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1.
Nat Commun ; 10(1): 2910, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266951

RESUMO

PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Quinases Ciclina-Dependentes/genética , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/metabolismo , Recombinação Homóloga , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Camundongos , Camundongos SCID , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Células-Tronco Neoplásicas/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Int J Cancer ; 145(11): 3040-3051, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31044426

RESUMO

Epidemiologic evidence relating fiber intake to colorectal cancer (CRC) remains inconclusive and data are limited on different food sources of fiber and heterogeneity by tumor subsite and molecular profile. We prospectively followed for CRC incidence 90,869 women from the Nurses' Health Study (1980-2012) and 47,924 men from the Health Professionals Follow-up Study (1986-2012), who completed a validated food frequency questionnaire every 4 years. Cox proportional hazards regression was used to examine the associations with CRC risk for total, cereal, fruit and vegetable fiber and whole grains. We also assessed the associations according to tumor subsites (proximal colon, distal colon and rectum) and molecular markers (microsatellite instability, BRAF mutation, CpG island methylator phenotype and KRAS mutation). We documented 3,178 CRC cases during 3,685,903 person-years of follow-up in the NHS and HPFS. Intake of total dietary fiber was not associated with CRC risk after multivariable adjustment in either women (hazard ratio [HR] comparing extreme deciles, 1.17; 95% CI, 0.92-1.48, ptrend = 0.55) or men (HR, 0.90; 95% CI, 0.67-1.21, ptrend = 0.47). Higher intake of cereal fiber and whole grains was associated with lower CRC risk in men with an HR of 0.75 (95% CI, 0.57-1.00) and 0.72 (95% CI, 0.54-0.96), respectively. No heterogeneity was detected by tumor subsite or molecular markers (pheterogeneity > 0.05). Higher intake of total dietary fiber within the range of a typical American diet is unlikely to substantially reduce CRC risk. The potential benefit of cereal fiber and whole grains in men warrants further confirmation.

3.
Cancer Causes Control ; 30(8): 799-811, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069578

RESUMO

An important premise of epidemiology is that individuals with the same disease share similar underlying etiologies and clinical outcomes. In the past few decades, our knowledge of disease pathogenesis has improved, and disease classification systems have evolved to the point where no complex disease processes are considered homogenous. As a result, pathology and epidemiology have been integrated into the single, unified field of molecular pathological epidemiology (MPE). Advancing integrative molecular and population-level health sciences and addressing the unique research challenges specific to the field of MPE necessitates assembling experts in diverse fields, including epidemiology, pathology, biostatistics, computational biology, bioinformatics, genomics, immunology, and nutritional and environmental sciences. Integrating these seemingly divergent fields can lead to a greater understanding of pathogenic processes. The International MPE Meeting Series fosters discussion that addresses the specific research questions and challenges in this emerging field. The purpose of the meeting series is to: discuss novel methods to integrate pathology and epidemiology; discuss studies that provide pathogenic insights into population impact; and educate next-generation scientists. Herein, we share the proceedings of the Fourth International MPE Meeting, held in Boston, MA, USA, on 30 May-1 June, 2018. Major themes of this meeting included 'integrated genetic and molecular pathologic epidemiology', 'immunology-MPE', and 'novel disease phenotyping'. The key priority areas for future research identified by meeting attendees included integration of tumor immunology and cancer disparities into epidemiologic studies, further collaboration between computational and population-level scientists to gain new insight on exposure-disease associations, and future pooling projects of studies with comparable data.

