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1.
Sci Rep ; 12(1): 10207, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35715570

RESUMO

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.


Assuntos
Neoplasias Colorretais , Mutação em Linhagem Germinativa , Desequilíbrio Alélico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Predisposição Genética para Doença , Células Germinativas/patologia , Humanos , Polimorfismo de Nucleotídeo Único
2.
Int J Cancer ; 151(3): 348-360, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35383926

RESUMO

Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj : 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj : 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference  = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.


Assuntos
Neoplasias Colorretais , Diabetes Mellitus , Biomarcadores Tumorais/genética , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ilhas de CpG/genética , Metilação de DNA , Diabetes Mellitus/genética , Humanos , Instabilidade de Microssatélites , Mutação , Fenótipo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
3.
Cancer Epidemiol Biomarkers Prev ; 31(5): 1068-1076, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35247911

RESUMO

BACKGROUND: Colorectal cancer has a strong epigenetic component that is accompanied by frequent DNA methylation (DNAm) alterations in addition to heritable genetic risk. It is of interest to understand the interrelationship of germline genetics, DNAm, and colorectal cancer risk. METHODS: We performed a genome-wide methylation quantitative trait locus (meQTL) analysis in 1,355 people, assessing the pairwise associations between genetic variants and lymphocytes methylation data. In addition, we used penalized regression with cis-genetic variants ± 1 Mb of methylation to identify genome-wide heritable DNAm. We evaluated the association of genetically predicted methylation with colorectal cancer risk based on genome-wide association studies (GWAS) of over 125,000 cases and controls using the multivariate sMiST as well as univariately via examination of marginal association with colorectal cancer risk. RESULTS: Of the 142 known colorectal cancer GWAS loci, 47 were identified as meQTLs. We identified four novel colorectal cancer-associated loci (NID2, ATXN10, KLHDC10, and CEP41) that reside over 1 Mb outside of known colorectal cancer loci and 10 secondary signals within 1 Mb of known loci. CONCLUSIONS: Leveraging information of DNAm regulation into genetic association of colorectal cancer risk reveals novel pathways in colorectal cancer tumorigenesis. Our summary statistics-based framework sMiST provides a powerful approach by combining information from the effect through methylation and residual direct effects of the meQTLs on disease risk. Further validation and functional follow-up of these novel pathways are needed. IMPACT: Using genotype, DNAm, and GWAS, we identified four new colorectal cancer risk loci. We studied the landscape of genetic regulation of DNAm via single-SNP and multi-SNP meQTL analyses.


Assuntos
Neoplasias Colorretais , Metilação de DNA , Neoplasias Colorretais/genética , Epigenômica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Proteínas , Locos de Características Quantitativas
4.
Cancer Epidemiol Biomarkers Prev ; 31(6): 1216-1226, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35266989

RESUMO

BACKGROUND: The etiology of colorectal cancer is not fully understood. METHODS: Using genetic variants and metabolomics data including 217 metabolites from the Framingham Heart Study (n = 1,357), we built genetic prediction models for circulating metabolites. Models with prediction R2 > 0.01 (Nmetabolite = 58) were applied to predict levels of metabolites in two large consortia with a combined sample size of approximately 46,300 cases and 59,200 controls of European and approximately 21,700 cases and 47,400 controls of East Asian (EA) descent. Genetically predicted levels of metabolites were evaluated for their associations with colorectal cancer risk in logistic regressions within each racial group, after which the results were combined by meta-analysis. RESULTS: Of the 58 metabolites tested, 24 metabolites were significantly associated with colorectal cancer risk [Benjamini-Hochberg FDR (BH-FDR) < 0.05] in the European population (ORs ranged from 0.91 to 1.06; P values ranged from 0.02 to 6.4 × 10-8). Twenty one of the 24 associations were replicated in the EA population (ORs ranged from 0.26 to 1.69, BH-FDR < 0.05). In addition, the genetically predicted levels of C16:0 cholesteryl ester was significantly associated with colorectal cancer risk in the EA population only (OREA: 1.94, 95% CI, 1.60-2.36, P = 2.6 × 10-11; OREUR: 1.01, 95% CI, 0.99-1.04, P = 0.3). Nineteen of the 25 metabolites were glycerophospholipids and triacylglycerols (TAG). Eighteen associations exhibited significant heterogeneity between the two racial groups (PEUR-EA-Het < 0.005), which were more strongly associated in the EA population. This integrative study suggested a potential role of lipids, especially certain glycerophospholipids and TAGs, in the etiology of colorectal cancer. CONCLUSIONS: This study identified potential novel risk biomarkers for colorectal cancer by integrating genetics and circulating metabolomics data. IMPACT: The identified metabolites could be developed into new tools for risk assessment of colorectal cancer in both European and EA populations.


