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2.
Cells ; 11(15)2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35954306

RESUMO

We recently derived and validated a serum-based microRNA risk score (miR-score) which predicted colorectal cancer (CRC) occurrence with very high accuracy within 14 years of follow-up in a large population-based cohort. Here, we aimed to assess and compare the distribution of the miR-score among participants of screening colonoscopy at various stages of colorectal carcinogenesis. MicroRNAs (miRNAs) were profiled by quantitative-real-time-polymerase-chain-reaction in the serum samples of screening colonoscopy participants with CRC (n = 52), advanced colorectal adenoma (AA, n = 100), non-advanced colorectal adenoma (NAA, n = 88), and participants free of colorectal neoplasms (n = 173). The mean values of the miR-score were compared between groups by the Mann-Whitney U test. The associations of the miR-score with risk for colorectal neoplasms were evaluated using logistic regression analyses. MicroRNA risk scores were significantly higher among participants with AA than among those with NAA (p = 0.027) and those with CRC (p = 0.014), whereas no statistically significant difference was seen between those with NAA and those with no colorectal neoplasms (p = 0.127). When comparing adjacent groups, miR-scores were inversely associated with CRC versus AA and positively associated with AA versus NAA [odds ratio (OR), 0.37 (95% confidence interval (CI), 0.16-0.86) and OR, 2.22 (95% CI, 1.06-4.64) for the top versus bottom tertiles, respectively]. Our results are consistent with the hypothesis that a high miR-score may be indicative of an increased CRC risk by an increased tendency of progression from non-advanced to advanced colorectal neoplasms, along with a change of the miR-patterns after CRC manifestation.


Assuntos
Adenoma , Neoplasias Colorretais , MicroRNAs , Adenoma/genética , Carcinogênese , Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Detecção Precoce de Câncer/métodos , Humanos , Fatores de Risco
3.
Cancers (Basel) ; 14(15)2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35954499

RESUMO

Objective: Evidence on the cost-effectiveness of screening for colorectal cancer (CRC) in the German general population remains scarce as key input parameters, the costs to treat CRC, are largely unknown. Here, we provide detailed estimates on CRC treatment costs over time. Methods: Using insurance claims data from the Vilua healthcare research database, we included subjects with newly diagnosed CRC and subjects who died of CRC between 2012 and 2016. We assessed annualized CRC-related inpatient, outpatient and medication costs for up to five years after first diagnosis and prior to death, stratified by sex and age. Findings: We identified 1748 and 1117 subjects with follow-up data for at least 1 year after diagnosis and prior to death, respectively. In those newly diagnosed, average costs were highest in the first year after diagnosis (men, EUR 16,375-16,450; women, EUR 10,071-13,250) and dropped steeply in the following years, with no consistent pattern of differences with respect to age. Costs prior to death were substantially higher as compared to the initial phase of care and consistently on a high level even several years before death, peaking in the final year of life, with strong differences by sex and age (men vs. women, <70 years, EUR 34,351 vs. EUR 31,417; ≥70 years, EUR 14,463 vs. EUR 9930). Conclusion: Once clinically manifest, CRC causes substantial treatment costs over time, particularly in the palliative care setting. Strong differences in treatment costs by sex and age warrant further investigation.