4.
Cancer Causes Control ; 30(6): 637-649, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30963391

RESUMO

BACKGROUND: A preventive potential of high calcium intake against colorectal cancer has been indicated for distal colon cancer, which is inversely associated with high-level CpG island methylator phenotype (CIMP), high-level microsatellite instability (MSI), and BRAF and PIK3CA mutations. In addition, BRAF mutation is strongly inversely correlated with KRAS mutation. We hypothesized that the association between calcium intake and colon cancer risk might vary by these molecular features. METHODS: We prospectively followed 88,506 women from the Nurses' Health Study and 47,733 men from the Health Professionals Follow-up Study for up to 30 years. Duplication-method Cox proportional cause-specific hazards regression was used to estimate multivariable hazard ratios (HRs), and 95% confidence intervals (95% CIs) for the associations between calcium intake and the risk of colon cancer subtypes. By Bonferroni correction, the α-level was adjusted to 0.01. RESULTS: Based on 853 colon cancer cases, the inverse association between dietary calcium intake and colon cancer risk differed by CIMP status (pheterogeneity = 0.01). Per each 300 mg/day increase in intake, multivariable HRs were 0.84 (95% CI 0.76-0.94) for CIMP-negative/low and 1.12 (95% CI 0.93-1.34) for CIMP-high. Similar differential associations were suggested for MSI subtypes (pheterogeneity = 0.02), with the corresponding HR being 0.86 (95% CI 0.77-0.95) for non-MSI-high and 1.10 (95% CI 0.92-1.32) for MSI-high. No differential associations were observed by BRAF, KRAS, or PIK3CA mutations. CONCLUSION: The inverse association between dietary calcium intake and colon cancer risk may be specific to CIMP-negative/low and possibly non-MSI-high subtypes.


Assuntos
Cálcio/administração & dosagem , Neoplasias do Colo/patologia , Ilhas de CpG/genética , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Neoplasias do Colo/genética , Metilação de DNA , Feminino , Seguimentos , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Fenótipo , Modelos de Riscos Proporcionais , Risco
5.
Eur J Cancer ; 111: 82-93, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826660

RESUMO

BACKGROUND: Prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase-2, COX-2)-prostaglandin E2 (PGE2) pathway promotes tumour progression. Considering evidence suggesting increased PGE2 synthesis by BRAF mutation in tumour cells, we hypothesised that the association of tumour PTGS2 (COX-2) expression with colorectal cancer mortality might be stronger in BRAF-mutated tumours than in BRAF-wild-type tumours. METHODS: Using 1708 patients, including 1200 stage I-IV colorectal carcinoma cases in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) and 508 stage III colon cancer cases in a National Cancer Institute-sponsored randomised controlled trial of adjuvant therapy (CALGB/Alliance 89803), we evaluated tumour PTGS2 (COX-2) expression status using immunohistochemistry. We examined the prognostic association of PTGS2 (COX-2) expression in strata of BRAF mutation status by multivariable Cox proportional hazards regression models to adjust for potential confounders, including disease stage, tumour differentiation, microsatellite instability status and KRAS and PIK3CA mutations. RESULTS: In NHS and HPFS, the association of PTGS2 (COX-2) expression with colorectal cancer-specific survival differed by BRAF mutation status (Pinteraction = 0.0005); compared with PTGS2 (COX-2)-negative/low carcinomas, the multivariable-adjusted hazard ratios for PTGS2 (COX-2)-high carcinomas were 2.44 (95% confidence interval, 1.39-4.28) in BRAF-mutated cases and 0.82 (95% confidence interval, 0.65-1.04) in BRAF-wild-type cases. Differential prognostic associations of PTGS2 (COX-2) expression in strata of BRAF mutation status were similarly observed in CALGB/Alliance 89803 trial (Pinteraction = 0.03). CONCLUSIONS: The association of tumour PTGS2 (COX-2) expression with colorectal cancer mortality is stronger in BRAF-mutated tumours than in BRAF-wild-type tumours, supporting interactive roles of PTGS2 (COX-2) expression and BRAF mutation statuses in prognostication of patients with colorectal cancer; ClinicalTrials.gov Identifier, NCT00003835.

