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1.
Future Oncol ; 17(4): 363-369, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33397134

RESUMO

Lifestyle factors could plausibly modulate the host immune system, the tumor microenvironment and, hence, immune checkpoint inhibitor (ICI) response. As such, these factors should be considered in ICI studies.

2.
BMC Med ; 18(1): 396, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33327948

RESUMO

BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33199439

RESUMO

BACKGROUND: Radiation exposure is an established risk factor for the development of several forms of cancer, including gastrointestinal cancers. However, few studies have investigated the relationship between pre-diagnostic radiation exposure and survival after cancer diagnosis. METHODS: Participants in the Life Span Study (LSS) of atomic bomb survivors who were diagnosed with a first primary invasive stomach, colon, or rectal cancer between 1958-2009 were followed for mortality during 1958-2014. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of radiation dose from atomic bomb exposure with survival (cancer-specific and overall) after cancer diagnosis. Analyses were adjusted for city of primary exposure, sex, age at diagnosis, and year of diagnosis. RESULTS: We identified 7,728 eligible cancer patients for analysis. We observed no statistically significant associations between radiation dose and cancer-specific survival among LSS participants with a gastrointestinal cancer. Higher radiation doses (≥1 Gy) were suggestively, but not significantly, associated with modestly poorer cancer-specific survival for colon cancer only (HR=1.38, 95% CI: 0.90-2.12), and were associated with poorer overall survival regardless of cancer site. CONCLUSIONS: Although radiation exposure is associated with increased risk of gastrointestinal cancer incidence and mortality, study results are inconclusive about an association between pre-diagnostic radiation exposure and survival after gastrointestinal cancer diagnosis. IMPACT: Radiation exposure from the atomic bomb before gastrointestinal cancer diagnosis was not associated with cancer survival, but should be evaluated in relation to survival for other cancer types.

4.
BMC Med Genet ; 21(1): 228, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213418

RESUMO

BACKGROUND: Though bladder cancer has been the subject of many well-powered genome-wide association studies, the mechanisms involving bladder-cancer-associated single nucleotide polymorphisms (SNPs) remain largely unknown. This study focuses on rs798766, rs401681, rs2294008, and rs8102137, which have been associated with bladder cancer and are also cis-acting methylation quantitative loci (mQTL). METHODS: Among 412 bladder cancer cases and 424 controls from the Women's Health Initiative (WHI), we assessed whether the effects of these SNPs on bladder cancer are mediated through proximal DNA methylation changes in pre-diagnostic blood at mQTL-associated CpG sites, which we refer to as natural indirect effects (NIEs). We used a multiple-mediator mediation model for each of the four mQTL adjusted for matching variables and potential confounders, including race/ethnicity, smoking status, and pack-years of smoking. RESULTS: While not statistically significant, our results suggest that substantial proportions of the modest effects of rs401681 (ORNIE = 1.05, 95% confidence interval (CI) = 0.89 to 1.25; NIE percent = 98.5%) and rs2294008 (ORNIE = 1.10, 95% CI = 0.90 to 1.33; NIE percent = 77.6%) on bladder cancer risk are mediated through differential DNA methylation at nearby mQTL-associated CpG sites. The suggestive results indicate that rs2294008 may affect bladder cancer risk through a set of genes in the lymphocyte antigen 6 family, which involves genes that bind to and modulate nicotinic acetylcholine receptors. There was no suggestive evidence supporting mediation for rs8102137 and rs798766. CONCLUSIONS: Though larger studies are necessary, the methylation changes associated with rs401681 and rs2294008 at mQTL-associated CpG sites may be relevant for bladder carcinogenesis, and this study demonstrates how multi-omic data can be integrated to help understand the downstream effects of genetics variants.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33203692

RESUMO

BACKGROUND: Cetuximab, an epidermal growth factor receptor inhibitor used to treat multiple cancer types including colon cancer, causes severe skin toxicity in 5-20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity. METHODS: Our study included 1,209 stage III colon cancer patients randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating ~10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade >3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as p<5x10-8. RESULTS: Participants were predominantly middle-aged white men; 20% (n=243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity (OR = 3.93, 95% CI 2.47-6.25; p<7.8x10-9). Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions. CONCLUSIONS: Identified variants could represent a potential target for risk stratification of colon cancer patients receiving cetuximab. IMPACT: Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.

