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1.
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 (CRC) 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 CRC prognosis. METHODS: In a prospective German cohort of 3 593 CRC patients, we assessed the association of 771 SNPs in 58 T-reg related genes with overall and CRC-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated since tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2 047 CRC patients of the International Survival Analysis in Colorectal cancer Consortium (ISACC). RESULTS: A significant association of the TGFBR3 SNP rs7524066 with more favorable CRC-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 CRC patients. IMPACT: The implicated genes warrant further investigation.

2.
Cancer Immunol Res ; 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023967

RESUMO

Macrophages are among the most common cells in the colorectal cancer microenvironment, but their prognostic significance is incompletely understood. Using multiplexed immunofluorescence for CD68, CD86, IRF5, MAF, MRC1 (CD206), and KRT (cytokeratins) combined with digital image analysis and machine learning, we assessed the polarization spectrum of tumor-associated macrophages in 931 colorectal carcinomas. We then applied Cox proportional hazards regression to assess prognostic survival associations of intraepithelial and stromal densities of M1-like and M2-like macrophages, while controlling for potential confounders, including stage and microsatellite instability status. We found that high tumor stromal density of M2-like macrophages was associated with worse cancer-specific survival, whereas tumor stromal density of M1-like macrophages was not significantly associated with better cancer-specific survival. High M1:M2 density ratio in tumor stroma was associated with better cancer-specific survival. Overall macrophage densities in tumor intraepithelial or stromal regions were not prognostic. These findings suggested that macrophage polarization state, rather than their overall density, was associated with cancer-specific survival, with M1- and M2-like macrophage phenotypes exhibiting distinct prognostic roles. These results highlight the utility of a multimarker strategy to assess the macrophage polarization at single cell resolution within the tumor microenvironment.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32917664

RESUMO

BACKGROUND: Higher total 25-hydroxyvitamin D [25(OH)D] levels are associated with improved survival among patients with colorectal cancer, but the relationships between circulating vitamin D binding protein (VDBP), and bioavailable or free 25(OH)D, and colorectal cancer survival remain unknown. METHODS: We examined the associations between prediagnostic plasma levels of vitamin D-related markers and survival among 603 White participants diagnosed with colorectal cancer from two prospective U.S. cohorts. Plasma VDBP and total 25(OH)D were directly measured, while bioavailable and free 25(OH)D was calculated using a validated formula on the basis of total 25(OH)D, VDBP, and albumin levels. Cox proportional hazards regression was used to estimate HRs for overall and colorectal cancer-specific mortality, with adjustment for other prognostic markers and potential confounders. RESULTS: Higher VDBP levels were associated with improved overall (P trend = 0.001) and colorectal cancer-specific survival (P trend = 0.02). Compared with patients in the lowest quartile, those in the highest quartile of VDBP had a multivariate HR of 0.58 [95% confidence interval (CI), 0.41-0.80] for overall mortality and 0.58 (95% CI, 0.37-0.91) for colorectal cancer-specific mortality. The results remained similar after further adjustment for total 25(OH)D levels. In contrast, neither bioavailable nor free 25(OH)D levels were associated with overall or colorectal cancer-specific mortality (all P trend > 0.15). CONCLUSIONS: Prediagnostic circulating concentrations of VDBP were positively associated with survival among patients with colorectal cancer. IMPACT: The clinical utility of VDBP as a prognostic marker warrants further exploration, as well as research into underlying mechanisms of action.