6.
Cancer Prev Res (Phila) ; 12(5): 283-294, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30760501

RESUMO

Calcium intake has been associated with a lower risk of colorectal cancer. Calcium signaling may enhance T-cell proliferation and differentiation, and contribute to T-cell-mediated antitumor immunity. In this prospective cohort study, we investigated the association between calcium intake and colorectal cancer risk according to tumor immunity status to provide additional insights into the role of calcium in colorectal carcinogenesis. The densities of tumor-infiltrating T-cell subsets [CD3+, CD8+ , CD45RO (PTPRC) + , or FOXP3+ cell] were assessed using IHC and computer-assisted image analysis in 736 cancer cases that developed among 136,249 individuals in two cohorts. HRs and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. Total calcium intake was associated with a multivariable HR of 0.55 (comparing ≥1,200 vs. <600 mg/day; 95% CI, 0.36-0.84; P trend = 0.002) for CD8+ T-cell-low but not for CD8+ T-cell-high tumors (HR = 1.02; 95% CI, 0.67-1.55; P trend = 0.47). Similarly, the corresponding HRs (95% CIs) for calcium for low versus high T-cell-infiltrated tumors were 0.63 (0.42-0.94; P trend = 0.01) and 0.89 (0.58-1.35; P trend = 0.20) for CD3+ ; 0.58 (0.39-0.87; P trend = 0.006) and 1.04 (0.69-1.58; P trend = 0.54) for CD45RO+ ; and 0.56 (0.36-0.85; P trend = 0.006) and 1.10 (0.72-1.67; P trend = 0.47) for FOXP3+ , although the differences by subtypes defined by T-cell density were not statistically significant. These potential differential associations generally appeared consistent regardless of sex, source of calcium intake, tumor location, and tumor microsatellite instability status. Our findings suggest a possible role of calcium in cancer immunoprevention via modulation of T-cell function.

7.
Psychiatry Res ; 273: 67-74, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30640053

RESUMO

There were few reports of oxytocin (OXT) concentrations of autism spectrum disorder (ASD) patients with severe intellectual disabilities. We measured serum OXT concentrations in 79 hospitalized patients with severe intellectual disabilities (16-60 years old, 50 males and 29 females, 54 ASD patients) and investigated the associations between serum OXT concentration, symptom scores, sex differences, and autism spectrum disorder. There were no significant effects of diagnosis, severity of intellectual disabilities, and total score of the Japanese version of the Aberrant Behavior Checklist (ABC-J), the Childhood Autism Rating Scale-Tokyo Version (CARS-TV), and the Japanese version of the Repetitive Behavior Scale-Revised (RBS-R). However, there were sex differences in the correlations between OXT concentrations and subscale scores in the ASD group. The male ASD group (n = 39) showed negative correlations between RBS-R Self-injurious and Sameness subscale scores and serum OXT concentrations. In the female ASD group(n = 15), CARS-TV Nonverbal communication subscale scores and RBS-R Compulsive subscale scores were seen to positively correlate with serum OXT concentrations. These findings suggest that OXT functions differ in males and females with severe intellectual disabilities and that OXT partly affects autism and related to some of the repetitive behaviors and nonverbal communication, in ASD patients with severe intellectual disabilities.

8.
Clin Cancer Res ; 25(6): 1948-1956, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30587545

RESUMO

PURPOSE: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. RESULTS: The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. CONCLUSIONS: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30476588

RESUMO

BACKGROUND & AIMS: Red and processed meat intake is associated with colorectal cancer (CRC) incidence, but it is not clear if intake is associated with patient survival after diagnosis METHODS: We pooled data from 7627 patients with stage I-IV CRC from 10 studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of intake of red and processed meat before diagnosis with overall and CRC-specific survival. RESULTS: Among 7627 patients with CRC, 2338 died, including 1576 from CRC, over a median follow-up time of 5.1 years. In multivariable-adjusted analyses, higher intake of red or processed meat was not associated with overall survival of patients with stage I-III CRC: Q4 vs Q1 red meat hazard ratio [HR], 1.08 (95% CI, 0.93-1.26) and Q4 vs Q1 processed meat HR, 1.10 (95% CI, 0.93-1.32) or with CRC-specific survival: Q4 vs Q1 red meat HR, 1.09 (95% CI, 0.89-1.33) and Q4 vs Q1 processed meat HR, 1.11 (95% CI, 0.87-1.42). Results were similar for patients with stage IV CRC. However, patients with stage I-III CRC who reported an intake of processed meat above the study-specific medians had a higher risk of death from any cause (HR, 1.12; 95% CI, 1.01-1.25) than patients who reported eating at or less than the median. CONCLUSION: In this large consortium of CRC patient cohorts, intake of red and processed meat before a diagnosis of CRC was not associated with shorter survival time after diagnosis, although a possible weak adverse association cannot be excluded. Studies that evaluate dietary data from several time points before and after cancer diagnosis are required to confirm these findings.

