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1.
Int J Cancer ; 2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34278571

RESUMO

Colorectal cancer (CRC) incidence and prevalence of its precursors are substantially higher among males than among females in most countries but the reasons for the male excess risk are incompletely understood. We aimed to assess to what extent it is explained by known risk factors. Prevalence of advanced neoplasia (AN, i.e. CRC or advanced adenoma) and CRC risk and preventive factors were ascertained among 15,985 participants of screening colonoscopy aged 55-79 years in Germany. Logistic regression was used to calculate odds ratios (ORs) for the association between male sex and AN with and without adjustment for known risk and preventive factors. In age-adjusted comparisons, men had twofold increased risk for AN compared to women (OR=1.98, 95% CI 1.79-2.19). After comprehensive adjustment for medical, lifestyle and dietary factors, the OR was reduced to 1.52 (95% CI 1.30-1.77), suggesting that these factors accounted for 47% of male excess risk. Male excess risk increased from proximal colon to distal colon and rectum, with age-adjusted ORs (95% CI) of 1.63 (1.38-1.91), 2.13 (1.85-2.45) and 2.36 (1.95-2.85), respectively, and with the proportion of excess risk explained by covariates being lower for AN in the rectum (26%) than for AN in the proximal (52%) or distal colon (46%). Male excess risk was somewhat lower (age-adjusted OR 1.87) and explained excess risk was smaller (36%) when men were compared to women who never used hormone replacement therapy. In conclusion, most of the male excess risk and the potential to overcome it remain to be explored by further research. This article is protected by copyright. All rights reserved.

3.
Carcinogenesis ; 2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34216462

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P=7.14×10 -10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumor cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P=3.56×10 -6). This SNP is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

4.
Dtsch Arztebl Int ; 118(22): 376, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34250895
5.
Artigo em Inglês | MEDLINE | ID: mdl-34251458

RESUMO

BACKGROUND: Evidence about the clinical relevance of appropriate co-medication among older colorectal cancer (CRC) patients is sparse. METHODS: A cohort study was conducted with 3,239 CRC patients aged 65 years and older. To assess co-medication quality, we calculated the total Fit fOR The Aged (FORTA) score and its sub-scores for medication overuse, underuse, and potentially inappropriate medication use. Multivariable Cox proportional hazards or logistic regression models were performed to evaluate the association of co-medication quality with up to 5-year overall survival, CRC-specific survival, and chemotherapy-related adverse drug reactions (ADRs). RESULTS: Overall, 3,239 and 1,209 participants were included in analyses on survival and ADRs, respectively. The hazard ratios [95%-confidence intervals] for the total FORTA score ≥ 7 vs. 0-1 points were 1.83 [1.40-2.40] and 1.76 [1.22-2.52] for up to 5-year overall and CRC-specific survival, respectively. Worse up to 5-year OS and CSS was also evident for FORTA sub-scores for PIM use and overuse whereas no association was observed for underuse. Although results for the total FORTA and potentially inappropriate medication score were much stronger among patients receiving chemotherapy, no significant associations with chemotherapy-related ADRs were observed. Moreover, associations were particularly strong among men and rectal cancer patients as compared to women and colon cancer patients. CONCLUSIONS: Poor total co-medication quality was significantly associated with worse up to 5-year overall and CRC-specific survival. Randomized controlled trials are needed to test whether improved cancer co-medication management in older CRC patients prolongs survival.

6.
Br J Cancer ; 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215852

RESUMO

BACKGROUND: Cancer studies reported mixed results on benefit finding (BF) and posttraumatic growth (PTG) prevalence and few were focused on long-term survivors. METHODS: BF and PTG were assessed in a multi-regional population-based study in Germany with 6952 breast, colorectal and prostate cancer survivors, using the Benefit Finding Scale and Posttraumatic Growth Inventory. We calculated the age-adjusted prevalence, stratified by demographical and clinical characteristics. RESULTS: Overall, 66.0% of cancer survivors indicated moderate-to-high BF, and 20.5% moderate-to-high PTG. Age-adjusted prevalence of BF and PTG differed according to cancer type (breast > colorectal > prostate) and sex (female > male). BF and PTG prevalence were higher in younger than in older respondents; the age-adjusted prevalence was higher in respondents who survived more years after diagnosis. The strength and direction of associations of age-adjusted prevalence with cancer stage, disease recurrence, and time since diagnosis varied according to cancer type and sex. CONCLUSIONS: A substantial proportion of long-term cancer survivors reported moderate-to-high BF and PTG. However, the prevalence was lower in older and male cancer survivors, and during the earlier years after cancer diagnosis. Further longitudinal studies on PTG and BF in cancer survivors are warranted to address heterogeneity in survivors' experience after cancer diagnosis.

