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1.
Aging Cell ; : e13013, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31389184

RESUMO

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence-associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence-associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.

2.
Contemp Clin Trials ; 84: 105820, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400517

RESUMO

BACKGROUND: Clinical exome sequencing (CES) provides the advantage of assessing genetic variation across the human exome compared to a traditional stepwise diagnostic approach or multi-gene panels. Comparative effectiveness research methods offer an approach to better understand the patient-centered and economic outcomes of CES. PURPOSE: To evaluate CES compared to usual care (UC) in the diagnostic work-up of inherited colorectal cancer/polyposis (CRCP) in a randomized controlled trial (RCT). METHODS: The primary outcome was clinical sensitivity for the diagnosis of inherited CRCP; secondary outcomes included psychosocial outcomes, family communication, and healthcare resource utilization. Participants were surveyed 2 and 4 weeks after results return and at 3-month intervals up to 1 year. RESULTS: Evolving outcome measures and standard of care presented critical challenges. The majority of participants in the UC arm received multi-gene panels [94.73%]. Rates of genetic findings supporting the diagnosis of hereditary CRCP were 7.5% [7/93] vs. 5.4% [5/93] in the CES and UC arms, respectively (P = 0.28). Differences in privacy concerns after receiving CRCP results were identified (0.88 in UC vs 0.38 in CES, P = 0.05); however, healthcare resource utilization, family communication and psychosocial outcomes were similar between the two arms. More participants with positive results (17.7%) intended to change their life insurance 1  month after the first return visit compared to participants returned a variant of uncertain significance (9.1%) or negative result (4.8%) (P = 0.09). CONCLUSION: Our results suggest that CES provides similar clinical benefits to multi-gene panels in the diagnosis of hereditary CRCP.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30523039

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death. Biomarkers to predict treatment outcomes are needed, as is evidence whether post-diagnosis diet and lifestyle can affect well-being and clinical outcomes. The international ColoCare Consortium aims to identify new biologic markers (e.g., metabolomic, transcriptomic, metagenomic, genetic, epigenetic, proteomic) that predict clinical outcomes, and to characterize associations between modifiable risk factors (e.g., diet, supplement use, physical activity) with short-term and long-term patient-reported and clinical outcomes among CRC patients. METHODS/RESULTS: ColoCare is recruiting newly diagnosed CRC patients across six sites in the U.S. and one in Germany. As of April 2018 we have recruited >2,000 patients across all sites. Our projected enrollment is >4,000 multiethnic CRC patients. The study includes uniformly collected, comprehensive sets of data and biospecimens at multiple time points up to 5 years after diagnosis. Treatment and clinical data are abstracted from medical records and centrally harmonized. Biospecimens are archived according to standardized procedures. Our initial studies demonstrated metabolic differences in adipose tissue types. We further reported on associations of biological factors (e.g., inflammation, DNA methylation, metabolomics) with lifestyle factors (e.g., adiposity, smoking, physical activity, dietary supplement use) or joint associations with clinical outcomes. CONCLUSION: ColoCare is a consortium for the investigation of multi-level factors relevant to CRC survivorship. IMPACT: The combination of a comprehensive set of biospecimens collected at multiple time points, jointly with detailed assessments of health behaviors and other prognostic factors, results in a unique resource that facilitates wide-ranging, innovative, and impactful research on CRC.

4.
Int J Epidemiol ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30476131

RESUMO

Background: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. Methods: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. Results: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. Conclusions: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.

5.
Cancer Res ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30291105

RESUMO

Many normal tissues undergo age-related drift in DNA methylation, providing a quantitative measure of tissue age. Here we identify and validate 781 CpG-islands (CGI) that undergo significant methylomic drift in 232 normal colorectal tissues and show that these CGI continue to drift in neoplasia while retaining significant correlations across samples. However, compared with normal colon, this drift advanced (~3-4 fold) faster in neoplasia, consistent with increased cell proliferation during neoplastic progression. The observed drift patterns were broadly consistent with modeled adenoma-carcinoma sojourn time distributions from colorectal cancer (CRC) incidence data. These results support the hypothesis that, beginning with the founder premalignant cell, cancer precursors frequently sojourn for decades before turning into cancer, implying that the founder cell typically arises early in life. At least 77-89% of the observed drift variance in distal and rectal tumors was explained by stochastic variability associated with neoplastic progression, while only 55% of the variance was explained for proximal tumors. However, gene-CGI pairs in the proximal colon that underwent drift were significantly and primarily negatively correlated with cancer gene expression, suggesting that methylomic drift participates in the clonal evolution of CRC. Methylomic drift advanced in colorectal neoplasia consistent with extended sojourn time distributions, which accounts for a significant fraction of epigenetic heterogeneity in CRC. Importantly, these estimated long-duration premalignant sojourn times suggest that early dietary and lifestyle interventions may be more effective than later changes in reducing CRC incidence.

