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1.
Artigo em Inglês | MEDLINE | ID: mdl-33318029

RESUMO

BACKGROUND: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. METHODS: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labelling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N=3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N=31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). RESULTS: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2 and ARFIP2 expression and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR:1.08, 95% CI:1.03-1.13, OR:3.33, 95% CI:2.46-4.50 and OR:1.15, 95% CI:1.02-1.29, respectively). CONCLUSIONS: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation indicating a possible role in aspirin's reduction of metastasis. IMPACT: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

2.
Elife ; 92020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33135632

RESUMO

To better understand a role of eIF4E S209 in oncogenic translation, we generated EIF4ES209A/+ heterozygous knockin (4EKI) HCT 116 human colorectal cancer (CRC) cells. 4EKI had little impact on total eIF4E levels, cap binding or global translation, but markedly reduced HCT 116 cell growth in spheroids and mice, and CRC organoid growth. 4EKI strongly inhibited Myc and ATF4 translation, the integrated stress response (ISR)-dependent glutamine metabolic signature, AKT activation and proliferation in vivo. 4EKI inhibited polyposis in ApcMin/+ mice by suppressing Myc protein and AKT activation. Furthermore, p-eIF4E was highly elevated in CRC precursor lesions in mouse and human. p-eIF4E cooperated with mutant KRAS to promote Myc and ISR-dependent glutamine addiction in various CRC cell lines, characterized by increased cell death, transcriptomic heterogeneity and immune suppression upon deprivation. These findings demonstrate a critical role of eIF4E S209-dependent translation in Myc and stress-driven oncogenesis and as a potential therapeutic vulnerability.

3.
Cancer Epidemiol Biomarkers Prev ; 29(12): 2441-2453, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33033144

RESUMO

Biomarkers have a wide range of applications in the clinical management of cancer, including screening and therapeutic management. Tumor DNA released from neoplastic cells has become a particularly active area of cancer biomarker development due to the critical role somatic alterations play in the pathophysiology of cancer and the ability to assess released tumor DNA in accessible clinical samples, in particular blood (i.e., liquid biopsy). Many of the early applications of tumor DNA as a biomarker were pioneered in colorectal cancer due to its well-defined genetics and common occurrence, the effectiveness of early detection, and the availability of effective therapeutic options. Herein, in the context of colorectal cancer, we describe how the intended clinical application dictates desired biomarker test performance, how features of tumor DNA provide unique challenges and opportunities for biomarker development, and conclude with specific examples of clinical application of tumor DNA as a biomarker with particular emphasis on early detection.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

4.
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.

6.
Theranostics ; 10(18): 8098-8110, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32724460

RESUMO

Intrinsic and acquired resistance to targeted therapies is a significant clinical problem in cancer. We previously showed that resistance to regorafenib, a multi-kinase inhibitor for treating colorectal cancer (CRC) patients, can be caused by mutations in the tumor suppressor FBW7, which block degradation of the pro-survival Bcl-2 family protein Mcl-1. We tested if Mcl-1 inhibition can be used to develop a precision combination therapy for overcoming regorafenib resistance. METHODS: Small-molecule Mcl-1 inhibitors were tested on CRC cells with knock-in (KI) of a non-degradable Mcl-1. Effects of Mcl-1 inhibitors on regorafenib sensitivity were determined in FBW7-mutant and -wild-type (WT) CRC cells and tumors, and in those with acquired regorafenib resistance due to enriched FBW7 mutations. Furthermore, translational potential was explored by establishing and analyzing FBW7-mutant and -WT patient-derived organoid (PDO) and xenograft (PDX) tumor models. RESULTS: We found that highly potent and specific Mcl-1 inhibitors such as S63845 overcame regorafenib resistance by restoring apoptosis in multiple regorafenib-resistant CRC models. Mcl-1 inhibition re-sensitized CRC tumors with intrinsic and acquired regorafenib resistance in vitro and in vivo, including those with FBW7 mutations. Importantly, Mcl-1 inhibition also sensitized FBW7-mutant PDO and PDX models to regorafenib. In contrast, Mcl-1 inhibition had no effect in FBW7-WT CRCs. CONCLUSIONS: Our results demonstrate that Mcl-1 inhibitors can overcome intrinsic and acquired regorafenib resistance in CRCs by restoring apoptotic response. FBW7 mutations might be a potential biomarker predicting for response to the regorafenib/Mcl-1 inhibitor combination.