6.
Int J Mol Sci ; 21(22)2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33233617

RESUMO

Obstructive sleep apnoea (OSA) is a prevalent disorder associated with increased cardiovascular, metabolic and neurocognitive morbidity. Recently, an increasing number of basic, clinical and epidemiological reports have suggested that OSA may also increase the risk of cancer, and adversely impact cancer progression and outcomes. This hypothesis is convincingly supported by biological evidence linking certain solid tumours and hypoxia, as well as by experimental studies involving cell and animal models testing the effects of intermittent hypoxia and sleep fragmentation that characterize OSA. However, the clinical and epidemiological studies do not conclusively confirm that OSA adversely affects cancer, even if they hold true for specific cancers such as melanoma. It is likely that the inconclusive studies reflect that they were not specifically designed to test the hypothesis or because of the heterogeneity of the relationship of OSA with different cancer types or even sub-types. This review critically focusses on the extant basic, clinical, and epidemiological evidence while formulating proposed directions on how the field may move forward.

7.
Cancer Epidemiol Biomarkers Prev ; 29(12): 2719-2728, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33008876

RESUMO

BACKGROUND: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. METHODS: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). RESULTS: A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer-specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74-0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68-0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. CONCLUSIONS: Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. IMPACT: The implicated genes warrant further investigation.

8.
JNCI Cancer Spectr ; 4(5): pkaa042, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32923935

RESUMO

Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. Methods: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided. Results: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; P het =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; P het =.01) tumors. Conclusions: We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

9.
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.

10.
Nat Commun ; 11(1): 3644, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686686

RESUMO

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Neoplasias/genética , Neoplasias do Colo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Mutação , Prognóstico , Proteína Supressora de Tumor p53/genética
11.
Clin Infect Dis ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32133490

RESUMO

BACKGROUND: Sepsis, a life-threatening immunological response to an infection, disproportionality affects allogeneic hematopoietic cell transplant (HCT) recipients and is challenging to define. Clinical criteria that predict mortality and intensive care unit endpoints in patients with suspected infections (SI) have been adopted in sepsis definitions, but their predictive value among immunocompromised populations is largely unknown. Here, we evaluate three criteria among allogeneic HCT recipients. METHODS: We evaluated Systemic Inflammatory Response Syndrome (SIRS), quick-Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS) criteria in relation to short-term mortality among HCT recipients with SIs. Data from the first 100-days post-transplant were analyzed for patients transplanted between September 2010 - July 2017. We used the following cut-points (qSOFA/SIRS: 2+; NEWS: 7+) and restricted to first SI per hospital encounter. RESULTS: Of the 880 HCT recipients who experienced ≥ 1 SI, 58 (6.6%) died within 28 days and 22 (2.5%) within 10 days of a SI. In relation to 10-day mortality, SIRS was the most sensitive: 91.3% (95% CI:72.0 - 98.9%) but least specific: 35.0% (32.6 - 37.5%) whereas qSOFA was the most specific: 90.5% (88.9 - 91.9%) but least sensitive: 47.8% (26.8 - 69.4%). NEWS was moderately sensitive 78.3% (56.3 - 92.5%) and specific 70.2% (67.8 - 72.4%). CONCLUSION: NEWS outperformed qSOFA and SIRS, but all three criteria had low to moderate predictive accuracy and the magnitude of the known predictive limitations of qSOFA and SIRS were at least as large as in general populations. Our data suggest that population-specific sepsis criteria are needed for immunocompromised patients.

12.
J Clin Sleep Med ; 16(5): 667-673, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32022671

RESUMO

STUDY OBJECTIVES: In vitro and animal studies suggest that intermittent hypoxia characterizing sleep apnea contributes to accelerated cancer progression. However, the impact of sleep apnea on survival subsequent to cancer diagnosis is unknown. METHODS: We identified a cohort of 1,575 adults diagnosed with sleep apnea between 2005 and 2014 with a subsequent cancer diagnosis via linkage of the University of Washington Medicine system and a population-based cancer registry serving the same Seattle-Puget Sound region. We computed age-standardized 5-year relative survival after cancer diagnosis for all cancers combined, and for specific cancer sites, for both the sleep apnea cohort and the general Seattle-Puget Sound population, and we used US life tables as the reference population. Relative survival was estimated by sex, cancer stage, and health care engagement. RESULTS: Five-year overall relative survival for cancer was more favorable in the sleep apnea cohort than in the general population [83.6%, 95% confidence interval (CI): 79.8%-86.8% vs 71.6%, 95% CI: 71.3%-71.9%]; this pattern was applicable to most specific cancer sites. However, 5-year relative survival was slightly less favorable in the sleep apnea cohort among patients with melanoma (97.7%, 95% CI: 84.6%-99.7% vs 99.2%, 95% CI: 98.8%-99.5%) and cancer of the corpus uteri (84.0%, 95% CI: 58.2%-94.5% vs 84.6%, 95% CI: 83.1%-86.0%). CONCLUSIONS: The fact that survival after cancer, overall and for most cancer sites, was more favorable in patients with sleep apnea warrants larger community-based studies to further tease out effects of sleep apnea and treatment on site-specific survival for different cancer types, particularly in patients with melanoma or uterine cancer.