10.
J Natl Cancer Inst ; 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30312431

RESUMO

Background: Evidence indicates not only carcinogenic effect of cigarette smoking but also its immunosuppressive effect. We hypothesized that the association of smoking with colorectal cancer risk might be stronger for tumors with lower anti-tumor adaptive immune response. Methods: During follow-up of 134 981 participants (3 490 851 person-years) in the Nurses' Health Study and Health Professionals Follow-up Study, we documented 729 rectal and colon cancer cases with available data on T-cell densities in tumor microenvironment. Using the duplication-method Cox regression model, we examined a differential association of smoking status with risk of colorectal carcinoma subclassified by densities of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells. All statistical tests were two-sided. Results: The association of smoking status with colorectal cancer risk differed by CD3+ cell density (Pheterogeneity = .007). Compared with never smokers, multivariable-adjusted hazard ratios for CD3+ cell-low colorectal cancer were 1.38 (95% confidence interval = 1.09 to 1.75) in former smokers and 1.59 (95% confidence interval = 1.14 to 2.23) in current smokers (Ptrend = .002, across smoking status categories). In contrast, smoking status was not associated with CD3+ cell-high cancer risk (Ptrend = .52). This differential association appeared consistent in strata of microsatellite instability, CpG island methylator phenotype, or BRAF mutation status. There was no statistically significant differential association according to densities of CD8+ cells, CD45RO+ cells, or FOXP3+ cells (Pheterogeneity > .04, with adjusted α of 0.01). Conclusions: Colorectal cancer risk increased by smoking was stronger for tumors with lower T-lymphocyte response, suggesting an interplay of smoking and immunity in colorectal carcinogenesis.

11.
Am J Pathol ; 188(12): 2839-2852, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30243655

RESUMO

Evidence indicates a complex link between microbiota, tumor characteristics, and host immunity in the tumor microenvironment. In experimental studies, bifidobacteria appear to modulate intestinal epithelial cell differentiation. Accumulating evidence suggests that bifidobacteria may enhance the antitumor immunity and efficacy of immunotherapy. We hypothesized that the amount of bifidobacteria in colorectal carcinoma tissue might be associated with tumor differentiation and higher immune response to colorectal cancer. Using a molecular pathologic epidemiology database of 1313 rectal and colon cancers, we measured the amount of Bifidobacterium DNA in carcinoma tissue by a quantitative PCR assay. The multivariable regression model was used to adjust for potential confounders, including microsatellite instability status, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Intratumor bifidobacteria were detected in 393 cases (30%). The amount of bifidobacteria was associated with the extent of signet ring cells (P = 0.002). Compared with Bifidobacterium-negative cases, multivariable odd ratios for the extent of signet ring cells were 1.29 (95% CI, 0.74-2.24) for Bifidobacterium-low cases and 1.87 (95% CI, 1.16-3.02) for Bifidobacterium-high cases (Ptrend = 0.01). The association between intratumor bifidobacteria and signet ring cells suggests a possible role of bifidobacteria in determining distinct tumor characteristics or as an indicator of dysfunctional mucosal barrier in colorectal cancer.