6.
Hum Genet ; 137(10): 795-806, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30267214

RESUMO

Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.


Assuntos
Proteína BRCA2/genética , Neoplasias Colorretais/genética , Desoxirribonuclease (Dímero de Pirimidina)/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Loci Gênicos , Variação Genética , RNA Helicases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
Dev Cell ; 45(6): 738-752.e6, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29920278

RESUMO

Normal cells acquire aggressive behavior by modifying signaling pathways. For instance, alteration of endocytosis profoundly impacts both proliferation and migration during tumorigenesis. Here we investigate the mechanisms that enable the endocytic machinery to coordinate these processes. We show that a membrane curvature-sensing protein, endophilin A3, promotes growth and migration of colon cancer cells through two competing mechanisms: an endocytosis pathway that is required for proliferation and a GTPase regulatory pathway that controls cell motility. EndoA3 stimulates cell migration by binding the Rac GEF TIAM1 leading to activation of small GTPases. Competing interactions of EndoA3 with membrane versus TIAM1 modulate hyperproliferative and metastatic phenotypes. Disruption of EndoA3-membrane interactions stimulates TIAM1 and small GTPases in vitro, and further promotes pro-metastatic phenotypes in vivo. Together, these results uncover a coupling mechanism, by which EndoA3 promotes growth and migration of colon cancers, by linking membrane dynamics to GTPase regulation.


Assuntos
Aciltransferases/metabolismo , Neoplasias do Colo/metabolismo , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/metabolismo , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Transformação Celular Neoplásica , Neoplasias do Colo/patologia , Endocitose/fisiologia , GTP Fosfo-Hidrolases/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Camundongos , Metástase Neoplásica , Transdução de Sinais , Peixe-Zebra , Proteínas rac1 de Ligação ao GTP/metabolismo
8.
Gut ; 2018 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884612

RESUMO

OBJECTIVE: To identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett's oesophagus (BE). DESIGN: We performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies. RESULTS: We identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in ERBB2 (p<0.05, Student's t-test) and the highest global mutation load (p<0.05, Fisher's exact test). PTPN13 was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored PTPN13 expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch's t-test). Inhibition of PTPN13 expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment. CONCLUSIONS: We identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.

9.
Methods Mol Biol ; 1768: 363-383, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29717454

RESUMO

Droplet digital (ddPCR) is a recent advance in PCR technology that enables the precise detection and absolute quantification of nucleic acid target sequences and that has a range of applications for both research and clinical diagnostic studies. Here, we discuss the parameters important in the design and performance of ddPCR for the detection and quantification of methylated DNA. We provide explicit instructions for conducting methylation specific ddPCR (aka MethyLight ddPCR). We also present an example that demonstrates the sensitivity and precision of the method for detecting methylated DNA in the promoter region of mir342/EVL, a potential DNA methylation biomarker for colon cancer risk. Common technical problems and troubleshooting for conducting successful MethyLight ddPCR assays are also discussed.

10.
Dig Dis Sci ; 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29766388

RESUMO

Esophageal adenocarcinoma (EAC) develops from Barrett's esophagus (BE), a condition where the normal squamous epithelia is replaced by specialized intestinal metaplasia in response to chronic gastroesophageal acid reflux. In a minority of individuals, BE can progress to low- and high-grade dysplasia and eventually to intra-mucosal and then invasive carcinoma. BE provides researchers with a unique model to characterize the process by which a carcinoma arises from its precursor lesion. Molecular studies of BE have demonstrated that it is not simply a metaplastic tissue, but rather it harbors frequent alterations that are also present in dysplastic BE and in EAC. Both BE and EAC are characterized by loss of heterozygosity, aneuploidy, specific genetic mutations, and clonal diversity. Epigenetic abnormalities, primary alterations in DNA methylation, are also frequently seen in BE and EAC. Candidate gene and array-based approaches have demonstrated that numerous tumor suppressor genes exhibit aberrant promoter methylation, and some of these altered genes are associated with the neoplastic progression of BE. It has also been shown that the BE and EAC epigenomes are characterized by hypomethylation of intragenic and non-coding regions Recent studies have also provided new insight into the evolutionary forces underlying the molecular alterations seen in BE and EAC and into the molecular pathogenesis of EAC.

11.
Br J Cancer ; 118(12): 1639-1647, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29795306

RESUMO

BACKGROUND: Substantial evidence supports an association between use of menopausal hormone therapy and decreased colorectal cancer (CRC) risk, indicating a role of exogenous sex hormones in CRC development. However, findings on endogenous oestrogen exposure and CRC are inconsistent. METHODS: We used a Mendelian randomisation approach to test for a causal effect of age at menarche and age at menopause as surrogates for endogenous oestrogen exposure on CRC risk. Weighted genetic risk scores based on 358 single-nucleotide polymorphisms associated with age at menarche and 51 single-nucleotide polymorphisms associated with age at menopause were used to estimate the association with CRC risk using logistic regression in 12,944 women diagnosed with CRC and 10,741 women without CRC from three consortia. Sensitivity analyses were conducted to address pleiotropy and possible confounding by body mass index. RESULTS: Genetic risk scores for age at menarche (odds ratio per year 0.98, 95% confidence interval: 0.95-1.02) and age at menopause (odds ratio 0.98, 95% confidence interval: 0.94-1.01) were not significantly associated with CRC risk. The sensitivity analyses yielded similar results. CONCLUSIONS: Our study does not support a causal relationship between genetic risk scores for age at menarche and age at menopause and CRC risk.

12.
Cancer Discov ; 8(6): 730-749, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29510987

RESUMO

To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/ß-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/ß-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730-49. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.

13.
Gut ; 67(11): 1995-2005, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-28982739

RESUMO

OBJECTIVE: Mutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC). DESIGN: Genome-wide methylation microarrays of CRC cell lines (n=149) identified five cancer-specific methylated loci (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC). Digital PCR assays were employed to measure methylation of these genes in tumour tissue DNA (n=82) and cfDNA from patients with mCRC (n=182). Plasma longitudinal assessment was performed in a patient subset treated with chemotherapy or targeted therapy. RESULTS: Methylation in at least one marker was detected in all tumour tissue samples and in 156 mCRC patient cfDNA samples (85.7%). Plasma marker prevalence was 71.4% for EYA4, 68.5% for GRIA4, 69.7% for ITGA4, 69.1% for MAP3K14-AS1% and 65.1% for MSC. Dynamics of methylation markers was not affected by treatment type and correlated with objective tumour response and progression-free survival. CONCLUSION: This five-gene methylation panel can be used to circumvent the absence of patient-specific mutations for monitoring tumour burden dynamics in liquid biopsy under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/metabolismo , Neoplasias Colorretais/genética , Metilação de DNA/genética , Adulto , Idoso , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral , Ácidos Nucleicos Livres/efeitos dos fármacos , Ácidos Nucleicos Livres/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reação em Cadeia da Polimerase , Resultado do Tratamento
14.
Clin Epigenetics ; 9: 113, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29046735

RESUMO

BACKGROUND: Recent studies have identified age-related changes in DNA methylation patterns in normal and cancer tissues in a process that is called epigenetic drift. However, the evolving patterns, functional consequences, and dynamics of epigenetic drift during carcinogenesis remain largely unexplored. Here we analyze the evolution of epigenetic drift patterns during progression from normal squamous esophagus tissue to Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) using 173 tissue samples from 100 (nonfamilial) BE patients, along with publically available datasets including The Cancer Genome Atlas (TCGA). RESULTS: Our analysis reveals extensive methylomic drift between normal squamous esophagus and BE tissues in nonprogressed BE patients, with differential drift affecting 4024 (24%) of 16,984 normally hypomethylated cytosine-guanine dinucleotides (CpGs) occurring in CpG islands. The majority (63%) of islands that include drift CpGs are associated with gene promoter regions. Island CpGs that drift have stronger pairwise correlations than static islands, reflecting collective drift consistent with processive DNA methylation maintenance. Individual BE tissues are extremely heterogeneous in their distribution of methylomic drift and encompass unimodal low-drift to bimodal high-drift patterns, reflective of differences in BE tissue age. Further analysis of longitudinally collected biopsy samples from 20 BE patients confirm the time-dependent evolution of these drift patterns. Drift patterns in EAC are similar to those in BE, but frequently exhibit enhanced bimodality and advanced mode drift. To better understand the observed drift patterns, we developed a multicellular stochastic model at the CpG island level. Importantly, we find that nonlinear feedback in the model between mean island methylation and CpG methylation rates is able to explain the widely heterogeneous collective drift patterns. Using matched gene expression and DNA methylation data in EAC from TCGA and other publically available data, we also find that advanced methylomic drift is correlated with significant transcriptional repression of ~ 200 genes in important regulatory and developmental pathways, including several checkpoint and tumor suppressor-like genes. CONCLUSIONS: Taken together, our findings suggest that epigenetic drift evolution acts to significantly reduce the expression of developmental genes that may alter tissue characteristics and improve functional adaptation during BE to EAC progression.