Assuntos
Neoplasias Colorretais , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Glicerofosfolipídeos , Humanos , Lipídeos , Metabolômica/métodos
5.
J Natl Cancer Inst ; 114(4): 528-539, 2022 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-35026030

RESUMO

BACKGROUND: The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants. METHODS: Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve. RESULTS: Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores. CONCLUSIONS: Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.


Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , Idoso , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco
6.
J Natl Cancer Inst ; 114(5): 740-752, 2022 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-35048991

RESUMO

BACKGROUND: Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type 2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. METHODS: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). RESULTS: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. CONCLUSIONS: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.


Assuntos
Neoplasias Colorretais , Diabetes Mellitus Tipo 2 , Hiperinsulinismo , Glicemia/análise , Glicemia/genética , Neoplasias Colorretais/complicações , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla , Hemoglobina A Glicada/análise , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/genética , Insulina , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
7.
Sci Rep ; 12(1): 127, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996992

RESUMO

Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10-8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30-1.69, p = 8.47 × 10-9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65-2.77, p = 9.19 × 10-9 and rs144717887, HR = 2.01, 95% CI 1.57-2.58, p = 3.14 × 10-8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Medição de Risco , Fatores de Risco , Adulto Jovem
8.
Cancer Causes Control ; 33(3): 455-461, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35040017

RESUMO

PURPOSE: Physical activity (pre- and post-diagnosis) has been studied in prevention and survivorship contexts for endometrial cancer. However, the association of physical activity (PA) across the lifespan on mortality risk among endometrial cancer survivors is understudied. The study's objective was to identify the association of lifetime PA on mortality risk in endometrial cancer survivors. METHODS: Seven hundred forty-five endometrial cancer survivors drawn from a population-based cancer registry (diagnosed between 1991 and 1994) reported the frequency (sessions/week) of moderate- and vigorous intensity physical activity (MVPA) at age 12, age 20, and 5 years pre-interview (post-diagnosis). Cox proportional hazards were used to estimate hazard ratios (HR) and 95% confidence intervals for the association between PA, all-cause, and cardiovascular disease mortality as assessed in 2016. MVPA was modeled using natural cubic splines. RESULTS: Diagnosis age, body mass index, and smoking (pack-years) were each positively associated with increased all-cause mortality risk. Those who did one session of MVPA 5 years pre-interview had a lower mortality risk (HR 0.61; 95% CI 0.41-0.92) compared to those with no MVPA. Those reporting one session of MVPA was similarly observed at age 12 (HR 0.95; 95% CI 0.86-1.06) and at age 20 (HR 0.87; 95% CI 0.65-1.16). CONCLUSION: Those who participated in PA, compared to those who did not, in the 5 years before diagnosis had a lower mortality risk. While PA was not independently protective against mortality risk at ages 12 or 20, PA is still important for endometrial cancer survivors for other non-mortality outcomes.


Assuntos
Sobreviventes de Câncer , Neoplasias do Endométrio , Adulto , Criança , Neoplasias do Endométrio/epidemiologia , Exercício Físico , Feminino , Humanos , Longevidade , Fatores de Risco , Sobreviventes , Adulto Jovem
9.
Int J Cancer ; 150(9): 1447-1454, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34888857

RESUMO

Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected Pinteraction  = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.


Assuntos
Proteína C-Reativa , Neoplasias Colorretais , Proteína C-Reativa/análise , Proteína C-Reativa/genética , Feminino , Humanos , Estilo de Vida , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sobrevida
10.
Cancer Epidemiol Biomarkers Prev ; 31(1): 210-220, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34737207

RESUMO

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. METHODS: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer-specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer-specific mortality, and somatic mutations. RESULTS: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer-specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07-3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer-specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. CONCLUSIONS: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer-specific mortality and specific somatic mutated genes. IMPACT: Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.


Assuntos
Neoplasias Colorretais , Fusobacterium nucleatum , Carcinogênese , Neoplasias Colorretais/genética , Humanos , RNA Ribossômico 16S
11.
Nutrients ; 13(11)2021 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-34836419

RESUMO

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.


Assuntos
Aspirina/uso terapêutico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Ácido Salicílico/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/prevenção & controle , Dieta , Feminino , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Ácido Salicílico/administração & dosagem
12.
JNCI Cancer Spectr ; 5(5)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34738070