4.
Environ Res ; 190: 109781, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32791343

RESUMO

INTRODUCTION: Reasons why pancreatic ductal adenocarcinoma (PDAC) continues to have poor survival are only partly known. No previous studies have analyzed the combined influence of KRAS mutations, persistent organic pollutants (POPs), and trace elements upon survival in PDAC or in any other human cancer. OBJECTIVE: To analyze the individual and combined influence of KRAS mutations, POPs, and trace elements upon survival from PDAC. METHODS: Incident cases of PDAC (n = 185) were prospectively identified in five hospitals in Eastern Spain in 1992-1995 and interviewed face-to-face during hospital admission. KRAS mutational status was determined from tumour tissue through polymerase chain reaction and artificial restriction fragment length polymorphism. Blood and toenail samples were obtained before treatment. Serum concentrations of POPs were analyzed by high-resolution gas chromatography with electron-capture detection. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Multivariable Cox proportional hazards regression was used to assess prognostic associations. RESULTS: Patients with a KRAS mutated tumor had a 70% higher risk of early death than patients with a KRAS wild-type PDAC (hazard ratio [HR] = 1.7, p = 0.026), adjusting for age, sex, and tumor stage. KRAS mutational status was only modestly and not statistically significantly associated with survival when further adjusting by treatment or by treatment intention. The beneficial effects of treatment remained unaltered when KRAS mutational status was taken into account, and treatment did not appear to be less effective in the subgroup of patients with a KRAS mutated tumor. POPs did not materially influence survival: the adjusted HR of the highest POP tertiles was near unity for all POPs. When considering the joint effect on survival of POPs and KRAS, patients with KRAS mutated tumors had modest and nonsignificant HRs (most HRs around 1.3 to 1.4). Higher concentrations of lead, cadmium, arsenic, vanadium, and aluminium were associated with better survival. When KRAS status, POPs, and trace elements were simultaneously considered along with treatment, only the latter was statistically significantly related to survival. CONCLUSIONS: In this study based on molecular, clinical, and environmental epidemiology, KRAS mutational status, POPs, and trace elements were not adversely related to PDAC survival when treatment was simultaneously considered; only treatment was independently related to survival. The lack of adverse prognostic effects of POPs and metals measured at the time of diagnosis provide scientific and clinical reassurance on the effects of such exposures upon survival of patients with PDAC. The weak association with KRAS mutations contributes to the scant knowledge on the clinical implications of a genetic alteration highly frequent in PDAC.

5.
Cancer Res ; 80(20): 4578-4590, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32816852

RESUMO

Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65-1.04)] but not BRAF-wildtype tumors [1.09 (0.97-1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case-control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (P trend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. SIGNIFICANCE: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.

7.
Cancer Prev Res (Phila) ; 13(8): 699-706, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727821

RESUMO

Growing data indicate an association between periodontal disease and the development of cancer. However, the evidence for colorectal cancer has been inconsistent and longitudinal study examining its precursor lesions is lacking. We prospectively collected information on periodontal disease and number of tooth loss in the Nurses' Health Study (1992-2002) and the Health Professionals Follow-up Study (1992-2010). Polyp diagnosis was acquired via self-reported questionnaires and confirmed through review of medical records. We used logistic regression to calculate the multivariate-adjusted ORs and 95% confidence intervals (CI) with adjustment for smoking and other known risk factors for periodontal disease and colorectal cancer. In this study, we included 17,904 women and 24,582 men. We documented 2,336 cases of serrated polyps and 4,102 cases of conventional adenomas among 84,714 person-endoscopies throughout follow-up. The ORs of serrated polyps and conventional adenomas comparing individuals with and without periodontal disease were 1.17 (95% CI, 1.06-1.29) and 1.11 (95% CI, 1.02-1.19), respectively. Compared with participants without tooth loss, those who lost ≥4 teeth had 20% (OR, 1.20; 95% CI, 1.03-1.39) greater risk of serrated polyps (P trend 0.01). Among never smokers, similar associations with periodontal disease were observed for both serrated polyps (OR, 1.20; 95% CI, 1.02-1.41) and conventional adenomas (OR, 1.12; 95% CI, 1.00-1.26). History of periodontal disease and possibly higher number of tooth loss may modestly increase the risk of developing colorectal precursor lesions. Our findings advance our understanding of the interplay between oral health, microbiome, and early colorectal carcinogenesis.