12.
Cancer Immunol Res ; 6(11): 1327-1336, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30228205

RESUMO

The presence of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in the tumor-immune microenvironment between MSI-high and non-MSI-high carcinomas, we hypothesized that the association of F. nucleatum with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study, we measured F. nucleatum DNA in tumor tissue by a quantitative polymerase chain reaction assay. Multivariable logistic regression models were used to examine the association between F. nucleatum status and histopathologic lymphocytic reactions or density of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells in strata of tumor MSI status. We adjusted for potential confounders, including CpG island methylator phenotype; LINE-1 methylation; and KRAS, BRAF, and PIK3CA mutations. The association of F. nucleatum with tumor-infiltrating lymphocytes (TIL) and intratumoral periglandular reaction differed by tumor MSI status (P interaction = 0.002). The presence of F. nucleatum was negatively associated with TIL in MSI-high tumors [multivariable odds ratio (OR), 0.45; 95% confidence interval (CI), 0.22-0.92], but positively associated with TIL in non-MSI-high tumors (multivariable OR 1.91; 95% CI, 1.12-3.25). No significant differential association was observed for peritumoral lymphocytic reaction, Crohn-like lymphoid reaction, or T-cell densities. In conclusion, the association of F. nucleatum with immune response to colorectal carcinoma differs by tumor MSI status, suggesting that F. nucleatum and MSI status interact to affect antitumor immune reactions. Cancer Immunol Res; 6(11); 1327-36. ©2018 AACR See related Spotlight on p. 1290.

13.
Eur J Cancer ; 103: 98-107, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30219720

RESUMO

BACKGROUND: High-level plasma 25-hydroxyvitamin D [25(OH)D] has been associated with lower colorectal cancer incidence and mortality. Considering evidence indicating immunomodulatory effects of vitamin D, we hypothesised that survival benefits from high systemic vitamin D level might be stronger for colorectal carcinoma with lower immune response to tumour. METHODS: Using 869 colon and rectal cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study, we assessed the prognostic association of postdiagnosis 25(OH)D score [derived from diet and lifestyle variables to predict plasma 25(OH)D level] in strata of levels of histopathologic lymphocytic reaction. The Cox proportional hazards regression model was adjusted for potential confounders, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, PTGS2 (cyclooxygenase-2) expression and KRAS, BRAF and PIK3CA mutations. RESULTS: The association of postdiagnosis 25(OH)D score with colorectal cancer-specific mortality differed by levels of peritumoural lymphocytic reaction (pinteraction = 0.001). Multivariable-adjusted mortality hazard ratios for a quintile-unit increase of 25(OH)D score were 0.69 [95% confidence interval (CI), 0.54-0.89] in cases with negative/low peritumoural lymphocytic reaction, 1.08 (95% CI, 0.93-1.26) in cases with intermediate peritumoural reaction and 1.25 (95% CI, 0.75-2.09) in cases with high peritumoural reaction. The survival association of the 25(OH)D score did not significantly differ by Crohn's-like lymphoid reaction, intratumoural periglandular reaction or tumour-infiltrating lymphocytes. CONCLUSIONS: The association between the 25(OH)D score and colorectal cancer survival is stronger for carcinomas with lower peritumoural lymphocytic reaction. Our results suggesting interactive effects of vitamin D and immune response may contribute to personalised dietary and lifestyle intervention strategies.

14.
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.

15.
Annu Rev Pathol ; 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-30125150

RESUMO

Evidence indicates that diet, nutrition, lifestyle, the environment, the microbiome, and other exogenous factors have pathogenic roles and also influence the genome, epigenome, transcriptome, proteome, and metabolome of tumor and nonneoplastic cells, including immune cells. With the need for big-data research, pathology must transform to integrate data science fields, including epidemiology, biostatistics, and bioinformatics. The research framework of molecular pathological epidemiology (MPE) demonstrates the strengths of such an interdisciplinary integration, having been used to study breast, lung, prostate, and colorectal cancers. The MPEresearch paradigm not only can provide novel insights into interactions among environment, tumor, and host but also opens new research frontiers. New developments-such as computational digital pathology, systems biology, artificial intelligence, and in vivo pathology technologies-will further transform pathology and MPE. Although it is necessary to address the rarity of transdisciplinary education and training programs, MPE provides an exemplary model of integrative scientific approaches and contributes to advancements in precision medicine, therapy, and prevention. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 14 is January 24, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