4.
Artigo em Inglês | MEDLINE | ID: mdl-35964896

RESUMO

BACKGROUND & AIMS: The screening yield and related cost of a risk-adapted screening approach compared with established screening strategies in population-based CRC screening are not clear. METHODS: We randomly allocated 19,373 participants into one of the three screening arms in a 1:2:2 ratio: (1) one-time colonoscopy (n=3,883); (2) annual fecal immunochemical test (FIT) (n=7,793); (3) annual risk-adapted screening (n=7,697), in which, based on the risk-stratification score, high-risk participants were referred for colonoscopy, and low-risk ones were referred for FIT. Three consecutive screening rounds were conducted for both the FIT and the risk-adapted screening arms. Follow-up to trace the health outcome for all the participants was conducted over the 3-year study period. The detection rate of advanced colorectal neoplasia (CRC and advanced precancerous lesions) was the main outcome. The trial was registered in the Chinese Clinical Trial Registry (number: ChiCTR1800015506). RESULTS: In the colonoscopy, FIT, and risk-adapted screening arms over three screening rounds, the participation rates were 42.4%, 99.3%, and 89.2%, respectively; the detection rates for advanced neoplasm (intention-to-treat analysis) were 2.76%, 2.17%, and 2.35%, respectively, with odds ratio (OR)colonoscopyvs.FIT of 1.27 (95% confidence interval [CI]: 0.99-1.63; P=0.056), ORcolonoscopyvs.risk-adapted screening of 1.17 (95% CI: 0.91-1.49; P=0.218), and ORrisk-adapted screeningvs.FIT of 1.09 (95% CI: 0.88-1.35; P=0.438); the numbers of colonoscopies needed to detect one advanced neoplasm were 15.4, 7.8, and 10.2, respectively; the costs for detecting one advanced neoplasm from a government perspective using package payment format were CNY6,928 ($1,004), CNY5,821 ($844), and CNY6,694 ($970), respectively. CONCLUSIONS: The risk-adapted approach is a feasible and cost-favorable strategy for population-based CRC screening, and therefore could complement the well-established one-time colonoscopy and annual repeated FIT screening strategies.

5.
Nat Genet ; 54(8): 1167-1177, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35915169

RESUMO

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Pulmonares , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Proteínas de Ligação a RNA/genética
6.
Eur J Prev Cardiol ; 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35972749

RESUMO

AIMS: The 2021 ESC guideline on cardiovascular disease (CVD) prevention categorizes moderate and severe chronic kidney disease (CKD) as high and very-high CVD risk status regardless of other factors like age and does not include estimated glomerular filtration rate (eGFR) and albuminuria in its algorithms, SCORE2 and SCORE2-OP, to predict CVD risk. We developed and validated an "Add-on" to incorporate CKD measures into these algorithms, using a validated approach. METHODS: In 3,054,840 participants from 34 datasets, we developed three Add-ons (eGFR only, eGFR + urinary albumin-to-creatinine ratio [ACR] [the primary Add-on], and eGFR + dipstick proteinuria) for SCORE2 and SCORE2-OP. We validated c-statistics and net reclassification improvement (NRI), accounting for competing risk of non-CVD death, in 5,997,719 participants from 34 different datasets. RESULTS: In the target population of SCORE2 and SCORE2-OP without diabetes, the CKD Add-on (eGFR only) and CKD Add-on (eGFR + ACR) improved c-statistic by 0.006 (95%CI 0.004-0.008) and 0.016 (0.010-0.023), respectively, for SCORE2 and 0.012 (0.009-0.015) and 0.024 (0.014-0.035), respectively, for SCORE2-OP. Similar results were seen when we included individuals with diabetes and tested the CKD Add-on (eGFR + dipstick). In 57,485 European participants with CKD, SCORE2 or SCORE2-OP with a CKD Add-on showed a significant NRI (e.g., 0.100 [0.062-0.138] for SCORE2) compared to the qualitative approach in the ESC guideline. CONCLUSION: Our Add-ons with CKD measures improved CVD risk prediction beyond SCORE2 and SCORE2-OP. This approach will help clinicians and patients with CKD refine risk prediction and further personalize preventive therapies for CVD.

