasias Hepáticas/genética , Mutação , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Proteínas do Citoesqueleto/genética , Progressão da Doença , Feminino , Genômica , Humanos , Proteínas com Domínio LIM/genética , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Sequenciamento Completo do Exoma/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA