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1.
J Gastroenterol ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33079233

RESUMO

BACKGROUND AND AIMS: Verrucous esophageal carcinoma (VEC) is a rare malignancy that presents a diagnostic challenge. We aim to characterize the clinical and genomic features, tumor behavior, and treatment outcomes of VEC to guide clinical practice. METHODS: We performed a systematic review of the literature and identified additional cases from Massachusetts General Hospital records and The Cancer Genome Atlas (TCGA). We obtained individual VEC patient data and analyzed publicly available clinicogenomic data from TCGA. We performed a regression analysis comparing cases of VEC to esophageal squamous cell carcinoma (ESCC) to identify factors influencing survival. RESULTS: A total of 135 patients were reported in 82 publications, and four unpublished cases from Massachusetts General Hospital (median age 65 years, 69% males, 48% smokers, 33% consumed alcohol). Symptoms were present at diagnosis in 95% of patients, most commonly dysphagia and weight loss. Median symptom onset to diagnosis time was 11.5 months with frequent misdiagnosis as Candida esophagitis. Among VEC cases with pathologic staging, lymph node metastases were rare (5%) compared to ESCC (40%). VEC was genomically characterized by enrichment of SMARCA4 missense mutations and a lack of pathogenic TP53 mutations. Despite its diagnostic elusiveness, in a multivariate regression analysis, VEC was detected at earlier stages (p = < 0.001) compared to ESCC, and advanced stage was the only significant factor affecting survival (p = 0.013). CONCLUSIONS: VEC is a rare, clinically and genomically distinct subtype of ESCC. Recognition and diagnosis of this lesion may allow the pursuit of curative and less morbid treatment strategies.

2.
Cancer Epidemiol Biomarkers Prev ; 29(12): 2719-2728, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33008876

RESUMO

BACKGROUND: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. METHODS: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). RESULTS: A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer-specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74-0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68-0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. CONCLUSIONS: Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. IMPACT: The implicated genes warrant further investigation.

3.
Cancer Prev Res (Phila) ; 13(10): 877-888, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32718943

RESUMO

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8-12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (-4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group (P = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (-15%; P = 0.018) or 325 mg/day (-28%; P < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.

4.
Clin Transl Gastroenterol ; 11(3): e00149, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32352724

RESUMO

INTRODUCTION: Somatic mutations in BRCA1/2 and other homologous recombination repair (HRR) genes have been associated with sensitivity to PARP inhibitors and/or platinum agents in several cancers, whereas hypermutant tumors caused by alterations in POLE or mismatch repair genes have demonstrated robust responses to immunotherapy. We investigated the relationship between somatic truncations in HRR genes and hypermutation in colorectal cancer (CRC) and endometrial cancer (EC). METHODS: We analyzed the mutational spectra associated with somatic BRCA1/2 truncations in multiple genomic cohorts (N = 2,335). From these results, we devised a classifier incorporating HRR genes to predict hypermutator status among microsatellite stable (MSS) tumors. Using additional genomic cohorts (N = 1,439) and functional in vivo assays, we tested the classifier to disambiguate POLE variants of unknown significance and identify MSS hypermutators without somatic POLE exonuclease domain mutations. RESULTS: Hypermutator phenotypes were prevalent among CRCs with somatic BRCA1/2 truncations (50/62, 80.6%) and ECs with such mutations (44/47, 93.6%). The classifier predicted MSS hypermutators with a cumulative true-positive rate of 100% in CRC and 98.0% in EC and a false-positive rate of 0.07% and 0.63%. Validated by signature analyses of tumor exomes and in vivo assays, the classifier accurately reassigned multiple POLE variants of unknown significance as pathogenic and identified MSS hypermutant samples without POLE exonuclease domain mutations. DISCUSSION: Somatic truncations in HRR can accurately fingerprint MSS hypermutators with or without known pathogenic exonuclease domain mutations in POLE and may serve as a low-cost biomarker for immunotherapy decisions in MSS CRC and EC.

5.
Proc Natl Acad Sci U S A ; 117(21): 11667-11673, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32393626

RESUMO

Alcohol-related liver disease (ALD) accounts for the majority of cirrhosis and liver-related deaths worldwide. Activation of IFN-regulatory factor (IRF3) initiates alcohol-induced hepatocyte apoptosis, which fuels a robust secondary inflammatory response that drives ALD. The dominant molecular mechanism by which alcohol activates IRF3 and the pathways that amplify inflammatory signals in ALD remains unknown. Here we show that cytoplasmic sensor cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS) drives IRF3 activation in both alcohol-injured hepatocytes and the neighboring parenchyma via a gap junction intercellular communication pathway. Hepatic RNA-seq analysis of patients with a wide spectrum of ALD revealed that expression of the cGAS-IRF3 pathway correlated positively with disease severity. Alcohol-fed mice demonstrated increased hepatic expression of the cGAS-IRF3 pathway. Mice genetically deficient in cGAS and IRF3 were protected against ALD. Ablation of cGAS in hepatocytes only phenocopied this hepatoprotection, highlighting the critical role of hepatocytes in fueling the cGAS-IRF3 response to alcohol. We identified connexin 32 (Cx32), the predominant hepatic gap junction, as a critical regulator of spreading cGAS-driven IRF3 activation through the liver parenchyma. Disruption of Cx32 in ALD impaired IRF3-stimulated gene expression, resulting in decreased hepatic injury despite an increase in hepatic steatosis. Taken together, these results identify cGAS and Cx32 as key factors in ALD pathogenesis and as potential therapeutic targets for hepatoprotection.


Assuntos
Junções Comunicantes/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Hepatopatias Alcoólicas/metabolismo , Nucleotidiltransferases/metabolismo , Adulto , Animais , Apoptose , Feminino , Hepatócitos/metabolismo , Humanos , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Nucleotidiltransferases/genética , Transdução de Sinais
7.
Int J Epidemiol ; 49(1): 259-269, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31038671

RESUMO

BACKGROUND: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown. METHODS: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis. RESULTS: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584). CONCLUSIONS: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.


Assuntos
Adenoma/genética , Neoplasias do Colo/genética , Neoplasias Colorretais/genética , Pólipos/genética , Idoso , Estudos de Coortes , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Seguimentos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Pólipos/patologia , Estudos Prospectivos , Fatores de Risco
8.
Int J Cancer ; 146(2): 363-372, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31209889

RESUMO

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.


Assuntos
Neoplasias do Colo/genética , Reparo do DNA/genética , Predisposição Genética para Doença , Neoplasias Retais/genética , Adulto , Idoso , Variação Biológica da População/genética , Carcinogênese/genética , Estudos de Casos e Controles , Colo/patologia , Neoplasias do Colo/patologia , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Retais/patologia , Reto/patologia , Sistema de Registros/estatística & dados numéricos , Medição de Risco , Proteínas Supressoras de Tumor/genética , Adulto Jovem
9.
Clin Transl Gastroenterol ; 12(1): e00272, 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33464729

RESUMO

INTRODUCTION: The expression of LGR5, a known stem cell marker, is poorly understood in Barrett's esophagus (BE) and related neoplasia. The aim of this study was to evaluate LGR5 in BE and related neoplasia and to evaluate its utility as a potential biomarker of progression to advanced neoplasia. METHODS: We evaluated total 137 patients, including 119 with BE and 18 with normal gastroesophageal mucosa for expression of LGR5 using RNA in situ hybridization; this also included 28 progressors and 30 nonprogressors. The LGR5 stain was evaluated using 1 qualitative and 2 quantitative parameters, using manual and automated platforms. RESULTS: Surface LGR5 expression was mainly seen in high-grade dysplasia (12/18) compared with low-grade dysplasia (1/8) and nondysplastic BE (0/17) (P < 0.0001). In contrast to nondysplastic BE, low- and high-grade dysplasia showed a higher percentage of mean number of LGR5-positive crypts per patient (P < 0.0001) and an increase in the mean number of LGR5 transcripts per cell (P < 0.0001). The mean percentage of LGR5-positive crypts per patient and the mean number of LGR5 transcripts per cell were also significantly higher in nondysplastic BE from progressor compared with nonprogressor (P < 0.0001, P = 0.014). The sensitivity and specificity of LGR5 for distinguishing progressor from nonprogressor were 50% and 87%, respectively. DISCUSSION: BE-related advanced neoplasia shows an expansion of the LGR5-positive cellular compartment, supporting its role as a stem cell marker in this disease. Quantitative LGR5 expression and surface epithelial reactivity are novel biomarkers of increased risk of progression to advanced neoplasia in BE.

10.
Hepatol Commun ; 2(7): 786-797, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30202815

RESUMO

Emerging data highlight the critical role for the innate immune system in the progression of nonalcoholic fatty liver disease (NAFLD). Connexin 32 (Cx32), the primary liver gap junction protein, is capable of modulating hepatic innate immune responses and has been studied in dietary animal models of steatohepatitis. In this work, we sought to determine the association of hepatic Cx32 with the stages of human NAFLD in a histologically characterized cohort of 362 patients with NAFLD. We also studied the hepatic expression of the genes and proteins known to interact with Cx32 (known as the connexome) in patients with NAFLD. Last, we used three independent dietary mouse models of nonalcoholic steatohepatitis to investigate the role of Cx32 in the development of steatohepatitis and fibrosis. In a univariate analysis, we found that Cx32 hepatic expression associates with each component of the NAFLD activity score and fibrosis severity. Multivariate analysis revealed that Cx32 expression most closely associated with the NAFLD activity score and fibrosis compared to known risk factors for the disease. Furthermore, by analyzing the connexome, we identified novel genes related to Cx32 that associate with NAFLD progression. Finally, we demonstrated that Cx32 deficiency protects against liver injury, inflammation, and fibrosis in three murine models of nonalcoholic steatohepatitis by limiting initial diet-induced hepatoxicity and subsequent increases in intestinal permeability. Conclusion: Hepatic expression of Cx32 strongly associates with steatohepatitis and fibrosis in patients with NAFLD. We also identify novel genes associated with NAFLD and suggest that Cx32 plays a role in promoting NAFLD development. (Hepatology Communications 2018;2:786-797).

11.
Genome Biol ; 19(1): 142, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30253799

RESUMO

BACKGROUND: Previous approaches to defining subtypes of colorectal carcinoma (CRC) and other cancers based on transcriptomes have assumed the existence of discrete subtypes. We analyze gene expression patterns of colorectal tumors from a large number of patients to test this assumption and propose an approach to identify potentially a continuum of subtypes that are present across independent studies and cohorts. RESULTS: We examine the assumption of discrete CRC subtypes by integrating 18 published gene expression datasets and > 3700 patients, and contrary to previous reports, find no evidence to support the existence of discrete transcriptional subtypes. Using a meta-analysis approach to identify co-expression patterns present in multiple datasets, we identify and define robust, continuously varying subtype scores to represent CRC transcriptomes. The subtype scores are consistent with established subtypes (including microsatellite instability and previously proposed discrete transcriptome subtypes), but better represent overall transcriptional activity than do discrete subtypes. The scores are also better predictors of tumor location, stage, grade, and times of disease-free survival than discrete subtypes. Gene set enrichment analysis reveals that the subtype scores characterize T-cell function, inflammation response, and cyclin-dependent kinase regulation of DNA replication. CONCLUSIONS: We find no evidence to support discrete subtypes of the CRC transcriptome and instead propose two validated scores to better characterize a continuity of CRC transcriptomes.


Assuntos
Neoplasias Colorretais/genética , Transcriptoma , Neoplasias Colorretais/classificação , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Humanos , Microambiente Tumoral
12.
Am J Hum Genet ; 102(5): 904-919, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29727690

RESUMO

Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants for many complex diseases; however, these variants explain only a small fraction of the heritability. Recently, genetic association studies that leverage external transcriptome data have received much attention and shown promise for discovering novel variants. One such approach, PrediXcan, is to use predicted gene expression through genetic regulation. However, there are limitations in this approach. The predicted gene expression may be biased, resulting from regularized regression applied to moderately sample-sized reference studies. Further, some variants can individually influence disease risk through alternative functional mechanisms besides expression. Thus, testing only the association of predicted gene expression as proposed in PrediXcan will potentially lose power. To tackle these challenges, we consider a unified mixed effects model that formulates the association of intermediate phenotypes such as imputed gene expression through fixed effects, while allowing residual effects of individual variants to be random. We consider a set-based score testing framework, MiST (mixed effects score test), and propose two data-driven combination approaches to jointly test for the fixed and random effects. We establish the asymptotic distributions, which enable rapid calculation of p values for genome-wide analyses, and provide p values for fixed and random effects separately to enhance interpretability over GWASs. Extensive simulations demonstrate that our approaches are more powerful than existing ones. We apply our approach to a large-scale GWAS of colorectal cancer and identify two genes, POU5F1B and ATF1, which would have otherwise been missed by PrediXcan, after adjusting for all known loci.


Assuntos
Estudo de Associação Genômica Ampla , Genômica , Modelos Genéticos , Neoplasias Colorretais/genética , Biologia Computacional , Simulação por Computador , Genes Neoplásicos , Humanos , Análise Numérica Assistida por Computador , Software
13.
Dig Dis Sci ; 63(3): 738-745, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29372477

RESUMO

BACKGROUND: While monoclonal antibodies against tumor necrosis factor-α (TNFα) are effective in treating Crohn's disease (CD), approximately one-third of patients lose response. The mechanisms underlying this loss of response remain elusive. AIM: We sought to determine if novel biological pathways, including TNFα-independent inflammatory pathways, emerge in those with loss of response to anti-TNFα. METHODS: Using RNA microarray technology in 28 patients with CD, we examined the colonic gene expression differences between those with active inflammation in the setting of loss of response to TNFα-antagonist therapy ("loss of responders") compared to anti-TNFα naïve patients with active inflammation and those on anti-TNF therapy in disease remission. Pathway enrichment analyses were performed. RESULTS: We found that colonic expression of chemokines known to drive inflammation (CXCL20, CXCL9, and CXCL10) was elevated in those with loss of response compared to those in remission. Expression of genes critical to modulating oxidative stress burden (DUOX2, DUOXA2, and NOS2) was also elevated. Additionally, MMP3, MMP1, and MMP12 were elevated in those with continued inflammation. Gene enrichment analysis revealed that loss of responders exhibited dysregulation in the cysteine and methionine metabolism pathway, suggesting alteration in oxidative stress burden. There were no differences in genes or pathways between loss of responders and those who were TNFα-naïve. However, loss of response occurred despite the ability of anti-TNFα therapy to normalize APO gene expression. CONCLUSION: Our analyses suggest that loss of response to anti-TNFα is not driven by the emergence of pathways that bypass the action or induce resistance to anti-TNFα therapy.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doença de Crohn/tratamento farmacológico , Tolerância a Medicamentos/fisiologia , Fármacos Gastrointestinais/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Feminino , Humanos , Infliximab/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Estresse Oxidativo/fisiologia , Indução de Remissão , Adulto Jovem
14.
Clin Transl Gastroenterol ; 8(2): e73, 2017 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-28181993

RESUMO

OBJECTIVES: Obesity is an important risk factor for the development of colorectal cancer (CRC). Although the impact of bariatric surgery on CRC is conflicting, its impact on precursor lesions is unknown. The aim of this study was to determine whether bariatric surgery before index screening colonoscopy is associated with decreased development of colorectal adenomas. METHODS: We performed a retrospective cohort study of bariatric surgery patients who had undergone index, screening colonoscopy at an academic center from 2001 to 2014. Patients who had bariatric surgery at least 1 year before index colonoscopy were compared with those who had surgery after colonoscopy, using multivariable logistic regression to control for presurgical body mass index, sex, gender, race, type of surgery, aspirin use, metformin use, smoking, and age at colonoscopy. RESULTS: One hundred and twenty-five obese individuals who had bariatric surgery before colonoscopy were compared with 223 individuals who had colonoscopy after surgery. Adenomatous polyps were found in 16.8% of individuals who had surgery first vs. 35.5% who had colonoscopy before bariatric surgery (unadjusted odds ratio (OR) 0.37, 95% confidence interval (CI): 0.21-0.64, P=0.0003). After multivariable adjustment, bariatric surgery before index screening colonoscopy was associated with a decreased risk of adenomas at index colonoscopy (adjusted OR 0.37, 95% CI: 0.19-0.69, P=0.002). CONCLUSIONS: Bariatric surgery is associated with a decreased risk of colorectal adenomas in obese individuals without a family history of CRC.

15.
Trials ; 18(1): 50, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28143522

RESUMO

BACKGROUND: Although aspirin is recommended for the prevention of colorectal cancer, the specific individuals for whom the benefits outweigh the risks are not clearly defined. Moreover, the precise mechanisms by which aspirin reduces the risk of cancer are unclear. We recently launched the ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED) trial to address these uncertainties. METHODS/DESIGN: ASPIRED is a prospective, double-blind, multidose, placebo-controlled, biomarker clinical trial of aspirin use in individuals previously diagnosed with colorectal adenoma. Individuals (n = 180) will be randomized in a 1:1:1 ratio to low-dose (81 mg/day) or standard-dose (325 mg/day) aspirin or placebo. At two study visits, participants will provide lifestyle, dietary and biometric data in addition to urine, saliva and blood specimens. Stool, grossly normal colorectal mucosal biopsies and cytology brushings will be collected during a flexible sigmoidoscopy without bowel preparation. The study will examine the effect of aspirin on urinary prostaglandin metabolites (PGE-M; primary endpoint), plasma inflammatory markers (macrophage inhibitory cytokine-1 (MIC-1)), colonic expression of transcription factor binding (transcription factor 7-like 2 (TCF7L2)), colonocyte gene expression, including hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and those that encode Wnt signaling proteins, colonic cellular nanocytology and oral and gut microbial composition and function. DISCUSSION: Aspirin may prevent colorectal cancer through multiple, interrelated mechanisms. The ASPIRED trial will scrutinize these pathways and investigate putative mechanistically based risk-stratification biomarkers. TRIAL REGISTRATION: This protocol is registered with the U.S. National Institutes of Health trial registry, ClinicalTrials.gov, under the identifier NCT02394769 . Registered on 16 March 2015.


