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1.
Nat Commun ; 13(1): 3254, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35668106

RESUMO

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.


Assuntos
Neoplasias Colorretais , DNA Glicosilases , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , DNA Glicosilases/genética , Análise Mutacional de DNA , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Mutação
2.
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
3.
Blood Adv ; 2022 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-35584396

RESUMO

Survivors of hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can negatively impact quality of life. Given limited studies, we aimed to describe the neurocognitive outcomes in a cohort of long-term adult HCT survivors. Eligible survivors (age ≥21y at HCT and alive ≥2y following HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL) and the Childhood Cancer Survivor Study Neurocognitive Questionnaire (NCQ). Analyses of risk factors included univariate comparisons and multivariable logistic regression. Survivors (n=1861, 47.7% female, 65.6% allogeneic HCT) were surveyed at a median age of 64.2y (interquartile range [IQR] 56.8-70.5) and a median 12.0y (IQR 6.0-21.0) from HCT. Survivors reported average Neuro-QoL scores (50.0 allogeneic; 49.2 autologous survivors) compared with an expected mean of 50 in the general population. On the NCQ, 17.4-31.2% of survivors reported impairments (Z-score >1.28) in task efficiency, memory, emotional regulation, or organization, compared with an expected 10% in the general population (all p<0.01). In multivariable regression analyses, impaired Neuro-QoL (T-score <40) was independently associated with hearing issues (OR 2.13, 95% CI 1.46-3.10) and sleep impairment (OR 4.41, 95% CI 2.80-6.94) among allogeneic survivors, with comparable associations in autologous survivors. Overall, long-term adult HCT survivors reported average cognitive quality of life compared with the general population. Subsets of survivors with hearing issues and sleep impairments were more likely to report lower quality of life and impaired neurocognitive function, which may facilitate targeted monitoring or interventions following HCT.

4.
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
5.
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
6.
Elife ; 112022 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-35346416

RESUMO

Background: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. Methods: We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Results: Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. Conclusions: GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results. Funding: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.


Have you noticed that some people seem to get older faster than others? Scientists have previously found that a chemical tag on DNA known as DNA methylation can be used to predict an individual's chronological age. However, age predicted using DNA methylation (also known as biological or epigenetic age) does not always perfectly correspond to chronological age. Indeed, some people's biological age is higher than their years, while other people's is lower. When an individual's biological age is higher than their chronological age, they are said to be experiencing 'epigenetic age acceleration'. This type of accelerated ageing, which can be measured with 'epigenetic clocks' based on DNA methylation, has been associated with several adverse health outcomes, including cancer. This means that epigenetic clocks may improve our ability to predict cancer risk and detect cancer early. However, it is still unclear whether accelerated biological ageing causes cancer, or whether it simply correlates with the disease. Morales-Berstein et al. wanted to investigate whether epigenetic age acceleration, as measured by epigenetic clocks, plays a role in the development of several cancers. To do so, they used an approach known as Mendelian randomization. Using genetic variants as natural experiments, they studied the effect of different measures of epigenetic age acceleration on cancer risk. Their work focused on five types of cancer: breast, colorectal, prostate, ovarian and lung cancer. They used genetic association data from people of European ancestry to determine whether genetic variants that are strongly associated with accelerated ageing are also strongly associated with cancer. The results showed that one of the DNA methylation markers used as an estimate of biological ageing could be directly related to the risk of developing colorectal cancer. This work provides new insights into the relationship between markers of biological ageing and cancer. Similar relationships should also be studied in other groups of people and for other cancer sites. The results suggest that reversing biological ageing by altering DNA methylation could prevent or delay the development of colorectal cancer.