13.
Otolaryngol Head Neck Surg ; 162(4): 581-588, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32013761

RESUMO

OBJECTIVE: To test the association between preexisting obstructive sleep apnea (OSA) and subsequent cancer in a large long-term cohort of veteran patients. STUDY DESIGN: Retrospective matched cohort study. SETTING: The Veterans Affairs Health Care System. SUBJECTS AND METHODS: All veteran patients diagnosed with OSA between 1993 and 2013 by International Classification of Diseases, Ninth Revision (ICD-9) codes in any Veterans Affairs facility and veteran patients without an OSA diagnosis, matched to patients with OSA by age and index year. Cancer diagnoses were identified by ICD-9 codes for the time period at least 2 years after OSA diagnosis or index date. We tested the association between OSA and cancer using multivariate Cox regression with time since cohort entry as the time axis, adjusting for potential confounders. RESULTS: The cohort included 1,377,285 patients (726,008 with and 651,277 without an OSA diagnosis) with mean age of 55 years, predominantly male (94%), a minority obese (32%), and median follow-up of 7.4 years (range, 2.0-25.2). The proportion of patients diagnosed with cancer was higher in those with vs without an OSA diagnosis (8.3% vs 3.6%; mean difference 4.8%; 95% confidence interval [CI], 4.7%-4.8%; P < .001). After adjusting for age, sex, year of cohort entry, smoking status, alcohol use, obesity, and comorbidity, the hazard of incident cancer was nearly double in patients with vs without an OSA diagnosis (hazard ratio, 1.97; 95% CI, 1.94-2.00; P < .001). CONCLUSION: Preexisting OSA was strongly associated with subsequent cancer in this veteran cohort, independent of several known cancer risk factors. These findings suggest that OSA may be a strong, independent risk factor for subsequent cancer development.


Assuntos
Neoplasias/complicações , Neoplasias/epidemiologia , Apneia Obstrutiva do Sono/complicações , Saúde dos Veteranos , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
14.
Gastroenterology ; 158(8): 2158-2168.e4, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32088204

RESUMO

BACKGROUND AND AIMS: The heterogeneity among colorectal tumors is probably due to differences in developmental pathways and might associate with patient survival times. We studied the relationship among markers of different subtypes of colorectal tumors and patient survival. METHODS: We pooled data from 7 observational studies, comprising 5010 patients with colorectal cancer. All the studies collected information on microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in KRAS and BRAF in tumors. Tumors with complete marker data were classified as type 1 (MSI-high, CIMP-positive, with pathogenic mutations in BRAF but not KRAS), type 2 (not MSI-high, CIMP-positive, with pathogenic mutations in BRAF but not KRAS), type 3 (not MSI-high or CIMP, with pathogenic mutations in KRAS but not BRAF), type 4 (not MSI-high or CIMP, no pathogenic mutations in BRAF or KRAS), or type 5 (MSI-high, no CIMP, no pathogenic mutations in BRAF or KRAS). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for associations of these subtypes and tumor markers with disease-specific survival (DSS) and overall survival times, adjusting for age, sex, stage at diagnosis, and study population. RESULTS: Patients with type 2 colorectal tumors had significantly shorter time of DSS than patients with type 4 tumors (HRDSS 1.66; 95% CI 1.33-2.07), regardless of sex, age, or stage at diagnosis. Patients without MSI-high tumors had significantly shorter time of DSS compared with patients with MSI-high tumors (HRDSS 0.42; 95% CI 0.27-0.64), regardless of other tumor markers or stage, or patient sex or age. CONCLUSIONS: In a pooled analysis of data from 7 observational studies of patients with colorectal cancer, we found that tumor subtypes, defined by combinations of 4 common tumor markers, were associated with differences in survival time. Colorectal tumor subtypes might therefore be used in determining patients' prognoses.