8.
Int J Cancer ; 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32638350

RESUMO

The influence of polyunsaturated fatty acids (PUFAs) on risk of colorectal cancer precursors remains largely unknown. We examined the associations of erythrocyte PUFAs, including n-3 and n-6 PUFAs, with risk of colorectal conventional adenomas and serrated polyps in 4517 participants from three US prospective cohorts who had provided a blood sample and undergone at least one endoscopic examination. We calculated the multivariable odds ratios (ORs) per 1 SD increment in individual PUFAs and the ratio of n-6/n-3 PUFAs. We considered P < .005 statistically significant to account for multiple testing. During a median of 20 years of follow-up, we documented 493 conventional adenomas and 316 serrated polyps. After adjusting for various CRC risk factors, no associations for PUFAs achieved the stringent statistical significance for either conventional adenomas or serrated polyps (ORs per 1 SD ranged from 0.90 to 1.14). Some associations achieved nominal significance (P < .05), including the association of dihomogammalinolenic acid (DGLA) (20:3, n-6) with lower risk of conventional adenomas (OR = 0.91; 95% confidence interval [CI] = 0.83-1.00), total n-6 PUFAs with higher risk of proximal serrated polyps (OR = 1.32; 95% CI = 1.01-1.74) and eicosadienoic acid (20:2, n-6) and DGLA with lower risk of advanced adenomas (OR = 0.83; 95% CI = 0.71-0.97 and OR = 0.84; 95% CI = 0.72-0.98, respectively). Our findings indicate that erythrocyte PUFAs in a typical American diet are unlikely to have a substantial influence on risk of colorectal cancer precursors. The subgroup associations require further confirmation.

9.
EBioMedicine ; 57: 102860, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32652320

RESUMO

BACKGROUND: Tumour budding and poorly differentiated clusters (PDC) represent forms of tumour invasion. We hypothesised that T-cell densities (reflecting adaptive anti-tumour immunity) might be inversely associated with tumour budding and PDC in colorectal carcinoma. METHODS: Utilising 915 colon and rectal carcinomas in two U.S.-wide prospective cohort studies, and multiplex immunofluorescence combined with machine learning algorithms, we assessed CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 co-expression patterns in lymphocytes. Tumour budding and PDC at invasive fronts were quantified by digital pathology and image analysis using the International tumour Budding Consensus Conference criteria. Using covariate data of 4,420 incident colorectal cancer cases, inverse probability weighting (IPW) was integrated with multivariable logistic regression analysis that assessed the association of T-cell subset densities with tumour budding and PDC while adjusting for selection bias due to tissue availability and potential confounders, including microsatellite instability status. FINDINGS: Tumour budding counts were inversely associated with density of CD3+CD8+ [lowest vs. highest: multivariable odds ratio (OR), 0.50; 95% confidence interval (CI), 0.35-0.70; Ptrend < 0.001] and CD3+CD8+CD45RO+ cells (lowest vs. highest: multivariable OR, 0.44; 95% CI, 0.31-0.63; Ptrend < 0.001) in tumour epithelial region. Tumour budding levels were associated with higher colorectal cancer-specific mortality (multivariable hazard ratio, 2.13; 95% CI, 1.57-2.89; Ptrend < 0.001) in Cox regression analysis. There were no significant associations of PDC with T-cell subsets. INTERPRETATION: Tumour epithelial naïve and memory cytotoxic T cell densities are inversely associated with tumour budding at invasive fronts, suggesting that cytotoxic anti-tumour immunity suppresses tumour microinvasion.

10.
Eur J Nutr ; 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32548645

RESUMO

PURPOSE: Although evidence suggests an inverse association between yogurt consumption and the risk of disorders, such as type 2 diabetes and certain cancers, the mechanisms remain poorly understood. We aimed to examine the association between yogurt consumption and concentrations of plasma soluble CD14, a marker of gut barrier dysfunction. METHODS: We analyzed cross-sectional data from 632 women in the Nurses' Health Study (1989-1990) and 444 men in the Health Professionals Follow-up Study (1993-1994) with soluble CD14 concentrations. We estimated yogurt consumption from food frequency questionnaires. We used multivariable-adjusted linear regression models to estimate the percentage difference (95% CI) of soluble CD14 concentrations by yogurt consumption. RESULTS: Among men, higher consumption was associated with a lower soluble CD14 concentration (at least 2 cups/week vs. non-consumers; unadjusted % difference: - 7.6%; 95% CI - 13.0%, - 2.1%; Ptrend = 0.003). The inverse association was slightly attenuated following multivariable adjustment (% difference: - 5.8%; 95% CI - 11.0%, - 0.1%; Ptrend = 0.01). For the same comparison, yogurt consumption was inverse, but not statistically significant associated with soluble CD14 concentration in women (% difference: - 1.2%; 95% CI - 5.6%, 3.5%; Ptrend = 0.64). In stratified analyses, the inverse association between yogurt consumption and the concentrations of soluble CD14 was slightly stronger in men who consumed alcohol at least 20 g/day. CONCLUSIONS: Higher yogurt consumption was associated with lower soluble CD14 concentrations, especially in men. Our findings suggest the strengthening of gut barrier function as a plausible mechanism for the observed inverse associations of yogurt consumption with gastrointestinal diseases and disorders involving other systems.