Assuntos
Adenocarcinoma/genética , Esôfago de Barrett/genética , Metilação de DNA , Neoplasias Esofágicas/genética , Deriva Genética , Idoso , Ilhas de CpG , Bases de Dados Genéticas , Progressão da Doença , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Genéticos
15.
Br J Cancer ; 117(8): 1202-1210, 2017 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-28809863

RESUMO

BACKGROUND: Plasma microRNAs (miRNAs) are promising non-invasive biomarkers for colorectal cancer (CRC) prognosis. However, the published studies to date have yielded conflicting and inconsistent results for specific plasma miRNAs. METHODS: We have conducted a study using robust assays to assess a panel of nine miRNAs for CRC prognosis and early detection of recurrence. Plasma samples from 144 patients in a prospective CRC cohort study were collected at diagnosis, 6, 12, and 24 months after diagnosis. miRNAs were assayed by Taqman qRT-PCR to generate miRNA normalised copy numbers. RESULTS: Preoperative high plasma miRNA levels were associated with increased recurrence risk for miR-200b (HR [95% CI]=2.04 [1.00, 4.16], P=0.05), miR-203 (HR=4.2 [1.48, 11.93], P=0.007), miR-29a (HR=2.61 [1.34,5.07], P=0.005), and miR-31 (HR=4.03 [1.76, 9.24], P=0.001). Both plasma miR-31 (AUC: 0.717) and miR-29a (AUC: 0.703) could discriminate recurrence from these patients without recurrence. In addition, high levels of miR-31 during surveillance was associated with a three-fold increased risk of recurrence across all time points. Dynamic postoperative plasma miR-141 and 16 levels correlated with recurrence in the surveillance samples. CONCLUSIONS: Pre-operative plasma miR-29a, 200b, 203, and 31 are potential CRC prognosis biomarkers. In addition, dynamic postoperative miR-31, 141 and 16 levels are potential biomarkers for the early detection of recurrence during CRC surveillance.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma/diagnóstico , Neoplasias Colorretais/diagnóstico , MicroRNAs/sangue , Recidiva Local de Neoplasia/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Carcinoma/sangue , Carcinoma/genética , Carcinoma/cirurgia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Detecção Precoce de Câncer , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/genética , Período Pós-Operatório , Período Pré-Operatório , Prognóstico , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Medição de Risco , Adulto Jovem
16.
Clin Epigenetics ; 9: 46, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28469732

RESUMO

BACKGROUND: The CpG island methylator phenotype (CIMP) in stage III colon cancer (CRC) has been associated with improved survival after treatment with adjuvant irinotecan-based chemotherapy. In this analysis, we determine whether CIMP status in the primary CRC is concordant with the CIMP status of matched metastases in order to determine if assessment of CIMP status in the primary tumor can be used to predict CIMP status of metastatic disease, which is relevant for patient management as well as for understanding the biology of CIMP CRCs. METHODS: We assessed the CIMP status of 70 pairs of primary CRC and matched metastases using a CRC-specific panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) where CIMP positive was defined as 3/5 positive markers at a percent methylated reference threshold of ≥10%. Concordance was compared using the Fisher's exact test and P < 0.05 was considered significant. RESULTS: Sixty-nine of the pairs (98.6%) showed concordant CIMP status in the primary tumor and matched metastasis; five (7.0%) of the pairs were concordantly CIMP positive. Only one pair (1.4%) had divergent CIMP status, demonstrating CIMP positivity (4/5 markers positive) in the primary tumor, while the matched metastasis was CIMP negative (0 markers positive). CONCLUSIONS: CIMP status is generally concordant between primary CRCs and matched metastases. Thus, CIMP status in the primary tumor is maintained in matched metastases and can be used to inform CIMP-based therapy options for the metastases.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Metilação de DNA , Adulto , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Canais de Cálcio Tipo T/genética , Neoplasias Colorretais/patologia , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Fator de Crescimento Insulin-Like II/genética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Proteínas do Tecido Nervoso/genética , Fenótipo , Proteína 1 Supressora da Sinalização de Citocina/genética
17.
Expert Rev Gastroenterol Hepatol ; 11(8): 723-729, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28503955