7.
Lancet Reg Health Eur ; 2: 100044, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: covidwho-1051823
8.
Acta Oncol ; 60(8): 1000-1010, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34137351

RESUMO

BACKGROUND: Inpatient rehabilitation therapy (IRT) is commonly offered to cancer patients during or after cancer treatment in Germany. However, little is known about utilization and long-term effects of this offer in colorectal cancer (CRC) patients. We aimed to assess IRT utilization, determinants of utilization and the association between IRT and survival in CRC patients. MATERIALS AND METHODS: CRC patients diagnosed in 2005-2014 recruited in the population-based DACHS study in South West Germany were included. Determinants of IRT utilization were assessed by multivariable logistic regression. Hazard ratios (HRs) of the association of IRT with overall and disease-specific survival were estimated by adjusted Cox proportional hazards models. Modified landmark approach was applied to avoid immortal time biased results. RESULTS: Among the included CRC patients (n = 3704), 43.6% underwent IRT. Patients who did not live in a relationship with a partner, worked as employee and who reported higher levels of physical activity were more likely to undergo IRT. Patients were less likely to undergo IRT if they had private health insurance, were diagnosed with cancer stage IV, received no or laparoscopic cancer surgery or were treated in a hospital with medium vs. high surgical volume. The median follow-up time was 4.4 years (post-landmark). Utilization of IRT was associated with better overall (HR 0.81, 95% confidence interval 0.72-0.92) and disease-specific survival (HR 0.72, 95% confidence interval 0.61-0.85). CONCLUSION: Almost every other CRC patient underwent IRT. Next to clinical characteristics, identified social and lifestyle characteristics seemed to play an essential role in the decision-making. Use of IRT was associated with better overall and disease-specific survival.


Assuntos
Neoplasias Colorretais , Estudos de Coortes , Alemanha/epidemiologia , Humanos , Pacientes Internados , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco
9.
Artigo em Inglês | MEDLINE | ID: mdl-34173262

RESUMO

BACKGROUND: The hormone leptin has been suggested to play a role in the respiratory and immune systems. Evidence on sex-specific concentrations of leptin in human milk and sex-specific associations with the development of asthma and wheeze has been put forward but is still scarce. OBJECTIVE: To investigate whether male and female infants receive different levels of leptin through human milk and whether leptin is implicated in the development of asthma and wheeze in a sex-dependent manner using data from the two Ulm Birth Cohort studies. METHODS: Leptin data were available from human milk samples collected at 6 weeks (Ulm Birth Cohort Study [UBCS, n = 678; Ulm SPATZ Health Study, n = 587]), and, in SPATZ only, at 6 months (n = 377) and 12 months (n = 66) of lactation. Sex-specific associations with doctor-diagnosed asthma and wheeze phenotypes were assessed in crude and adjusted models using logistic regression. Adjustments were made for maternal allergy, exclusive breastfeeding, infant age at the time of milk sampling, and child BMI z-score. RESULTS: At 6 weeks, leptin levels (median [min, max], in ng/L) were higher in the milk for girls (197 [0.100, 4120]) than in milk for boys (159 [1.02, 3280], p = .045) in UBCS. No significant sex differences were observed in SPATZ (p = .152). There were no significant associations of leptin with asthma or wheeze in both studies, even in a sex-dependent manner (p > .05). CONCLUSION: It remains unclear whether male and female infants receive different levels of leptin through human milk. However, leptin in human milk may not be associated with history and development of asthma and wheeze in a sex-specific manner.

10.
Dtsch Arztebl Int ; 118(16): 281-287, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-34180790

RESUMO

BACKGROUND: The use of colonoscopy has increased and colorectal cancer (CRC) incidence has decreased after the introduction of screening colonoscopy in Germany. However, it remains unknown to what extent progress has been achieved in the prevention of cancer in the proximal colon, distal colon, and rectum. METHODS: We analyzed trends in CRC incidence (2000-2016) and mortality (2000-2018) in Germany by sex, age, and tumor location. RESULTS: The age-standardized incidence of CRC declined by 22.4% (from 65.3 to 50.7 per 100 000) in men and by 25.5% (from 42.7 to 31.8 per 100 000) in women. CRC mortality declined by 35.8% (from 29.6 to 19.0 per 100 000) in men and by 40.5% (19.0 to 11.3 per 100 000) in women. Despite demographic changes, the annual numbers of CRC cases and deaths still decreased from about 60 400 to 58 300 and from around 28 700 to 24 200, respectively. The decline in incidence was greatest in groups aged ≥ 55 years. While the incidence of cancer in the distal colon and rectum decreased by 34.5% and 26.2%, respectively, in men and by 41.0% and 27.9% in women, the incidence of proximal colon cancer remained stable in men and decreased by only 7.0% in women. However, a major shift towards earlier stages was observed for the proximal cancers. CONCLUSION: The results support the assumption that the increased use of colo - noscopy has contributed to substantial reductions in the incidence of distal CRC incidence and the mortality from cancers in the entire colon and rectum.