Assuntos
Adenoma/tratamento farmacológico , Anticarcinógenos/administração & dosagem , Aspirina/administração & dosagem , Carcinoma/prevenção & controle , Neoplasias Colorretais/tratamento farmacológico , Adenoma/metabolismo , Adenoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticarcinógenos/efeitos adversos , Aspirina/efeitos adversos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/urina , Boston , Carcinoma/metabolismo , Carcinoma/patologia , Protocolos Clínicos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Citocinas/sangue , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Prostaglandinas/urina , Fatores de Proteção , Projetos de Pesquisa , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
J Mol Diagn ; 18(5): 697-706, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27471182

RESUMO

Next-generation sequencing has evolved technically and economically into the method of choice for interrogating the genome in cancer and inherited disorders. The introduction of procedural code sets for whole-exome and genome sequencing is a milestone toward financially sustainable clinical implementation; however, achieving reimbursement is currently a major challenge. As part of a prospective quality-improvement initiative to implement the new code sets, we adopted Agile, a development methodology originally devised in software development. We implemented eight functionally distinct modules (request review, cost estimation, preauthorization, accessioning, prebilling, testing, reporting, and reimbursement consultation) and obtained feedback via an anonymous survey. We managed 50 clinical requests (January to June 2015). The fraction of pursued-to-requested cases (n = 15/50; utilization management fraction, 0.3) aimed for a high rate of preauthorizations. In 13 of 15 patients the insurance plan required preauthorization, which we obtained in 70% and ultimately achieved reimbursement in 50%. Interoperability enabled assessment of 12 different combinations of modules that underline the importance of an adaptive workflow and policy tailoring to achieve higher yields of reimbursement. The survey confirmed a positive attitude toward self-organizing teams. We acknowledge the individuals and their interactions and termed the infrastructure: human pipeline. Nontechnical barriers currently are limiting the scope and availability of clinical genomic sequencing. The presented human pipeline is one approach toward long-term financial sustainability of clinical genomics.


Assuntos
Assistência à Saúde , Genômica , Informática Médica/métodos , Software , Assistência à Saúde/economia , Assistência à Saúde/métodos , Assistência à Saúde/organização & administração , Exoma , Genômica/economia , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Informática Médica/economia , Encaminhamento e Consulta , Mecanismo de Reembolso , Pesquisa , Inquéritos e Questionários , Fluxo de Trabalho , Recursos Humanos
17.
Int J Cancer ; 139(12): 2655-2670, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27459707

RESUMO

Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.


Assuntos
Variação Genética , Neoplasias/epidemiologia , Neoplasias/genética , Homeostase do Telômero/genética , Telômero/genética , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Razão de Chances , Polimorfismo de Nucleotídeo Único , Risco , Telomerase/genética
18.
PLoS One ; 11(7): e0157521, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27379672

RESUMO

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Células A549 , Adulto , Idoso , Idoso de 80 Anos ou mais , Células CACO-2 , Mapeamento Cromossômico , Neoplasias Colorretais/patologia , Biologia Computacional/métodos , Feminino , Genótipo , Células HCT116 , Células Hep G2 , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , Adulto Jovem
19.
Gastroenterology ; 151(2): 351-363.e28, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27094239

RESUMO

BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse. CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.


Assuntos
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Cálculos Biliares/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Adulto , Afro-Americanos/genética , Idoso , Estudos de Casos e Controles , Colesterol/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Metabolismo dos Lipídeos/genética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único
20.
Carcinogenesis ; 37(1): 87-95, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26586795

RESUMO

Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10(-10) and HR = 1.8, P = 3.7×10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
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