11.
Br J Cancer ; 123(5): 844-851, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32541871

RESUMO

BACKGROUND: Despite several plausible biological mechanisms linking proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) with colorectal tumorigenesis, their association with risk of colorectal cancer (CRC) has not been adequately assessed in prospective epidemiological studies. METHODS: We evaluated the association of acid-suppressive medication use with CRC risk among 175,871 (PPI) and 208,831 (H2RA) participants from three large prospective cohort studies. Medication use was assessed at baseline and updated biennially. The association was evaluated using multivariate Cox proportional hazards regression models. RESULTS: There was no significant association between baseline PPI use (hazard ratio (HR) = 0.89, 95% confidence interval (CI), 0.71-1.12) or PPI use after a lag of 8-10 years (HR = 1.12, 95% CI, 0.78-1.59) with CRC risk. We observed no significant association between H2RA use after a lag of 8-10 years and CRC risk (HR = 1.02, 95% CI, 0.81-1.28), while risk was lower for participants with baseline H2RA use (HR = 0.76, 95% CI, 0.60-0.95). Duration of PPI use or H2RA use was not associated with CRC risk (P-trend = 0.21 and 0.95, respectively). CONCLUSIONS: Among participants from three large prospective cohorts, use of PPI or H2RA was not associated with higher risk of colorectal cancer.

12.
Adv Nutr ; 11(5): 1134-1149, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32488249

RESUMO

Multiple studies have suggested that ω-3 fatty acid intake may have a protective effect on cancer risk; however, its true association with cancer risk remains controversial. We performed an umbrella review of meta-analyses to summarize and evaluate the evidence for the association between ω-3 fatty acid intake and cancer outcomes. We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews from inception to December 1, 2018. We included meta-analyses of observational studies that examined associations between intake of fish or ω-3 fatty acid and cancer risk (gastrointestinal, liver, breast, gynecologic, prostate, brain, lung, and skin) and determined the level of evidence of associations. In addition, we appraised the quality of the evidence of significant meta-analyses by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. We initially screened 598 articles, and 15 articles, including 57 meta-analyses, were eligible. Among 57 meta-analyses, 15 reported statistically significant results. We found that 12 meta-analyses showed weak evidence of an association between ω-3 fatty acid intake and risk of the following types of cancer: liver cancer (n = 4 of 6), breast cancer (n = 3 of 14), prostate cancer (n = 3 of 11), and brain tumor (n = 2 of 2). In the other 3 meta-analyses, studies of endometrial cancer and skin cancer, there were no assessable data for determining the evidence levels. No meta-analysis showed convincing, highly suggestive, or suggestive evidence of an association. In the sensitivity analysis of meta-analyses by study design, we found weak associations between ω-3 fatty acid intake and breast cancer risk in cohort studies, but no statistically significant association in case-control studies. However, the opposite results were found in case of brain tumor risk. Although ω-3 fatty acids have been studied in several meta-analyses with regard to a wide range of cancer outcomes, only weak associations were identified in some cancer types, with several limitations. Considering the nonsignificant or weak evidence level, clinicians and researchers should cautiously interpret reported associations between ω-3 fatty acid consumption and cancer risks.

13.
J Transl Med ; 18(1): 205, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: covidwho-306010

RESUMO

The COVID-19 pandemic has become the leading societal concern. The pandemic has shown that the public health concern is not only a medical problem, but also affects society as a whole; so, it has also become the leading scientific concern. We discuss in this treatise the importance of bringing the world's scientists together to find effective solutions for controlling the pandemic. By applying novel research frameworks, interdisciplinary collaboration promises to manage the pandemic's consequences and prevent recurrences of similar pandemics.