7.
Lancet Reg Health Eur ; 20: 100451, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35799615

RESUMO

Background: Demographic aging is expected to increase the number of colorectal cancer (CRC) cases in many countries. Screening for CRC can substantially reduce the disease burden but its use has remained rather limited in Germany. We aimed to quantify the expected impact of demographic aging on the future CRC burden and the potential to reduce that burden by increased use of screening colonoscopy offers in Germany. Methods: We obtained sex- and age-specific data on colonoscopy use from AOK, the biggest health insurance provider in Germany, and combined these with the projected demographic development and current CRC incidence rates. We estimated the number of new CRC cases until 2060, assuming screening colonoscopy use to be constant or to increase to between 1·5 and 3 times the current levels. Findings: Ten-year screening colonoscopy utilization rates were low (<20% in both sexes in all age groups). Assuming no change in screening colonoscopy use, the overall annual caseload was predicted to increase from approximately 62,000 cases in 2020 to more than 70,000 cases by the year 2040 and more than 75,000 cases by 2050. To avoid increasing case numbers, an increase of screening colonoscopy use to more than 3 times current levels would be needed. Interpretation: At current levels of screening use, the strong effects of the demographic aging imply that the CRC caseload will significantly increase in the decades to come. CRC screening efforts will need to be substantially increased to even maintain the current level of incident cases. Funding: German Federal Ministry of Education and Research (grant 01GL1712).

8.
Lancet Reg Health Eur ; 21: 100458, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35832063

RESUMO

Background: An increasing proportion of colorectal cancers (CRCs) are detected through screening due to the availability of organised population-based programmes. We aimed to analyse survival probabilities of patients with screen-detected CRC in European countries. Methods: Data from CRC patients were obtained from 16 population-based cancer registries in nine European countries. We included patients with cancer diagnosed from the year organised CRC screening programmes were introduced until the most recent year with available data at the time of analysis, whose ages at diagnosis fell into the age groups targeted by screening. Patients were followed up with regards to vital status until 2016-2020 across the various countries. Overall and CRC-specific survival were analysed by mode of detection and stage at diagnosis for all countries combined and for each country separately using the Kaplan-Meier method. Findings: We included data from 228 134 patients, of whom 134 597 (aged 60-69 years at diagnosis targeted by screening in all countries) were considered in analyses for all countries combined. 22·3% (38 080/134 597) of patients had cancer detected through screening. Most screen-detected cancers were found at stages I-II (65·6% [12 772/19 469 included in stage-specific analyses]), while the majority of non-screen-detected cancers were found at stages III-IV (56·4% [31 882/56 543 included in stage-specific analyses]). Five-year overall and CRC-specific survival rates for patients with screen-detected cancer were 83·4% (95% CI 82·9-83·9) and 89·2% (88·8-89·7), respectively; for patients with non-screen-detected cancer, they were much lower (57·5% [57·2-57·8] and 65·7% [65·4-66·1], respectively). The favourable survival of patients with screen-detected cancer was also seen within each stage - five-year overall survival rates for patients with screen-detected stage I, II, III, and IV cancers were 92.4% (95% CI 91·6-93·1), 87·9% (86·6-89·1), 80·7% (79·3-82·0), and 32·3 (29·4-35·2), respectively. These patterns were also consistently seen for each individual country. Interpretation: Patients with cancer diagnosed at screening have a very favourable prognosis. In the rare case of detection of advanced stage cancer, survival probabilities are still much higher than those commonly reported for all patients regardless of mode of detection. Although these results cannot be taken to quantify screening effects, they provide useful and encouraging information for patients with screen-detected CRC and their physicians. Funding: This study was supported in part by grants from the German Federal Ministry of Education and Research and the German Cancer Aid.

9.
Alzheimers Dement ; 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35852967

RESUMO

INTRODUCTION: Blood-based biomarkers for Alzheimer's disease (AD) are urgently needed. Here, four plasma biomarkers were measured at baseline in a community-based cohort followed over 17 years, and the association with clinical AD risk was determined. METHODS: Amyloid beta (Aß) misfolding status as a structure-based biomarker as well as phosphorylated tau 181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) concentration levels were determined at baseline in heparin plasma from 68 participants who were diagnosed with AD and 240 controls without dementia diagnosis throughout follow-up. RESULTS: Aß misfolding exhibited high disease prediction accuracy of AD diagnosis within 17 years. Among the concentration markers, GFAP showed the best performance, followed by NfL and P-tau181. The combination of Aß misfolding and GFAP increased the accuracy. DISCUSSION: Aß misfolding and GFAP showed a strong ability to predict clinical AD risk and may be important early AD risk markers. Aß misfolding illustrated its potential as a prescreening tool for AD risk stratification in older adults.