RESUMO

Background: Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies, but current evidence on smoking in association with survival after CRC diagnosis is limited. Methods: We pooled data from 12 345 patients with stage I-IV CRC from 11 epidemiologic studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of prediagnostic smoking behavior with overall, CRC-specific, and non-CRC-specific survival. Results: Among 12 345 patients with CRC, 4379 (35.5%) died (2515 from CRC) over a median follow-up time of 7.5 years. Smoking was strongly associated with worse survival in stage I-III patients, whereas no association was observed among stage IV patients. Among stage I-III patients, clear dose-response relationships with all survival outcomes were seen for current smokers. For example, current smokers with 40 or more pack-years had statistically significantly worse overall, CRC-specific, and non-CRC-specific survival compared with never smokers (hazard ratio [HR] =1.94, 95% confidence interval [CI] =1.68 to 2.25; HR = 1.41, 95% CI = 1.12 to 1.78; and HR = 2.67, 95% CI = 2.19 to 3.26, respectively). Similar associations with all survival outcomes were observed for former smokers who had quit for less than 10 years, but only a weak association with non-CRC-specific survival was seen among former smokers who had quit for more than 10 years. Conclusions: This large consortium of CRC patient studies provides compelling evidence that smoking is strongly associated with worse survival of stage I-III CRC patients in a clear dose-response manner. The detrimental effect of smoking was primarily related to noncolorectal cancer events, but current heavy smoking also showed an association with CRC-specific survival.


Assuntos
Neoplasias Colorretais/mortalidade , Fumar/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Intervalos de Confiança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Tempo
13.
Eur J Cancer ; 159: 247-258, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34794066

RESUMO

BACKGROUND: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome. PATIENTS AND METHODS: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10-5), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas. RESULTS: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10-7). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10-2) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10-8). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10-2). CONCLUSIONS: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Receptor ErbB-4/genética , Adenocarcinoma/mortalidade , Neoplasias Colorretais/mortalidade , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
14.
J Immunother Cancer ; 9(9)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34548385

RESUMO

BACKGROUND: Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC). METHODS: A CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score. RESULTS: Three CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts. CONCLUSIONS: This study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Colorretais/imunologia , Metilação de DNA/imunologia , Imunidade/imunologia , Linfócitos do Interstício Tumoral/imunologia , Humanos , Prognóstico
15.
JNCI Cancer Spectr ; 5(4)2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34377935

RESUMO

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P trend < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; P difference = 2.1 x 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (P difference < .001). Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Instabilidade de Microssatélites , Mutação , Fumar/efeitos adversos , Fatores Etários , Estudos de Casos e Controles , Ilhas de CpG/genética , Feminino , Genes ras/genética , Marcadores Genéticos/genética , Humanos , Modelos Logísticos , Masculino , Metilação , não Fumantes , Estudos Observacionais como Assunto , Fenótipo , Proteínas Proto-Oncogênicas B-raf/genética , Fatores Sexuais , Fumantes
16.
J Pediatric Infect Dis Soc ; 10(12): 1080-1086, 2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-34402910

RESUMO

BACKGROUND: Approximately 30% of US children aged 24 months have not received all recommended vaccines. This study aimed to develop a prediction model to identify newborns at high risk for missing early childhood vaccines. METHODS: A retrospective cohort included 9080 infants born weighing ≥2000 g at an academic medical center between 2008 and 2013. Electronic medical record data were linked to vaccine data from the Washington State Immunization Information System. Risk models were constructed using derivation and validation samples. K-fold cross-validation identified risk factors for model inclusion based on alpha = 0.01. For each patient in the derivation set, the total number of weighted adverse risk factors was calculated and used to establish groups at low, medium, or high risk for undervaccination. Logistic regression evaluated the likelihood of not completing the 7-vaccine series by age 19 months. The final model was tested using the validation sample. RESULTS: Overall, 53.6% failed to complete the 7-vaccine series by 19 months. Six risk factors were identified: race/ethnicity, maternal language, insurance status, birth hospitalization length of stay, medical service, and hepatitis B vaccine receipt. Likelihood of non-completion was greater in the high (77.1%; adjusted odds ratio [AOR] 5.6; 99% confidence interval [CI]: 4.2, 7.4) and medium (52.7%; AOR 1.9; 99% CI: 1.6, 2.2) vs low (38.7%) risk groups in the derivation sample. Similar results were observed in the validation sample. CONCLUSIONS: Our prediction model using information readily available in birth hospitalization records consistently identified newborns at high risk for undervaccination. Early identification of high-risk families could be useful for initiating timely, tailored vaccine interventions.


Assuntos
Vacinas contra Hepatite B , Vacinação , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Razão de Chances , Estudos Retrospectivos , Fatores de Risco
17.
Br J Cancer ; 125(6): 806-815, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34230610