7.
Clin Gastroenterol Hepatol ; 18(12): 2667-2678.e2, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32634626

RESUMO

The American Gastroenterological Association's Center for Gastrointestinal Innovation and Technology convened a consensus conference in December 2018, entitled, "Colorectal Cancer Screening and Surveillance: Role of Emerging Technology and Innovation to Improve Outcomes." The goal of the conference, which attracted more than 60 experts in screening and related disciplines, including the authors, was to envision a future in which colorectal cancer (CRC) screening and surveillance are optimized, and to identify barriers to achieving that future. This White Paper originates from that meeting and delineates the priorities and steps needed to improve CRC outcomes, with the goal of minimizing CRC morbidity and mortality. A one-size-fits-all approach to CRC screening has not and is unlikely to result in increased screening uptake or desired outcomes owing to barriers stemming from behavioral, cultural, and socioeconomic causes, especially when combined with inefficiencies in deployment of screening technologies. Overcoming these barriers will require the following: efficient utilization of multiple screening modalities to achieve increased uptake; continued development of noninvasive screening tests, with iterative reassessments of how best to integrate new technologies; and improved personal risk assessment to better risk-stratify patients for appropriate screening testing paradigms.

8.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1817-1824, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32586834

RESUMO

BACKGROUND: Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated. METHODS: We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction. RESULTS: The association between minor allele of rs7200950 (ACD) with colorectal cancer-specific survival varied significantly by smoking pack-years (corrected P = 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer-specific survival in women but not in men. CONCLUSIONS: Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted. IMPACT: Our study found a gene-smoking and gene-sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.

9.
Prev Med ; 138: 106171, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32592796

RESUMO

Access to care varies by sex such that interactions with insurance status result in mixed patterns of preventive services utilization. We examined sex-specific effects of ACA Medicaid expansions on receipt of CRC screening. We used Behavioral Risk Factor Surveillance System data (2008-2016) for adults aged 50-64 years with household income ≤138% of federal poverty level to examine self-reported lifetime use of guideline-recommended CRC screening services overall and by screening modality. We employed difference-in-difference models comparing changes in CRC screening in 20 Medicaid expansion states before and after the ACA to changes in 18 states that did not expand Medicaid during our study period. We divided the expansion period into implementation (2014) and post-expansion (2016) periods to account for possible lagged effects. We observed time-varying effects of Medicaid expansion that revealed relative increases in CRC screening occurring during the post-expansion period. Heterogeneous effects by sex and by screening modality were also observed: there was a significant relative increase of 16.2 percentage points (95% CI [2.2, 30.2]; p-value = 0.023) in lifetime colonoscopy use among women in expansion states relative to non-expansion states in the post-expansion period. There were no significant effects of Medicaid expansion among men. Health insurance expansion had a lagged but significant effect on CRC screening among low-income non-elderly women in Medicaid expansion states, but no effect for men. The observed increase in CRC screening among women suggests that barriers to CRC screening may differ by sex, and tailored interventions to increase CRC screening improve outcomes.

10.
Cancer Epidemiol Biomarkers Prev ; 29(6): 1128-1134, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32188599

RESUMO

BACKGROUND: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer-specific survival. METHODS: Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer-specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer. RESULTS: The 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D-binding protein) was associated with poorer colorectal cancer-specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86-2.78] and colorectal cancer-specific mortality (HR = 1.76; 95% CI, 0.86-3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45-7.33; P heterogeneity = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50-11.43, P heterogeneity = 0.02). CONCLUSIONS: Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer-specific survival, although power might have been an issue. IMPACT: Further studies are warranted to investigate the association in specific subgroups.