11.
Clin Epigenetics ; 13(1): 121, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078457

RESUMO

BACKGROUND: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. RESULTS: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (ß = - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (ß = 0.12 [0.07, 0.16], p = 2.08E-06). The "first-generation" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. CONCLUSION: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

12.
Eur J Prev Cardiol ; 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34060615

RESUMO

AIMS: Low-density lipoprotein cholesterol (LDL-C) is an established causal driver of atherosclerotic cardiovascular disease (ASCVD), but its performance and age-dependency as a biomarker for incident events and mortality arising from ASCVD is less clear. The aim was to determine the value of LDL-C as a susceptibility/risk biomarker for incident coronary heart disease (CHD), ASCVD, and stroke events and deaths, for the age groups <50 and ≥50 years. METHODS AND RESULTS: The performance of LDL-C was evaluated in three cohorts, FINRISK 2002 (n = 7709), HUSK (n = 5431), and ESTHER (n = 4559), by Cox proportional hazards models, C-statistics, and net reclassification index calculations. Additionally, the hazard ratios (HRs) for the three cohorts were pooled by meta-analysis. The most consistent association was observed for CHD [95% confidence interval (CI) for HRs per standard deviation ranging from 0.99 to 1.37], whereas the results were more modest for ASCVD (0.96-1.18) due to lack of association with stroke (0.77-1.24). The association and discriminatory value of LDL-C with all endpoints in FINRISK 2002 and HUSK were attenuated in subjects 50 years and older [HRs (95% CI) obtained from meta-analysis 1.11 (1.04-1.18) for CHD, 1.15 (1.02-1.29) for CHD death, 1.02 (0.98-1.06) for ASCVD, 1.12 (1.02-1.23) for ASCVD death, and 0.97 (0.89-1.05) for stroke]. CONCLUSION: In middle-aged and older adults, associations between LDL-C and all the studied cardiovascular endpoints were relatively weak, while LDL-C showed stronger association with rare events of pre-mature CHD or ASCVD death among middle-aged adults. The predictive performance of LDL-C also depends on the studied cardiovascular endpoint.

13.
PLoS Med ; 18(6): e1003616, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34061847

RESUMO

BACKGROUND: Evidence-based guidance for starting ages of screening for first-degree relatives (FDRs) of patients with prostate cancer (PCa) to prevent stage III/IV or fatal PCa is lacking in current PCa screening guidelines. We aimed to provide evidence for risk-adapted starting age of screening for relatives of patients with PCa. METHODS AND FINDINGS: In this register-based nationwide cohort study, all men (aged 0 to 96 years at baseline) residing in Sweden who were born after 1931 along with their fathers were included. During the follow-up (1958 to 2015) of 6,343,727 men, 88,999 were diagnosed with stage III/IV PCa or died of PCa. The outcomes were defined as the diagnosis of stage III/IV PCa or death due to PCa, stratified by age at diagnosis. Using 10-year cumulative risk curves, we calculated risk-adapted starting ages of screening for men with different constellations of family history of PCa. The 10-year cumulative risk of stage III/IV or fatal PCa in men at age 50 in the general population (a common recommended starting age of screening) was 0.2%. Men with ≥2 FDRs diagnosed with PCa reached this screening level at age 41 (95% confidence interval (CI): 39 to 44), i.e., 9 years earlier, when the youngest one was diagnosed before age 60; at age 43 (41 to 47), i.e., 7 years earlier, when ≥2 FDRs were diagnosed after age 59, which was similar to that of men with 1 FDR diagnosed before age 60 (41 to 45); and at age 45 (44 to 46), when 1 FDR was diagnosed at age 60 to 69 and 47 (46 to 47), when 1 FDR was diagnosed after age 69. We also calculated risk-adapted starting ages for other benchmark screening ages, such as 45, 55, and 60 years, and compared our findings with those in the guidelines. Study limitations include the lack of genetic data, information on lifestyle, and external validation. CONCLUSIONS: Our study provides practical information for risk-tailored starting ages of PCa screening based on nationwide cancer data with valid genealogical information. Our clinically relevant findings could be used for evidence-based personalized PCa screening guidance and supplement current PCa screening guidelines for relatives of patients with PCa.