10.
Cancer Med ; 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35891576

RESUMO

INTRODUCTION: Whether and to what extent the relationship between physical activity (PA) and colorectal cancer (CRC) differs according to CRC-related genetic risk remains to be determined, and no studies to date have quantified how much genetically determined risk could be compensated for with active exercise. METHODS: Genetic risk was quantified by a polygenic risk score (PRS) summarizing the estimated effect of 140 CRC-associated genetic variants. Associations of PA with CRC risk were estimated by multivariable logistic regression across PRS levels. We also compared the impact of PA and specific PA types to the PRS using "genetic risk equivalent (GRE)", a novel approach to enhance effective risk communication. RESULTS: Among 5058 CRC patients and 4134 controls, we observed no significant association between overall PA level in quartiles and CRC risk. However, the highest versus lowest lifetime leisure time physical activity (LTPA) was associated with a 13% lower CRC risk [odds ratio 0.87, 95% confidence interval (CI) 0.77-1.00] independent of PRS levels (adjusted p value for interaction = 0.18). This effect was equivalent to the effect of having 11 percentiles lower PRS (GRE -10.6, 95% CI -20.7 to -0.6). The GRE (95% CI) for the highest lifetime sports tertile was -23.0 (-33.9 to -12.0). CONCLUSIONS: LTPA was inversely associated with CRC risk irrespective of polygenic risk for CRC, which reinforces the importance of LTPA in CRC prevention among the general population. Adequate sports activity can compensate for a large share of polygenic risk for CRC.

11.
Artigo em Inglês | MEDLINE | ID: mdl-35879433

RESUMO

PURPOSE: It is important to monitor disease-specific health-related quality of life (HRQoL) in breast cancer (BC) survivors to identify potential unmet supportive care needs. However, previous studies were characterized by small samples of mostly short-term survivors and were limited to certain age ranges, stages and/or treatments. METHODS: We used data from 3045 long-term BC survivors (5-15 years post-diagnosis) recruited in a German multi-regional population-based study. We assessed disease-specific HRQoL with the EORTC QLQ-BR23, scoring from 0 to 100. Differences in functioning and symptoms according to age at survey, self-reported treatments, stage, and disease status (disease-free vs. active disease) were assessed with multiple regression. Active disease was defined as any self-report of recurrence, metastasis or second primary cancer after the index cancer. RESULTS: Older BC survivors reported a higher body image and a better future perspective, but lower sexual functioning. Survivors aged 30-49 years who had breast-conserving therapy or mastectomy with breast reconstruction reported a better body image compared to those who had mastectomy only. We also found differences in symptoms according to treatments in some age groups. Stage at diagnosis was not associated with HRQoL overall and in most age subgroups. Disease-free BC survivors aged 30-79 years reported a better future perspective and less systemic therapy side effects than those with active disease. CONCLUSION: Several treatment-associated symptoms and functioning detriments were found 5-15 years after diagnosis. The results emphasize the need of a comprehensive, individualized survivorship care, recognizing differential needs of long-term BC survivors according to age, treatment modalities, and disease status.

12.
Age Ageing ; 51(7)2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35780433

RESUMO

BACKGROUND: Rapid population ageing has raised the proportion of older former smokers considerably, but a comprehensive assessment tool of former smoking-related health risks is absent. OBJECTIVE: We utilised the large-scale data of UK Biobank and ESTHER study to build a former smoking score (FSS) for older former smokers using three major former smoking traits: pack-years, smoking duration and time since smoking cessation. DESIGN: UK Biobank and ESTHER study are two cohorts of older adults with 502,528 and 9,940 participants from the UK and Germany, respectively. METHODS: Smoking history and covariates were retrieved from the self-administrated questionnaires and mortality and morbidity data were obtained through regular linkages to hospital records. RESULTS: We constructed the FSS based on the 94,446 former smokers of UK Biobank by retrieving the averaged effect estimates of each trait with a 100-time random sampling. This score was robustly associated with higher risks of mortality and incidence of major smoking-related diseases, outperforming each trait. In the validation panel of 2,683 former smokers from ESTHER study, the FSS was highly predictive of mortality and morbidities. Particularly, compared with the 1st quartile of the FSS group, the 4th quartile group had 114.1, 104.5 and 158.9% higher risks of all-cause, CVD and cancer mortality, respectively, and 41.9, 31.9, 52.4 and 831.3% higher risks of incident CVD, type 2 diabetes, any cancers and lung cancer, respectively. CONCLUSIONS: Our study demonstrates the large potential of refined risk assessment of former smokers by more comprehensive consideration of the major traits of former smoking.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Idoso , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Humanos , Morbidade , Fatores de Risco , Fumantes , Fumar/efeitos adversos , Fumar/epidemiologia , Reino Unido/epidemiologia
14.
EClinicalMedicine ; 49: 101460, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35747198