15.
Int J Cancer ; 147(7): 1808-1822, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32064598

RESUMO

We pooled multiethnic data from four population-based studies and examined associations of menstrual and reproductive characteristics with breast cancer (BC) risk by tumor hormone receptor (HR) status [defined by estrogen receptor (ER) and progesterone receptor (PR)]. We estimated odds ratios and 95% confidence intervals using multivariable logistic regression, stratified by age (<50, ≥50 years) and ethnicity, for 5,186 HR+ (ER+ or PR+) cases, 1,365 HR- (ER- and PR-) cases and 7,480 controls. For HR+ BC, later menarche and earlier menopause were associated with lower risk in non-Hispanic whites (NHWs) and Hispanics, and higher parity and longer breast-feeding were associated with lower risk in Hispanics and Asian Americans, and suggestively in NHWs. Positive associations with later first full-term pregnancy (FTP), longer interval between menarche and first FTP and shorter time since last FTP were limited to younger Hispanics and Asian Americans. Except for nulliparity, reproductive characteristics were not associated with risk in African Americans. For HR- BC, lower risk was associated with later menarche, except in African Americans and older Asian Americans and with longer breast-feeding in Hispanics and Asian Americans only. In younger African Americans, HR- BC risk associated with higher parity (≥3 vs. 1 FTP) was increased fourfold in women who never breast-fed, but not in those with a breast-feeding history, suggesting that breast-feeding may mitigate the adverse effect of higher parity in younger African American women. Further work needs to evaluate why menstrual and reproductive risk factors vary in importance according to age and ethnicity.

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

RESUMO

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


Assuntos
Neoplasias Colorretais/etiologia , Etanol/efeitos adversos , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Estudos de Casos e Controles , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de Risco
17.
Clin Gastroenterol Hepatol ; 18(12): 2717-2723.e3, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31811950

RESUMO

BACKGROUND & AIMS: Many genetic variants have been associated with colorectal cancer risk, although few have been associated with survival times of patients. Identification of genetic variants associated with survival times might improve our understanding of disease progression and aid in outcome prediction. We performed a genome-wide association study to identify variants associated with colon cancer survival time. METHODS: We performed a post hoc analysis of data from NCCTG N0147 (Alliance), a randomized phase 3 trial of patients with resected stage III colon cancer, and from NSABP C-08 (NRG), a phase 3 trial that compared therapy regimens for patients with resected stage II or III colon cancer. Genotype analyses were performed on DNA from blood samples from 4974 patients. We used Cox proportional hazards regression to evaluate the association of each single nucleotide polymorphism with times of overall survival and disease-free survival, adjusting for age at diagnosis, sex, treatment group, and principal components of genetic ancestry. We performed the analysis for studies N0147 and C-08 separately, and results were combined in a fixed-effects meta-analysis. RESULTS: A locus on chromosome 7p15.2 was significantly associated with overall survival time (P ≤ 5x10-08). The most significant variant at this locus, rs76766811 (P = 1.6x10-08), is common among African Americans (minor allele frequency, approximately 18%) but rare in European Americans (minor allele frequency <0.1%). Within strata of self-reported ancestry, this variant was associated with times of overall survival and disease-free survival in only African Americans (hazard ratio for overall survival, 2.82; 95% CI, 1.88-4.23; P = 5.0x10-07 and hazard ratio for disease-free survival, 2.27; 95% CI, 1.62-3.18; P = 1.8x10-06). CONCLUSIONS: In an analysis of data from 2 trials of patients with stage II or III colon cancer, we identified rs76766811 as a potential prognostic variant in African American patients. This finding should be confirmed in additional study populations. ClinicalTrials.gov Identifiers: NCT00096278 (NSABP C-08) and NCT00079274 (NCCTG N0147).