11.
Clin Gastroenterol Hepatol ; 18(13): 2937-2944.e1, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32017987

RESUMO

BACKGROUND & AIMS: The contribution of surveillance colonoscopy, as opposed to that of initial colonoscopy examination, to prevention of colorectal cancer (CRC) is uncertain. We estimated the preventive effect of surveillance colonoscopy by applying the recently developed metric of adenoma dwell time avoided needed to prevent 1 CRC case (DTA). METHODS: We followed subjects in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial who underwent colonoscopies following positive findings from sigmoidoscopies (colonoscopy cohort, n = 15,935) for CRC incidence for 10 years. The number and timing of adenomas removed during surveillance were measured in a subset (n = 3492) of patients and extrapolated to the entire cohort to estimate the total avoided adenoma dwell time. A previously determined DTA value of 612 dwell years was applied to estimate the number of CRC cases prevented by surveillance. Proportional reduction in CRC was computed as CP/(CO+CP), where CO and CP are observed and estimated prevented cases, respectively. RESULTS: In the colonoscopy cohort of the PLCO, 2882 subjects had advanced adenomas (AAs), 572 had 3 or more non-advanced adenomas (NAA3+), 4496 had 1-2 non-advanced adenomas (NAA1-2), and 7985 had no adenoma (NA). The mean number of subsequent colonoscopy examinations over 10 years were 1.80 for subjects with AAs, 1.63 for subjects with NAA3+, and 1.46 for subjects with NAA1-2. Average years of avoided adenoma dwell time per subject were 4.0 for subjects with AAs, 5.5 for subjects with NAA3+, and 2.4 for subjects with NAA1-2. There were 56 cases of CRC in subjects with AAs, 4 cases of CRC in subjects with NAA3+, and 33 cases of CRC in subjects with NAA1-2. Estimated proportional reductions in CRC incidence were 25.0% in subjects with AAs (95% CI, 16%-34%), 34.4% in subjects with NAA1-2 (95% CI, 25%-40%), and 30.4% overall (in subjects with AAs, NAA3+, or NAA1-2; 95% CI, 25%-40%). Absolute CRC incidence reductions were 7.1 per 10,000 PY in subjects with AAs and 4.1 per 10,000 PY in subjects with NAA1-2. CONCLUSIONS: Using the recently developed metric of DTA, we estimated that surveillance colonoscopy in the PLCO colonoscopy cohort during 10 years of follow up prevented 30% of CRC cases. Because the methodology for estimation is indirect, the true effect is uncertain.

12.
Cancer Epidemiol Biomarkers Prev ; 29(5): 982-989, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32051194

RESUMO

BACKGROUND: Colonoscopy follow-up recommendations depend on the presence or absence of polyps, and if found, their number, size, and histology. Patients may be responsible for conveying results between primary and specialty care or providing medical information to family members; thus, accurate reporting is critical. This analysis assessed the accuracy of self-reported colonoscopy findings. METHODS: 3,986 participants from the Study of Colonoscopy Utilization, an ancillary study nested within the Prostate, Lung, Colorectal, and Ovarian Screening Trial, were included. Self-reports of polyp and adenoma were compared to medical records, and measures of sensitivity and specificity were calculated. Correlates of accurate self-report of polyp were assessed using logistic regression and weighted to account for study sampling. RESULTS: The sensitivity and specificity of self-reported polyp findings were 88% and 85%, respectively, and for adenoma 11% and 99%, respectively. Among participants with a polyp, older age was associated with lower likelihood while polyp severity and non-white race were associated with increased likelihood of accurate recall. Among participants without a polyp, having multiple colonoscopies was associated with lower likelihood while family history of colorectal cancer was associated with increased likelihood of accurate recall. Among both groups, longer time since colonoscopy was associated with lower likelihood of accurate recall. CONCLUSIONS: Participants recalled with reasonable accuracy whether they had a prior polyp; however, recall of histology, specifically adenoma, was much less accurate. IMPACT: Identification of strategies to increase accurate self-report of colonic polyps are needed, particularly for patient-provider communications and patient reporting of results to family members.

13.
Proc Natl Acad Sci U S A ; 117(9): 4858-4863, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32075918

RESUMO

We report a sensitive PCR-based assay called Repetitive Element AneupLoidy Sequencing System (RealSeqS) that can detect aneuploidy in samples containing as little as 3 pg of DNA. Using a single primer pair, we amplified ∼350,000 amplicons distributed throughout the genome. Aneuploidy was detected in 49% of liquid biopsies from a total of 883 nonmetastatic, clinically detected cancers of the colorectum, esophagus, liver, lung, ovary, pancreas, breast, or stomach. Combining aneuploidy with somatic mutation detection and eight standard protein biomarkers yielded a median sensitivity of 80% in these eight cancer types, while only 1% of 812 healthy controls scored positive.


Assuntos
Aneuploidia , Neoplasias , Sequências Repetitivas de Ácido Nucleico , Biomarcadores Tumorais , DNA Tumoral Circulante , DNA/genética , Esôfago , Humanos , Biópsia Líquida , Mutação , Neoplasias/diagnóstico , Neoplasias/genética , Sequências Repetitivas de Ácido Nucleico/genética , Sequenciamento Completo do Genoma
14.
Gastroenterology ; 158(2): 418-432, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31394083

RESUMO

The incidence of colorectal cancer (CRC) is increasing worldwide. CRC has high mortality when detected at advanced stages, yet it is also highly preventable. Given the difficulties in implementing major lifestyle changes or widespread primary prevention strategies to decrease CRC risk, screening is the most powerful public health tool to reduce mortality. Screening methods are effective but have limitations. Furthermore, many screen-eligible people remain unscreened. We discuss established and emerging screening methods, and potential strategies to address current limitations in CRC screening. A quantum step in CRC prevention might come with the development of new screening strategies, but great gains can be made by deploying the available CRC screening modalities in ways that optimize outcomes while making judicious use of resources.