Assuntos
Pesquisa Biomédica/organização & administração , Infecções por Coronavirus/epidemiologia , Prestação Integrada de Cuidados de Saúde/organização & administração , Emergências , Necessidades e Demandas de Serviços de Saúde , Pandemias , Pneumonia Viral/epidemiologia , Betacoronavirus/patogenicidade , Pesquisa Biomédica/métodos , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Prestação Integrada de Cuidados de Saúde/métodos , História do Século XXI , Humanos , Comunicação Interdisciplinar , Estudos Interdisciplinares , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Saúde Pública/história , Saúde Pública/normas
14.
J Transl Med ; 18(1): 205, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32430070

RESUMO

The COVID-19 pandemic has become the leading societal concern. The pandemic has shown that the public health concern is not only a medical problem, but also affects society as a whole; so, it has also become the leading scientific concern. We discuss in this treatise the importance of bringing the world's scientists together to find effective solutions for controlling the pandemic. By applying novel research frameworks, interdisciplinary collaboration promises to manage the pandemic's consequences and prevent recurrences of similar pandemics.


Assuntos
Pesquisa Biomédica/organização & administração , Infecções por Coronavirus/epidemiologia , Prestação Integrada de Cuidados de Saúde/organização & administração , Emergências , Necessidades e Demandas de Serviços de Saúde , Pandemias , Pneumonia Viral/epidemiologia , Betacoronavirus/patogenicidade , Pesquisa Biomédica/métodos , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Prestação Integrada de Cuidados de Saúde/métodos , História do Século XXI , Humanos , Comunicação Interdisciplinar , Estudos Interdisciplinares , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Saúde Pública/história , Saúde Pública/normas
15.
Cancer Epidemiol Biomarkers Prev ; 29(8): 1586-1595, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32467349

RESUMO

BACKGROUND: Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes. METHODS: In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and IGF1R genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors. RESULTS: Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24-2.44; P trend = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00-1.92; P trend = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m2 (HR, 4.27; 95% CI, 2.03-8.96, comparing extreme tertiles; P interaction = 0.032). KRAS-mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in IGF1R were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, P < 0.001). CONCLUSIONS: Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC. IMPACT: IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.

16.
Clin Cancer Res ; 26(16): 4326-4338, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32439699

RESUMO

PURPOSE: Although high T-cell density is a well-established favorable prognostic factor in colorectal cancer, the prognostic significance of tumor-associated plasma cells, neutrophils, and eosinophils is less well-defined. EXPERIMENTAL DESIGN: We computationally processed digital images of hematoxylin and eosin (H&E)-stained sections to identify lymphocytes, plasma cells, neutrophils, and eosinophils in tumor intraepithelial and stromal areas of 934 colorectal cancers in two prospective cohort studies. Multivariable Cox proportional hazards regression was used to compute mortality HR according to cell density quartiles. The spatial patterns of immune cell infiltration were studied using the GTumor:Immune cell function, which estimates the likelihood of any tumor cell in a sample having at least one neighboring immune cell of the specified type within a certain radius. Validation studies were performed on an independent cohort of 570 colorectal cancers. RESULTS: Immune cell densities measured by the automated classifier demonstrated high correlation with densities both from manual counts and those obtained from an independently trained automated classifier (Spearman's ρ 0.71-0.96). High densities of stromal lymphocytes and eosinophils were associated with better cancer-specific survival [P trend < 0.001; multivariable HR (4th vs 1st quartile of eosinophils), 0.49; 95% confidence interval, 0.34-0.71]. High GTumor:Lymphocyte area under the curve (AUC0,20µm; P trend = 0.002) and high GTumor:Eosinophil AUC0,20µm (P trend < 0.001) also showed associations with better cancer-specific survival. High stromal eosinophil density was also associated with better cancer-specific survival in the validation cohort (P trend < 0.001). CONCLUSIONS: These findings highlight the potential for machine learning assessment of H&E-stained sections to provide robust, quantitative tumor-immune biomarkers for precision medicine.