RESUMO

Background: Evidence is lacking on the impact of alcohol consumption on colorectal cancer (CRC) risk (overall and by age at diagnosis) by polygenic risk score (PRS) levels, and it is unclear how the magnitude of CRC risk associated with alcohol consumption compares to the magnitude of genetically determined risk. Methods: Multiple logistic regression was used to assess the association between alcohol consumption and colorectal cancer (CRC) across PRS levels based on 140 CRC-related loci among 5104 CRC cases and 4131 controls from a large population-based case-control study. We compared the effects for alcohol consumption and PRS on CRC risk using the "Genetic Risk Equivalent (GRE)" for effective risk communication. Specific analyses were conducted for early-onset CRC (EOCRC, <55 years) and late-onset CRC (LOCRC, ≥55 years). Findings: High alcohol consumption, and to a lower extent, also alcohol abstinence were associated with increased CRC risk. Compared to low alcohol consumption (0·1-<25 g/d), lifetime average alcohol consumption ≥25 g/d was more strongly associated with EOCRC [odds ratio (OR) 1·8, 95% confidence interval (CI) 1·2-2·8] than with LOCRC risk (OR 1·3, 95% CI 1·1-1·4) (P-value for interaction with age =0·011). Interactions between alcohol consumption and PRS did not reach statistical significance for either EOCRC or LOCRC risk. The estimated impact of high lifetime alcohol consumption on EOCRC was equivalent to the effect of having 47 percentiles higher PRS (GRE 47, 95% CI 12-82), stronger than the impact on LOCRC (GRE 18, 95% CI 8-29). Interpretation: Excessive alcohol use was strongly associated with EOCRC risk, independent of PRS levels. Abstaining from heavy drinking could reduce risk for CRC, in particular for EOCRC to an extent that would be equivalent to having a much lower genetically determined risk. Funding: The first author (X.C.) was supported by the Guangzhou Elite Project (GEP). The DACHS study was supported by grants from the German Research Council (BR 1704/6-1, BR1704/6-3, BR 1704/6-4, BR 1704/6-6, CH 117/1-1, BR 1704/17-1, HO 5117/2-1) and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01GL1712).

15.
Eur J Ageing ; 19(2): 263-276, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35663910

RESUMO

Supportive family and friendship ties can serve different functions and thus might show different associations with an individual's health. Particularly, older adults might show varying health benefits of different types of supportive ties depending on their marital and retirement status. Our aim is to analyze relationships between different types of supportive social ties and autonomic nervous system (ANS) function, a physiological indicator of health that can help to establish the biological plausibility of the association-measured by heart rate variability (HRV). We present cross-sectional linear regression analyses of a German cohort of community-dwelling older adults (2008-2010; n = 1,548; mean age = 68.7 years). Our findings indicate that supportive friendship ties show significant positive associations (i.e., higher HRV) in individuals that are either not married or above retirement age. Supportive family ties show significant positive associations in individuals below retirement age. Significant results vanish or are reduced after accounting for behavioral/physical and psychological/cognitive indicators. We conclude that programs supporting the development or maintenance of friendship ties might be especially beneficial in unmarried older adults and adults above retirement age. Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-021-00638-2.