RESUMO

INTRODUCTION: Tumors in the large intestine have been postulated to arise via a stepwise accumulation of mutations, a process that takes up to 20 years. Recent advances in lineage tracing and DNA sequencing, however, are revealing new evolutionary models that better explain the vast amount of heterogeneity observed within and across colorectal tumors. Areas covered: A review of the literature supporting a novel model of colorectal tumor evolution was conducted. The following commentary examines the basic science and clinical evidence supporting a modified view of tumor initiation and progression in the colon. Expert commentary: The proposed 'cancer punctuated equilibrium' model of tumor evolution better explains the variability seen within and across polyps of the colon and rectum. Small colorectal polyps (6-9mm) followed longitudinally by interval imaging with CT colonography have been reported to have multiple fates: some growing, some remaining static in size, and others regressing in size over time. This new model allows for this variability in growth behavior and supports the hypothesis that some tumors can be 'born to be bad' as originally postulated by Sottoriva and colleagues, with very early molecular events impacting tumor fitness and growth behavior in the later stages of the disease process.


Assuntos
Evolução Biológica , Transformação Celular Neoplásica/patologia , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Animais , Biomarcadores Tumorais/genética , Proliferação de Células , Transformação Celular Neoplásica/genética , Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/genética , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/genética , Evolução Molecular , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Modelos Biológicos , Fenótipo , Fatores de Tempo , Carga Tumoral
18.
Gut ; 66(5): 852-862, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28389570

RESUMO

OBJECTIVE: Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD. DESIGN: We determined BVES promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured BVES mRNA levels in a tissue microarray consisting of normal colons and CAC samples. Bves-/- and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels. RESULTS: BVES mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, BVES promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, Bves was underexpressed in experimental inflammatory carcinogenesis, and Bves-/- mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of Bves-/- tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction. CONCLUSION: Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. BVES promoter methylation status may serve as a CAC biomarker.


Assuntos
Carcinogênese/genética , Moléculas de Adesão Celular/genética , Colite Ulcerativa/metabolismo , Neoplasias do Colo/metabolismo , Proteínas de Membrana/genética , Proteínas Musculares/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Biomarcadores Tumorais/genética , Células CACO-2 , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Colite Ulcerativa/genética , Colo/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Metilação de DNA , Sulfato de Dextrana , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/metabolismo , Via de Sinalização Wnt
20.
Proc Natl Acad Sci U S A ; 114(7): 1619-1624, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28143937

RESUMO

Rett syndrome (RS) is a debilitating neurological disorder affecting mostly girls with heterozygous mutations in the gene encoding the methyl-CpG-binding protein MeCP2 on the X chromosome. Because restoration of MeCP2 expression in a mouse model reverses neurologic deficits in adult animals, reactivation of the wild-type copy of MeCP2 on the inactive X chromosome (Xi) presents a therapeutic opportunity in RS. To identify genes involved in MeCP2 silencing, we screened a library of 60,000 shRNAs using a cell line with a MeCP2 reporter on the Xi and found 30 genes clustered in seven functional groups. More than half encoded proteins with known enzymatic activity, and six were members of the bone morphogenetic protein (BMP)/TGF-ß pathway. shRNAs directed against each of these six genes down-regulated X-inactive specific transcript (XIST), a key player in X-chromosome inactivation that encodes an RNA that coats the silent X chromosome, and modulation of regulators of this pathway both in cell culture and in mice demonstrated robust regulation of XIST. Moreover, we show that Rnf12, an X-encoded ubiquitin ligase important for initiation of X-chromosome inactivation and XIST transcription in ES cells, also plays a role in maintenance of the inactive state through regulation of BMP/TGF-ß signaling. Our results identify pharmacologically suitable targets for reactivation of MeCP2 on the Xi and a genetic circuitry that maintains XIST expression and X-chromosome inactivation in differentiated cells.


Assuntos
Proteína Morfogenética Óssea 2/genética , Proteína 2 de Ligação a Metil-CpG/genética , RNA Longo não Codificante/genética , Fator de Crescimento Transformador beta/genética , Inativação do Cromossomo X , Animais , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Biblioteca Gênica , Humanos , Camundongos , RNA Interferente Pequeno/genética , Síndrome de Rett/genética , Transdução de Sinais/genética , Ubiquitina-Proteína Ligases/genética
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