16.
Oncoimmunology ; 7(7): e1442999, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29900052

RESUMO

Inhibitors targeting the PDCD1 (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PDCD1 ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer. Using 812 colon and rectal carcinoma cases from the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association of tumor characteristics and survival outcomes with four TIME subtypes (TIME 1, CD274low/TILabsent; TIME 2, CD274high/TILpresent; TIME 3, CD274low/TILpresent; and TIME 4, CD274high/TILabsent). In survival analyses, Cox proportional hazards models were adjusted for potential confounders, including microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, LINE-1 methylation level, and KRAS, BRAF, and PIK3CA mutation status. TIME subtypes 1, 2, 3 and 4 had 218 (27%), 117 (14%), 103 (13%), and 374 (46%) colorectal cancer cases, respectively. Compared with TIL-absent subtypes (TIME 1 and 4), TIL-present subtypes (TIME 2 and 3) were associated with high-level MSI, high-degree CIMP, BRAF mutation, and higher amounts of neoantigens (p < 0.001). TIME subtypes were not significantly associated with colorectal cancer-specific or overall survival. In conclusion, TIL-present TIME subtypes of colorectal cancer are associated with high levels of MSI and neoantigen load, supporting better responsiveness to cancer immunotherapy. Further studies examining tumor molecular alterations and additional factors in the tumor microenvironment may inform development of immunoprevention and immunotherapy strategies.

17.
Clin Gastroenterol Hepatol ; 16(10): 1622-1631.e3, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29702299

RESUMO

BACKGROUND & AIMS: Specific nutritional components are likely to induce intestinal inflammation, which is characterized by increased levels of interleukin 6 (IL6), C-reactive protein (CRP), and tumor necrosis factor-receptor superfamily member 1B (TNFRSF1B) in the circulation and promotes colorectal carcinogenesis. The inflammatory effects of a diet can be estimated based on an empiric dietary inflammatory pattern (EDIP) score, calculated based on intake of 18 foods associated with plasma levels of IL6, CRP, and TNFRSF1B. An inflammatory environment in the colon (based on increased levels of IL6, CRP, and TNFRSF1B in peripheral blood) contributes to impairment of the mucosal barrier and altered immune cell responses, affecting the composition of the intestinal microbiota. Colonization by Fusobacterium nucleatum has been associated with the presence and features of colorectal adenocarcinoma. We investigated the association between diets that promote inflammation (based on EDIP score) and colorectal cancer subtypes classified by level of F nucleatum in the tumor microenvironment. METHODS: We calculated EDIP scores based on answers to food frequency questionnaires collected from participants in the Nurses' Health Study (through June 1, 2012) and the Health Professionals Follow-up Study (through January 31, 2012). Participants in both cohorts reported diagnoses of rectal or colon cancer in biennial questionnaires; deaths from unreported colorectal cancer cases were identified through the National Death Index and next of kin. Colorectal tumor tissues were collected from hospitals where the patients underwent tumor resection and F nucleatum DNA was quantified by a polymerase chain reaction assay. We used multivariable duplication-method Cox proportional hazard regression to assess the associations of EDIP scores with risks of colorectal cancer subclassified by F nucleatum status. RESULTS: During 28 years of follow-up evaluation of 124,433 participants, we documented 951 incident cases of colorectal carcinoma with tissue F nucleatum data. Higher EDIP scores were associated with increased risk of F nucleatum-positive colorectal tumors (Ptrend = .03); for subjects in the highest vs lowest EDIP score tertiles, the hazard ratio for F nucleatum-positive colorectal tumors was 1.63 (95% CI, 1.03-2.58). EDIP scores did not associate with F nucleatum-negative tumors (Ptrend = .44). High EDIP scores associated with proximal F nucleatum-positive colorectal tumors but not with proximal F nucleatum-negative colorectal tumors (Pheterogeneity = .003). CONCLUSIONS: Diets that may promote intestinal inflammation, based on EDIP score, are associated with increased risk of F nucleatum-positive colorectal carcinomas, but not carcinomas that do not contain these bacteria. These findings indicate that diet-induced intestinal inflammation alters the gut microbiome to contribute to colorectal carcinogenesis; nutritional interventions might be used in precision medicine and cancer prevention.