Assuntos
Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/normas , Carga Global da Doença , Implementação de Plano de Saúde/normas , Programas de Rastreamento/normas , Colonoscopia/normas , Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Detecção Precoce de Câncer/estatística & dados numéricos , Estilo de Vida Saudável , Humanos , Incidência , Programas de Rastreamento/organização & administração , Programas de Rastreamento/estatística & dados numéricos , Sangue Oculto , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Medição de Risco/normas , Sigmoidoscopia/normas , Sigmoidoscopia/estatística & dados numéricos
15.
Gastrointest Endosc ; 91(3): 634-640, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31521778

RESUMO

BACKGROUND AND AIMS: Guidelines recommend colonoscopy after an episode of diverticulitis to exclude neoplasia but the effectiveness of testing is uncertain. Patients with complicated diverticulitis may be at higher risk for neoplasia, but most patients have uncomplicated disease. We examined the incidence of colorectal cancer (CRC) and advanced adenoma (AA) in patients with diverticulitis compared with patients undergoing screening colonoscopy. METHODS: CT scans from January 1, 2008, to May 1, 2013, at the University of Pittsburgh Medical Center (UPMC) were reviewed to identify those with confirmed acute diverticulitis. Subsequent surgical, colonoscopy, and pathology reports were abstracted to identify those with a diagnosis of AA and CRC. The incidence of neoplasia was compared with that reported for screening colonoscopy from a meta-analysis (n = 68,324), and from colonoscopy examinations at UPMC between 2013 and 2015 (n = 28,573). RESULTS: A total of 5167 abdominal/pelvic CT scan reports identified 978 patients with acute diverticulitis, among which 474 (48.5%) patients had undergone at least 1 colonoscopy or gastrointestinal surgery to April 2015. The CRC rate in patients with diverticulitis (13/474, 2.7%) was significantly higher (P < .0001) compared with both the meta-analysis (0.8%) and UPMC (0.3%). The AA rate (19/474, 4.0%) was similar to the rate in the meta-analysis (5.0%, P = .39) but significantly lower than at UPMC (7.7%, P = .003). The incidence of AA or CRC in complicated diverticulitis (10/141, 7.1%) did not differ significantly (P = .85) from the incidence of AA or CRC in uncomplicated diverticulitis (22/332, 6.6%). CONCLUSIONS: CRC after diverticulitis was significantly higher than that observed at screening colonoscopy and was not limited to complicated disease. Colonoscopy is advisable after the diagnosis of diverticulitis.

16.
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
17.
Int J Cancer ; 146(3): 861-873, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31037736

RESUMO

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.


Assuntos
Neoplasias Colorretais/etiologia , Etanol/efeitos adversos , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Estudos de Casos e Controles , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de Risco
20.
Front Immunol ; 10: 1401, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275327

RESUMO

Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that accumulate in circulation of cancer patients and at tumor sites where they suppress anti-tumor immunity. We previously reported that in a colon cancer prevention trial of a MUC1 vaccine tested in individuals at increased risk for colon cancer, those who did not mount immune response to the vaccine had higher pre-vaccination levels of circulating MDSC compared to those who did. We also reported that individuals with pancreatic premalignancy, Intraductal Papillary Mucinous Neoplasm (IPMN), had increased circulating levels of MDSC that inversely correlated with spontaneous antibody responses against the pancreatic tumor associated antigen MUC1, abnormally expressed on IPMN. Accumulation of MDSC in cancer and their immunosuppressive role had been well established but their presence in premalignancy was unexpected. In this study we compared MDSC in premalignancy with those in cancer with the hypothesis that there might be differences in the composition of various MDSC subpopulations and their immunosuppressive functions due to different lengths of exposure to disease and/or different tissue microenvironments. In cohorts of patients with premalignant polyps, colon cancer, premalignant IPMN, and pancreatic cancer, we confirmed higher levels of MDSC in premalignancy compared to healthy controls, higher levels of MDSC in cancer compared to premalignancy, but no difference in their subpopulation composition or immunosuppressive capacity. We show that levels of MDSC in premalignancy correlate negatively in vivo with spontaneous MUC1-specific antibody responses and in vitro with polyclonal T cell proliferation and IFN-γ secretion.


Assuntos
Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Lesões Pré-Cancerosas , Biomarcadores , Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Humanos , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Neoplasias/patologia , Fenótipo , Microambiente Tumoral
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