14.
Addiction ; 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34105209

RESUMO

AIM: To test the association of alcohol consumption with total and cause-specific mortality risk. DESIGN: Prospective observational multi-centre population-based study. SETTING: Sixteen cohorts (15 from Europe) in the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project. PARTICIPANTS: A total of 142 960 individuals (mean age 50 ± 13 years, 53.9% men). MEASUREMENTS: Average alcohol intake by food frequency questionnaire, total and cause-specific mortality. FINDINGS: In comparison with life-time abstainers, consumption of alcohol less than 10 g/day was associated with an average 11% [95% confidence interval (CI) = 7-14%] reduction in the risk of total mortality, while intake > 20 g/day was associated with a 13% (95% CI = 7-20%) increase in the risk of total mortality. Comparable findings were observed for cardiovascular (CV) deaths. With regard to cancer, drinking up to 10 g/day was not associated with either mortality risk reduction or increase, while alcohol intake > 20 g/day was associated with a 22% (95% CI = 10-35%) increased risk of mortality. The association of alcohol with fatal outcomes was similar in men and women, differed somewhat between countries and was more apparent in individuals preferring wine, suggesting that benefits may not be due to ethanol but other ingredients. Mediation analysis showed that high-density lipoprotein cholesterol explained 2.9 and 18.7% of the association between low alcohol intake and total as well as CV mortality, respectively. CONCLUSIONS: In comparison with life-time abstainers, consuming less than one drink per day (nadir at 5 g/day) was associated with a reduced risk of total, cardiovascular and other causes mortality, except cancer. Intake of more than two drinks per day was associated with an increased risk of total, cardiovascular and especially cancer mortality.

15.
Am J Hum Genet ; 108(7): 1190-1203, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34146516

RESUMO

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).

16.
Lancet Reg Health Eur ; 2: 100044, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34173633
18.
Aliment Pharmacol Ther ; 54(2): 167-175, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34114659

RESUMO

BACKGROUND: The regular use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced colorectal cancer (CRC) risk. AIM: To explore whether this association varies according to background polygenic risk for CRC. METHODS: Data were collected from a large population-based case-control study on CRC in Germany. A polygenic risk score (PRS) based on 140 CRC-related risk loci was used to quantify the genetic risk. The associations of regular use of NSAIDs (≥2times per week for at least 1 year) with CRC risk were estimated in the whole population and in subgroups according to PRS levels using multivariable logistic regression. The impact of NSAIDs on CRC risk was compared to PRS using the 'genetic risk equivalent' (GRE), a recently developed metric for effective risk communication. RESULTS: In total 5129 CRC cases and 4093 controls were included in this analysis. The regular use of NSAIDs (including aspirin) was associated with reduced CRC risk [odds ratio (OR) 0.66, 95% confidence interval (CI) 0.59, 0.74], as was regular use of aspirin only (OR 0.73, 95% CI 0.65, 0.83), without indication of interaction with the PRS (P = 0.10 and 0.22 respectively). The effect of NSAID use was equivalent to the effect of having a 32 percentiles lower PRS (GRE -32, 95% CI -41, -22). CONCLUSIONS: The regular use of NSAIDs is associated with greatly reduced CRC risk regardless of individual genetic profile. With an equivalent reduction of relative risk across all polygenic risk groups, absolute risk reduction would be expected to be strongest among those with the highest polygenic risk score.

20.
Transl Psychiatry ; 11(1): 261, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33934115

RESUMO

Alzheimer's disease is highly heritable and characterized by amyloid plaques and tau tangles in the brain. The aim of this study was to investigate the association between genetic predisposition, Aß misfolding in blood plasma, a unique marker of Alzheimer associated neuropathological changes, and Alzheimer's disease occurrence within 14 years. Within a German community-based cohort, two polygenic risk scores (clinical Alzheimer's disease and Aß42 based) were calculated, APOE genotype was determined, and Aß misfolding in blood plasma was measured by immuno-infrared sensor in 59 participants diagnosed with Alzheimer's disease during 14 years of follow-up and 581 participants without dementia diagnosis. Associations between each genetic marker and Aß misfolding were assessed through logistic regression and the ability of each genetic marker and Aß misfolding to predict Alzheimer's disease was determined. The Alzheimer's disease polygenic risk score and APOE ε4 presence were associated to Aß misfolding (odds ratio, 95% confidence interval: per standard deviation increase of score: 1.25, 1.03-1.51; APOE ε4 presence: 1.61, 1.04-2.49). No association was evident for the Aß polygenic risk score. All genetic markers were predictive of Alzheimer's disease diagnosis albeit much less so than Aß misfolding (areas under the curve: Aß polygenic risk score: 0.55; AD polygenic risk score: 0.59; APOE ε4: 0.63; Aß misfolding: 0.84). Clinical Alzheimer's genetic risk was associated to early pathological changes (Aß misfolding) measured in blood, however, predicted Alzheimer's disease less accurately than Aß misfolding itself. Genetic predisposition may provide information regarding disease initiation, while Aß misfolding could be important in clinical risk prediction.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Predisposição Genética para Doença , Humanos , Placa Amiloide , Plasma
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