Assuntos
Neoplasias Colorretais , Análise da Randomização Mendeliana , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Epigênese Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
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.
Support Care Cancer ; 30(5): 3829-3838, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35034197

RESUMO

BACKGROUND: Sleep problems (SP) are common in cancer patients but have not been previously assessed in patients receiving immune checkpoint inhibitors (ICI). METHODS: We collected questionnaire data on sleep apnea risk, insomnia, and general sleep patterns. We used an adjusted multivariate Poisson regression to calculate prevalence ratios (PRs) and associated 95% confidence intervals (CIs) for associations between these SP and metastatic versus localized cancer stage (M1 vs. M0), and adjusted logistic regression models to calculate ORs for associations between SP with the number of ICI infusions completed (6 + vs. < 6). RESULTS: Among 32 patients who received ICI treatment, the prevalence of low, intermediate, and high-risk OSA risk was 36%, 42%, and 21%, respectively. Overall, 58% of participants reported clinically significant insomnia. We did not find a significant association between intermediate or high risk OSA (vs. low risk) and metastatic cancer status (PR = 1.01 (95% CI: 0.28, 3.67)). Patients in the cohort who reported taking > 15 min to fall asleep were 3.6 times more likely to be diagnosed with metastatic cancer compared to those reporting shorter sleep latency (95% CI (1.74, 7.35)). We did not find a significant association between SP and number of ICI infusions completed. CONCLUSION: Our data associating sleep apnea risk, insomnia, and sleep patterns with more advanced cancer encourages further exploration in larger-scale observational studies and suggests interventional clinical trials focused on sleep quality improvement that could result in better outcomes for these patients.


Assuntos
Neoplasias , Apneia Obstrutiva do Sono , Distúrbios do Início e da Manutenção do Sono , Humanos , Neoplasias/complicações , Projetos Piloto , Polissonografia , Apneia Obstrutiva do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/complicações , Distúrbios do Início e da Manutenção do Sono/etiologia
9.
Cancer Epidemiol ; 76: 102057, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34798387

RESUMO

BACKGROUND: Sleep problems (SP) can indicate underlying sleep disorders, such as obstructive sleep apnea, which may adversely impact cancer risk and mortality. METHODS: We assessed the association of baseline and longitudinal sleep apnea and insomnia symptoms with incident cancer (N = 3930) and cancer mortality (N = 4580) in the Cardiovascular Health Study. We used Cox proportional hazards regression to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) to evaluate the associations. RESULTS: Overall, 885 incident cancers and 804 cancer deaths were identified over a median follow-up of 12 and 14 years, respectively. Compared to participants who reported no sleep apnea symptoms, the risk of incident cancer was inversely associated [(HR (95%CI)] with snoring [0.84 (0.71, 0.99)]. We noted an elevated prostate cancer incidence for apnea [2.34 (1.32, 4.15)] and snoring [1.69 (1.11, 2.57)]. We also noted an elevated HR for lymphatic or hematopoietic cancers [daytime sleepiness: 1.81 (1.06, 3.08)]. We found an inverse relationship for cancer mortality with respect to snoring [0.73 (0.62, 0.8)] and apnea [(0.69 (0.51, 0.94))]. We noted a significant inverse relationship between difficulty falling asleep and colorectal cancer death [0.32 (0.15, 0.69)] and snoring with lung cancer death [0.56 (0.35, 0.89)]. CONCLUSIONS: The relationship between SP and cancer risk and mortality was heterogeneous. Larger prospective studies addressing more cancer sites, molecular type-specific associations, and better longitudinal SP assessments are needed for improved delineation of SP-cancer risk dyad.


Assuntos
Neoplasias , Síndromes da Apneia do Sono , Transtornos do Sono-Vigília , Humanos , Incidência , Masculino , Neoplasias/complicações , Neoplasias/epidemiologia , Estudos Prospectivos , Síndromes da Apneia do Sono/complicações , Síndromes da Apneia do Sono/epidemiologia , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/epidemiologia , Ronco/complicações , Ronco/epidemiologia
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.
Int J Cancer ; 150(2): 208-220, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34469597