RESUMO

BACKGROUND: Biomarker studies on colorectal cancer (CRC) prognosis are limited to pre-diagnostic or pre-operative measures. Post-treatment biomarkers are not well understood for their associations with CRC survival. METHODS: We included 306 eligible incident stage II-III CRC cases from the population-based Seattle Colon Cancer Family Registry. Concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), adiponectin, and leptin were measured using post-treatment plasma samples. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and CRC-specific mortality were calculated using Cox proportional hazard models. RESULTS: Elevated levels of CRP, IL-6, MCP-1, and adiponectin were significantly associated with a higher risk of all-cause mortality within 10 years post blood draw with HRs (95% CI) of 1.32 (1.10-2.59), 2.72 (2.07-3.56), 1.97 (1.18-3.28) and 1.71 (1.14-2.58), respectively. IL-6 and adiponectin had a dose-response effect (Ptrend < 0.0001). For CRC-specific mortality, we observed positive associations for CRP (HR = 1.75, 95% CI: 1.2-2.56), IL-6 (HR = 5.02, 95% CI: 2.92-8.59), MCP-1 (HR = 3.78, 95% CI: 1.41-10.08), and adiponectin (HR = 3.16, 95% CI: 1.27-7.86), and inverse association for leptin (HR = 0.44, 95% CI: 0.29-0.68) within the first year of blood draw, whereas the association for IL-6 remained statistically significant over 10 years. CONCLUSION: Our results support the role of chronic inflammation in CRC progression and suggested several post-treatment inflammatory biomarkers, particularly IL-6, are promising prognostic markers for stage II-III CRC patients.


Assuntos
Adiponectina/sangue , Proteína C-Reativa/análise , Quimiocina CCL2/sangue , Neoplasias Colorretais/patologia , Interleucina-6/sangue , Leptina/sangue , Adulto , Idoso , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/mortalidade , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
18.
Cancers (Basel) ; 13(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070246

RESUMO

PURPOSE: Sleep quality in relation to anatomic site among colorectal cancer (CRC) patients is not well understood, though discerning the relationship could contribute to improved survivorship care. METHODS: We ascertained sleep quality (Pittsburgh Sleep Quality Index) and other personal characteristics within an ongoing population-based study of CRC patients identified through a cancer registry (N = 1453). Differences in sleep quality by CRC site were analyzed using chi-square and ANOVA tests. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of tumor site with sleep quality concerns, adjusting for patient attributes and time since diagnosis. RESULTS: Sleeping problems were reported by 70% of CRC patients. Overall, participants with rectal (vs. colon) cancer were more likely (OR (95% CI)) to report general trouble sleeping (1.58 (1.19, 2.10)). Rectal cancer patients were also more likely than colon cancer patients to report changes in sleep patterns after cancer diagnosis (1.38 (1.05, 1.80)), and trouble sleeping specifically due to getting up to use the bathroom (1.53 (1.20, 1.96)) or pain (1.58 (1.15, 2.17)), but were less likely to report trouble sleeping specifically due to issues with breathing/coughing/snoring (0.51 (0.27, 0.99)). CONCLUSION: Overall, rectal cancer patients were more likely to have sleep complications compared to colon cancer patients. This suggests sleep-focused survivorship care may be adapted according to CRC site to ensure patients receive appropriate support.

19.
J Clin Oncol ; 39(23): 2564-2573, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34101481

RESUMO

PURPOSE: This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS: A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor-specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS: The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION: PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.


Assuntos
Neoplasias da Mama/genética , Variação Genética/genética , Adulto , Idoso , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Fatores de Risco
20.
Breast Cancer Res Treat ; 189(2): 463-470, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34129117

RESUMO

PURPOSE: Controversy remains regarding the optimal margin width for patients with ductal carcinoma in situ (DCIS) who undergo breast conserving surgery (BCS). METHODS: Women with a primary DCIS diagnosis were enrolled in a statewide population-based cohort from 1997 to 2006. Patients were surveyed every two years with follow-up data available through 2016. Surgical pathology reports were collected for 559 participants following breast conserving surgery. Multivariable Cox proportional hazard models evaluated relationships between locoregional recurrence (LRR) and margin width in the presence or absence of adjuvant radiation therapy while controlling for age, menopausal status and duration of endocrine therapy use. RESULTS: The majority of women in this study were over 50yo (74%), 34% had high grade disease, and 77% underwent radiation. The overall LRR rate was 12%. A LRR occurred in 46 women who had radiation (11%) and 23 women who did not undergo radiation (19%). Univariate analysis identified smaller margin width, younger age, premenopausal status, no radiotherapy, and shorter endocrine therapy use associated with LRR. Multivariable models demonstrated that close margins (< 2 mm) were associated with an increased risk of recurrence when compared to margins ≥ 2 mm in width whether women received radiation (HR 1.98 CI 0.87-4.54) or not (HR 1.32 CI 0.27-6.49), but confidence intervals were wide. CONCLUSIONS: In this study, patients with DCIS and close margins were less likely to experience recurrence after routine re-excision to margins greater than 2 mm.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Intraductal não Infiltrante/epidemiologia , Carcinoma Intraductal não Infiltrante/radioterapia , Carcinoma Intraductal não Infiltrante/cirurgia , Feminino , Humanos , Margens de Excisão , Mastectomia Segmentar , Recidiva Local de Neoplasia/epidemiologia
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