17.
Gastroenterology ; 159(1): 241-256.e13, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32247020

RESUMO

BACKGROUND & AIMS: The molecular features of colorectal tumors differ with their anatomic location. Colorectal tumors are usually classified as proximal or distal. We collected data from 3 cohorts to identify demographic, clinical, anthropometric, lifestyle, and dietary risk factors for colorectal cancer (CRC) at 7 anatomic subsites. We examined whether the associations differ among refined subsites and whether there are trends in associations from cecum to rectum. METHODS: We collected data from the Nurses' Health Study, Nurses' Health Study 2, and Health Professionals Follow-up Study (45,351 men and 178,016 women, followed for a median 23 years) on 24 risk factors in relation to risk of cancer in cecum, ascending colon, transverse colon, descending colon, sigmoid colon, rectosigmoid junction, and rectum. Hazard ratios were estimated using Cox proportional hazards regression. We tested for linear and nonlinear trends in associations with CRC among subsites and within proximal colon, distal colon, and rectum. RESULTS: We documented 3058 cases of CRC (474 in cecum, 633 in ascending colon, 250 in transverse colon, 221 in descending colon, 750 in sigmoid colon, 202 in rectosigmoid junction, and 528 in rectum). The positive associations with cancer risk decreased, from cecum to rectum, for age and family history of CRC. In contrast, the inverse associations with cancer risk increased, from cecum to rectum, for endoscopic screening and intake of whole grains, cereal fiber, and processed red meat. There was a significant nonlinear trend in the association between CRC and female sex, with hazard ratios ranging from 1.73 for ascending colon cancer to 0.54 for sigmoid colon cancer. For proximal colon cancers, the association with alcohol consumption and smoking before age 30 years increased from the cecum to transverse colon. For distal colon cancers, the positive association with waist circumference in men was greater for descending vs sigmoid colon cancer. CONCLUSIONS: In an analysis of 3058 cases of CRC, we found that risk factor profiles differed for cancers along the colorectum. Proximal vs distal classifications are not sufficient to encompass the regional variations in colorectal tumor features and risk factors.

18.
J Natl Cancer Inst ; 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32324875

RESUMO

BACKGROUND: Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. METHODS: We tested multiplicative statistical interactions between BMI (per 5 kg·m2) and approximately 2.7 million single nucleotide polymorphisms (SNPs) with colorectal cancer risk among 14,059 colorectal cancer case (53.2% women) and 14,416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included two-step (i.e., Cocktail method) and single-step (i.e., case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. RESULTS: Each 5 kg·m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR]: 1.14; 95% confidence intervals [CI]: 1.11-1.18; p-value: 9.75 x 10-17) than for men (OR: 1.26; 95% CI: 1.20-1.32; p-value: 2.13 x 10-24). The two-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; p-observed: 0.0009; p-threshold: 0.005). A joint 2-degree of freedom test was consistent with this finding for women (joint p-value: 2.43 x 10-10). Each 5 kg·m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR: 1.24; 95% CI: 1.16-1.32; p-value: 2.60 x 10-10) than for women with the CT (OR: 1.14; 95% CI: 1.09-1.19; p-value: 1.04 x 10-8) or TT (OR: 1.07; 95% CI: 1.01-1.14; p-value: 0.02) genotypes. CONCLUSION: These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.

19.
Br J Cancer ; 122(9): 1367-1377, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32157241

RESUMO

BACKGROUND: Histological lymphocytic reaction is regarded as an independent prognostic marker in colorectal cancer. Considering the lack of adequate statistical power, adjustment for selection bias and comprehensive tumour molecular data in most previous studies, we investigated the strengths of the prognostic associations of lymphocytic reaction in colorectal carcinoma by utilising an integrative database of two prospective cohort studies. METHODS: We examined Crohn's-like reaction, intratumoural periglandular reaction, peritumoural reaction and tumour-infiltrating lymphocytes in 1465 colorectal carcinoma cases. Using covariate data of 4420 colorectal cancer cases in total, inverse probability-weighted Cox proportional hazard regression model was used to control for selection bias (due to tissue availability) and potential confounders, including stage, MSI status, LINE-1 methylation, PTGS2 and CTNNB1 expression, KRAS, BRAF and PIK3CA mutations, and tumour neoantigen load. RESULTS: Higher levels of each lymphocytic reaction component were associated with better colorectal cancer-specific survival (Ptrend < 0.002). Compared with cases with negative/low intratumoural periglandular reaction, multivariable-adjusted HRs were 0.55 (95% CI, 0.42-0.71) in cases with intermediate reaction and 0.20 (95% CI, 0.12-0.35) in cases with high reaction. These relationships were consistent in strata of MSI status or neoantigen loads (Pinteraction > 0.2). CONCLUSIONS: The four lymphocytic reaction components are prognostic biomarkers in colorectal carcinoma.

20.
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.

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