RESUMO

Reproductive and hormonal factors may influence breast cancer risk via endogenous estrogen exposure. Cumulative menstrual months (CMM) can be used as a surrogate measure of this exposure. Using harmonized data from four population-based breast cancer studies (7284 cases and 7242 controls), we examined ethnicity-specific associations between CMM and breast cancer risk using logistic regression, adjusting for menopausal status and other risk factors. Higher CMM was associated with increased breast cancer risk in non-Hispanic Whites, Hispanics and Asian Americans regardless of menopausal status (all FDR adjusted P trends = .0004), but not in African Americans. In premenopausal African Americans, there was a suggestive trend of lower risk with higher CMM. Stratification by body mass index (BMI) among premenopausal African American women showed a nonsignificant positive association with CMM in nonobese (BMI <30 kg/m2 ) women and a significant inverse association in obese women (OR per 50 CMM = 0.56, 95% CI 0.37-0.87, Ptrend  = .03). Risk patterns were similar for hormone receptor positive (HR+; ER+ or PR+) breast cancer; a positive association was found in all premenopausal and postmenopausal ethnic groups except in African Americans. HR- (ER- and PR-) breast cancer was not associated with CMM in all groups combined, except for a suggestive positive association among premenopausal Asian Americans (OR per 50 CMM = 1.33, P = .07). In summary, these results add to the accumulating evidence that established reproductive and hormonal factors impact breast cancer risk differently in African American women compared to other ethnic groups, and also differently for HR- breast cancer than HR+ breast cancer.


Assuntos
Neoplasias da Mama/etiologia , Menstruação , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adolescente , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Pré-Menopausa , Prognóstico , Adulto Jovem
12.
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
13.
Int J Radiat Biol ; 97(11): 1548-1554, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34473600

RESUMO

PURPOSE: Analyses of the Life Span Study cohort of atomic bomb survivors have shown a statistically significant sex difference in the excess risk of incident lung cancer due to radiation exposure, with the radiation-related excess relative risk per gray (ERR/Gy) for women approximately 4 times that for men, after accounting for active smoking. We sought to determine the extent to which this risk difference could be explained by adjustment for passive smoke exposure, which is a known risk factor for lung cancer that was not measured among Life Span Study participants, and which could be particularly influential among female never-smokers. MATERIALS AND METHODS: The Life Span Study includes survivors of the atomic bombings of Hiroshima and Nagasaki and city residents who were not in either city at the time of the bombings, matched to survivors on city, sex, and age. First primary lung cancers were identified from population-based cancer registries between 1958 and 2009. Data on active smoking were obtained from mailed surveys and in-person questionnaires (1965-1991). We calculated passive smoke exposure for female never-smokers by attributing smoking pack-years at various intensities (5-50%) based on smoking patterns among men, stratified by city, birth year, radiation dose, and lung cancer status. Poisson regression models with additive and multiplicative interactions between radiation dose and smoking were used to estimate sex-specific radiation-related excess relative risks for lung cancer. RESULTS: During the study period, 2,446 first primary lung cancers were identified among 105,444 study participants. On average, male smokers started smoking 19.5 cigarettes per day at 21.5 years old. Partially attributing male smoking patterns to female never-smokers-to approximate passive smoke exposure-yielded lower radiation-related ERR/Gy estimates for women under a multiplicative radiation-smoking interaction model, leading to a lower female-to-male ratio of ERR/Gy estimates; however, this difference was evident only at very high passive smoke intensities. Under an additive radiation-smoking interaction model, the results were unchanged. CONCLUSIONS: Our results are consistent with the possibility that failure to account for passive smoke might contribute, in small part, to the higher radiation risk estimates for lung cancer among women compared to men in the Life Span Study.


Assuntos
Neoplasias Pulmonares , Neoplasias Induzidas por Radiação , Armas Nucleares , Sobreviventes de Bombas Atômicas , Feminino , Humanos , Longevidade , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Masculino , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/etiologia , Risco , Fatores de Risco , Fumaça , Adulto Jovem
14.
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
15.
Immun Inflamm Dis ; 9(4): 1786-1794, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34289529