18.
J Pediatr Pharmacol Ther ; 24(6): 489-496, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31719810

RESUMO

OBJECTIVES: Evidence suggests use of proton pump inhibitors (PPIs) and H2 blockers may provoke disease flares in individuals with established inflammatory bowel disease (IBD); however, there are no studies investigating the relationship of these medications with risk of developing pediatric IBD. The hypothesis was that use of acid suppression therapy in children might be associated with development of pediatric IBD. METHODS: This was a nested case-control study of 285 Kaiser Permanente Northern California members, age ≤21 years diagnosed with IBD from 1996 to 2016. Four controls without IBD were matched to each case on age, race, and membership status at the case's index date. Disease risk scores (DRS) were computed for each subject. Odds ratios and 95% confidence intervals were calculated by using conditional logistic regression models adjusted for DRS. RESULTS: The children's mean age was 15.1 ± 2.6 years and 49.5% were female. Six cases (n = 3 Crohn's disease [CD], n = 3 ulcerative colitis [UC]) and 6 controls were prescribed PPIs and 10 cases (n = 7 CD, n = 3 UC) and 28 controls were prescribed H2 blockers. The OR for the association of at least 1 PPI or H2 blocker prescription with subsequent IBD was 3.6 (95% CI, 1.1-11.7) for PPIs and 1.6 (95% CI, 0.7-3.7) for H2 blockers. CONCLUSIONS: Early-life PPI use appears to be associated with subsequent IBD risk. These findings have implications for clinical treatment of children with gastrointestinal symptoms and warrant further investigation in a larger cohort.

19.
Epigenetics ; 14(11): 1065-1073, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31232174

RESUMO

Smoking accounts for approximately 52% of bladder cancer incidence among postmenopausal women, but the underlying mechanism is poorly understood. Our study investigates whether changes in DNA methylation, as measured in blood, mediate the impact of smoking on bladder cancer risk among postmenopausal women. We conducted analyses among 206 cases and 251 controls that were current or never smokers at baseline from a previous case-control study of bladder cancer and genome-wide DNA methylation nested within the Women's Health Initiative. Separate mediation analyses were conducted for three CpG sites demonstrating robust associations with smoking in prior methylome-wide association studies: cg05575921 (AhRR), cg03636183 (F2RL3), and cg19859270 (GPR15). We estimated causal effects using the regression-based, four-way decomposition approach, which addresses the interaction between smoking and each CpG site. The overall proportion of the excess relative risk mediated by cg05575921 was 92% (p-value = 0.004) and by cg19859270 was 79% (p-value = 0.02). The largest component of the excess relative risk of bladder cancer due to 30 pack-years of smoking history in current smokers was the mediated interaction for both cg05575921 (72%, p = 0.02) and cg19859270 (72%, p-value = 0.04), where the mediated interaction is the effect of smoking on bladder cancer that both acts through differential methylation and depends on smoking history. There was little evidence that smoking was mediated through cg03636183. Our results suggest that differential methylation of cg05575921 and cg19859270 mediate the effects of smoking on bladder cancer, potentially revealing downstream effects of smoking relevant for carcinogenesis.


Assuntos
Metilação de DNA , Fumar Tabaco/genética , Neoplasias da Bexiga Urinária/genética , Idoso , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Ilhas de CpG , Feminino , Humanos , Pessoa de Meia-Idade , Receptores Acoplados a Proteínas-G/genética , Receptores de Peptídeos/genética , Receptores de Trombina/genética , Proteínas Repressoras/genética , Fumar Tabaco/epidemiologia , Neoplasias da Bexiga Urinária/epidemiologia
20.
Prev Med Rep ; 15: 100886, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31193286

RESUMO

In vitro and animal models suggest that obstructive sleep apnea (OSA) increases cancer risk. However, the impact of OSA severity on cancer risk is poorly understood. We conducted a case-cohort study (a variant of the case-control study design), nested in a cohort of patients with a clinical diagnosis of OSA. OSA patients diagnosed between 2005 and 2013 were linked to a population-based cancer registry to identify cancers diagnosed subsequent to OSA between 2005 and 2015. Medical records were reviewed for a representative sample of 1162 OSA patients from this cohort (including 24 with subsequent cancer), and for an additional 304 OSA patients diagnosed with cancer; information regarding OSA severity indicators, including apnea-hypopnea index (AHI) was abstracted from these records. Adjusted Cox proportional hazards regression were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for associations of OSA severity indicators on cancer incidence. Compared with individuals in the lowest AHI category (5-14.9), indicating mild OSA, the adjusted HR (95% CI) for cancer incidence associated with having moderate (15-29.9) or severe (30+) OSA were 0.72 (0.40-1.29) and 0.87 (0.52-1.45) respectively. Associations with other severity indicators were not significantly associated with cancer. However, the proportion of patients with severe OSA (AHI ≥30) was consistently higher across numerous cancer sites relative to the subcohort, suggesting increased cancer risk relative to patients with less severe OSA. The absence of significant associations with OSA severity measures suggest that the underlying mechanisms deserve further investigation.

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