18.
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.

19.
Clin Cancer Res ; 24(11): 2574-2584, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29511029

RESUMO

Purpose: Glioblastoma (GBM) is the most common primary central nervous system cancer in adults. Oncolytic HSV-1 (oHSV) is the first FDA-approved gene therapy approach for the treatment of malignant melanoma. For GBM, oHSVs need to be engineered to replicate within and be toxic to the glial tumor but not to normal brain parenchymal cells. We have thus engineered a novel oHSV to achieve these objectives.Experimental Design: NG34 is an attenuated HSV-1 with deletions in the genes encoding viral ICP6 and ICP34.5. These mutations suppress virus replication in nondividing brain neurons. NG34 expresses the human GADD34 gene under transcriptional control of a cellular Nestin gene promoter/enhancer element, whose expression occurs selectively in GBM. In vitro cytotoxicity assay and survival studies with mouse models were performed to evaluate therapeutic potency of NG34 against glioblastoma. In vivo neurotoxicity evaluation of NG34 was tested by intracerebral inoculation.Results: NG34 replicates in GBM cells in vitro with similar kinetics as those exhibited by an oHSV that is currently in clinical trials (rQNestin34.5). Dose-response cytotoxicity of NG34 in human GBM panels was equivalent to or improved compared with rQNestin34.5. The in vivo efficacy of NG34 against two human orthotopic GBM models in athymic mice was similar to that of rQNestin34.5, whereas intracerebral injection of NG34 in the brains of immunocompetent and athymic mice showed significantly better tolerability. NG34 was also effective in a syngeneic mouse glioblastoma model.Conclusions: A novel oHSV encoding GADD34 is efficacious and relatively nontoxic in mouse models of GBM. Clin Cancer Res; 24(11); 2574-84. ©2018 AACR.

20.
Gut ; 67(6): 1168-1180, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29437869

RESUMO

Immunotherapy strategies targeting immune checkpoints such as the CTLA4 and CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) T-cell coreceptor pathways are revolutionising oncology. The approval of pembrolizumab use for solid tumours with high-level microsatellite instability or mismatch repair deficiency by the US Food and Drug Administration highlights promise of precision immuno-oncology. However, despite evidence indicating influences of exogenous and endogenous factors such as diet, nutrients, alcohol, smoking, obesity, lifestyle, environmental exposures and microbiome on tumour-immune interactions, integrative analyses of those factors and immunity lag behind. Immune cell analyses in the tumour microenvironment have not adequately been integrated into large-scale studies. Addressing this gap, the transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to integrate tumour immunology into population health sciences, and link the exposures and germline genetics (eg, HLA genotypes) to tumour and immune characteristics. Multilevel research using bioinformatics, in vivo pathology and omics (genomics, epigenomics, transcriptomics, proteomics and metabolomics) technologies is possible with use of tissue, peripheral blood circulating cells, cell-free plasma, stool, sputum, urine and other body fluids. This immunology-MPE model can synergise with experimental immunology, microbiology and systems biology. GI neoplasms represent exemplary diseases for the immunology-MPE model, given rich microbiota and immune tissues of intestines, and the well-established carcinogenic role of intestinal inflammation. Proof-of-principle studies on colorectal cancer provided insights into immunomodulating effects of aspirin, vitamin D, inflammatory diets and omega-3 polyunsaturated fatty acids. The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine.


Assuntos
Imunoterapia/métodos , Neoplasias/imunologia , Patologia Molecular/métodos , Medicina de Precisão , Alergia e Imunologia , Humanos , Fatores Imunológicos/imunologia , Neoplasias/epidemiologia , Neoplasias/terapia
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