RESUMO

INTRODUCTION: The increasing proportion of outpatient allogeneic hematopoietic cell transplants (HCTs) coupled with increased access of once-daily broad-spectrum antibiotics and evidence that outpatient antibiotic treatment may be safer and less costly than inpatient treatment, suggest that allogeneic HCT recipients with Gram-negative rod bacteremia (GNRBs) are increasingly being treated in ambulatory care settings. METHODS: Using data from the first GNRB event that occurred within the first 100 days posttransplantation among allogeneic HCT recipients transplanted at a single center between 2007 and 2016, we estimated the temporal trends in GNRB incidence and treatment management of GNRBs and identified if patient or infection characteristics impacted observed trends. RESULTS: A total of 11% (238/2165) of the observed allogeneic HCT recipients experienced ≥1 GNRB with available resistance data and contributed antibiotic treatment time. Patients, on average, received 55.1% of their antibiotic treatment in an outpatient setting and we observed a significant decline in the proportion of treatment time spent outpatient (crude: -3.3% [95% confidence interval: -5.0, -1.6%]). We observed similar declines in the proportion of treatment time spent outpatient among patients with similar GNRB and pretransplant complexity factors but not among patients with similar posttransplant complications (p value: .165). CONCLUSION: These results suggest that, despite increased availability of outpatient suitable treatment options, allogeneic HCT recipients with GNRBs received less treatment in outpatient settings. However, among patients with similar posttransplant complications, the lack of significant decline suggests that treatment location decisions remained consistent for patients with similar posttransplant complications. These findings suggest the need for additional interventions targeting outpatient antibiotic treatment among allogeneic HCT recipients with GNRBs.


Assuntos
Bacteriemia , Transplante de Células-Tronco Hematopoéticas , Antibacterianos , Bacteriemia/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pacientes Ambulatoriais , Estudos Retrospectivos , Transplantados
16.
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.

17.
Cancer Epidemiol Biomarkers Prev ; 30(7): 1366-1374, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33947657

RESUMO

BACKGROUND: Existing evidence indicates household income as a predictor of health-related quality of life (HRQoL) following a colorectal cancer diagnosis. This association likely varies with neighborhood socioeconomic status (nSES), but evidence is limited. METHODS: We included data from 1,355 colorectal cancer survivors participating in the population-based Puget Sound Colorectal Cancer Cohort (PSCCC). Survivors reported current annual household income; we measured HRQoL via the Functional Assessment of Cancer Therapy - Colorectal (FACT-C) tool. Using neighborhood data summarized within a 1-km radial buffer of Census block group centroids, we constructed a multidimensional nSES index measure. We employed survivors' geocoded residential addresses to append nSES score for Census block group of residence. With linear generalized estimating equations clustered on survivor location, we evaluated associations of household income with differences in FACT-C mean score, overall and stratified by nSES. We used separate models to explore relationships for wellbeing subscales. RESULTS: We found lower household income to be associated with clinically meaningful differences in overall FACT-C scores [<$30K: -13.6; 95% confidence interval (CI): -16.8 to -10.4] and subscale wellbeing after a recent colorectal cancer diagnosis. Relationships were slightly greater in magnitude for survivors living in lower SES neighborhoods. CONCLUSIONS: Our findings suggest that recently diagnosed lower income colorectal cancer survivors are likely to report lower HRQoL, and modestly more so in lower SES neighborhoods. IMPACT: The findings from this work will aid future investigators' ability to further consider the contexts in which the income of survivors can be leveraged as a means of improving HRQoL.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias Colorretais/psicologia , Renda/estatística & dados numéricos , Qualidade de Vida , Características de Residência/estatística & dados numéricos , Idoso , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Classe Social , Inquéritos e Questionários/estatística & dados numéricos
18.
JAMA Netw Open ; 4(4): e214514, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33871619

RESUMO

Importance: Sepsis disproportionately affects recipients of allogeneic hematopoietic cell transplant (allo-HCT), and timely detection is crucial. However, the atypical presentation of sepsis within this population makes detection challenging, and existing clinical sepsis tools have limited prognostic value among this high-risk population. Objective: To develop a full risk factor (demographic, transplant, clinical, and laboratory factors) and clinical factor-specific automated bacterial sepsis decision support tool for recipients of allo-HCT with potential bloodstream infections (PBIs). Design, Setting, and Participants: This prognostic study used data from adult recipients of allo-HCT transplanted at the Fred Hutchinson Cancer Research Center, Seattle, Washington, between June 2010 and June 2019 randomly divided into 70% modeling and 30% validation data sets. Tools were developed using the area under the curve (AUC) optimized SuperLearner, and their performance was compared with existing clinical sepsis tools: National Early Warning Score (NEWS), quick Sequential Organ Failure Assessment (qSOFA), and Systemic Inflammatory Response Syndrome (SIRS), using the validation data set. Data were analyzed between January and October of 2020. Main Outcomes and Measures: The primary outcome was high-sepsis risk bacteremia (culture confirmed gram-negative species, Staphylococcus aureus, or Streptococcus spp bacteremia), and the secondary outcomes were 10- and 28-day mortality. Tool discrimination and calibration were examined using accuracy metrics and expected vs observed probabilities. Results: Between June 2010 and June 2019, 1943 recipients of allo-HCT received their first transplant, and 1594 recipients (median [interquartile range] age at transplant, 54 [43-63] years; 911 [57.2%] men; 1242 individuals [77.9%] identifying as White) experienced at least 1 PBI. Of 8131 observed PBIs, 238 (2.9%) were high-sepsis risk bacteremia. Compared with high-sepsis risk bacteremia, the full decision support tool had the highest AUC (0.85; 95% CI, 0.81-0.89), followed by the clinical factor-specific tool (0.72; 95% CI, 0.66-0.78). SIRS had the highest AUC of existing tools (0.64; 95% CI, 0.57-0.71). The full decision support tool had the highest AUCs for PBIs identified in inpatient (0.82; 95% CI, 0.76-0.89) and outpatient (0.82; 95% CI, 0.75-0.89) settings and for 10-day (0.85; 95% CI, 0.79-0.91) and 28-day (0.80; 95% CI, 0.75-0.84) mortality. Conclusions and Relevance: These findings suggest that compared with existing tools and the clinical factor-specific tool, the full decision support tool had superior prognostic accuracy for the primary (high-sepsis risk bacteremia) and secondary (short-term mortality) outcomes in inpatient and outpatient settings. If used at the time of culture collection, the full decision support tool may inform more timely sepsis detection among recipients of allo-HCT.


Assuntos
Técnicas de Apoio para a Decisão , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Aprendizado de Máquina/normas , Sepse/diagnóstico , Adulto , Feminino , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Imunocompetência , Masculino , Pessoa de Meia-Idade , Curva ROC , Distribuição Aleatória , Estudos Retrospectivos , Medição de Risco , Sepse/sangue , Sepse/etiologia , Sepse/microbiologia
19.
Clin Cancer Res ; 27(10): 2816-2826, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33632927

RESUMO

PURPOSE: While evidence indicates that Fusobacterium nucleatum (F. nucleatum) may promote colorectal carcinogenesis through its suppressive effect on T-cell-mediated antitumor immunity, the specific T-cell subsets involved remain uncertain. EXPERIMENTAL DESIGN: We measured F. nucleatum DNA within tumor tissue by quantitative PCR on 933 cases (including 128 F. nucleatum-positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on Bifidobacterium, microsatellite instability (MSI), tumor whole-exome sequencing, and M1/M2-type tumor-associated macrophages [TAM; by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between F. nucleatum and T-cell subsets. RESULTS: The amount of F. nucleatum was inversely associated with tumor stromal CD3+ lymphocytes [multivariable OR, 0.47; 95% confidence interval (CI), 0.28-0.79, for F. nucleatum-high vs. -negative category; P trend = 0.0004] and specifically stromal CD3+CD4+CD45RO+ cells (corresponding multivariable OR, 0.52; 95% CI, 0.32-0.85; P trend = 0.003). These relationships did not substantially differ by MSI status, neoantigen load, or exome-wide tumor mutational burden. F. nucleatum was not significantly associated with tumor intraepithelial T cells or with M1 or M2 TAMs. CONCLUSIONS: The amount of tissue F. nucleatum is associated with lower density of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.


Assuntos
Neoplasias Colorretais/etiologia , Infecções por Fusobacterium/complicações , Infecções por Fusobacterium/imunologia , Infecções por Fusobacterium/microbiologia , Fusobacterium nucleatum/fisiologia , Subpopulações de Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Biomarcadores , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/metabolismo , Suscetibilidade a Doenças , Feminino , Imunofluorescência , Infecções por Fusobacterium/epidemiologia , Humanos , Imuno-Histoquímica , Incidência , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Vigilância da População , Subpopulações de Linfócitos T/metabolismo , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Estados Unidos/epidemiologia
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