16.
Cancer Prev Res (Phila) ; 15(8): 543-552, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35679356

RESUMO

Fecal immunochemical tests (FITs) are increasingly used as noninvasive screening tests in colorectal cancer-screening programs. Polygenic risk scores (PRS) are increasingly propagated for risk stratification in colorectal cancer screening. We aimed to assess the potential of combining FIT results and PRS to enhance diagnostic accuracy of detecting advanced neoplasia (AN) compared with using FIT results alone. Of 10,362 participants of screening colonoscopy in Southern Germany who conducted either one of two quantitative FITs, genotyping was done in all participants with AN (colorectal cancer or advanced adenoma) and a random subset of controls. Among 5,306 individuals, a PRS was calculated on the basis of the number of risk alleles in 140 SNPs. Partial areas under the receiver operating characteristics (ROC) curves (pAUCs) were computed for FIT and PRS alone and combined, focusing on a specificity range of 100%-80%. Both FITs showed similar performance characteristics with pAUCs of 0.661 (95% confidence interval (CI), 0.625-0.698; Ridascreen Hemoglobin) and 0.682 (95% CI, 0.661-0.701; FOB Gold) for AN detection. PRS alone reached a pAUC of 0.524 (95% CI, 0.499-0.550) and 0.530 (95% CI, 0.516-0.545), respectively, and its addition to FIT did not improve pAUCs (0.659; 95% CI, 0.622-0.697) and 0.667 (95% CI, 0.650-0.687), respectively. This finding was confirmed by investigating sensitivities at fixed specificities at 85%, 90%, and 95%. Partial AUCs also did not improve when adding the weighted PRS to FIT instead of the unweighted PRS. In summary, the combination with PRS did not improve diagnostic accuracy of FIT-based screening in a large asymptomatic colorectal cancer screening population from South-Western Germany. PREVENTION RELEVANCE: In our study, combining polygenic risk score with fecal immunochemical test (FIT) did not improve diagnostic accuracy for advanced colorectal neoplasia detection compared with FIT alone. So far, such a combination cannot be recommended because it would come at extra costs and effort despite no relevant gain in neoplasia detection.


Assuntos
Neoplasias Colorretais , Sangue Oculto , Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Detecção Precoce de Câncer/métodos , Fezes , Humanos , Fatores de Risco
17.
Nat Commun ; 13(1): 3254, 2022 06 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
18.
Cancer Commun (Lond) ; 42(7): 648-662, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35666080

RESUMO

BACKGROUND: We previously observed decreasing resection rates of non-metastatic gastric adenocarcinoma (GaC) in the US and some European countries. If and to what extent these trends affect the trends in overall survival (OS) of patients with non-metastatic GaC at the population level remain unclear. This large international population-based cohort study aimed to assess the impact of the previously observed decreasing resection rates on multivariable-adjusted trends in the long-term OS of patients with non-metastatic GaC. METHODS: Individual-level data of patients with non-metastatic GaC were obtained from the national cancer registries of the Netherlands, Belgium, Sweden, Norway, and Slovenia, and the US Surveillance, Epidemiology, and End Results database. We analyzed data for each country separately. Associations between year of diagnosis and OS were assessed using Cox proportional hazards regression model with adjustment for multiple prognostic variables, with and without including resection and chemotherapy as potential explanatory variables. RESULTS: A total of 66,398 non-metastatic GaC patients diagnosed in 2003-2016 were analyzed, with an accumulated follow-up of 172,357 person-years. Without adjustment for resection, OS was improved only slightly in the US [hazard ratio (HR)per year = 0.99; HR≥ vs. <2010 = 0.96], and no improvement was observed in the investigated European countries, with OS even worsening in Sweden (HRper year = 1.03; HR≥ vs. <2010 = 1.17). After adjusting for resection, the increasing OS trend became stronger in the US (HRper year = 0.98; HR≥ vs. <2010 = 0.88), and the temporal trend became insignificant in Sweden. In Slovenia (HRper year = 0.99; HR≥ vs. <2010 = 0.92) and Norway (HRper year = 0.97; HR≥ vs. <2010 = 0.86), improved OS over time emerged after resection adjustment. Improved OS in patients undergoing resection was observed in the US, the Netherlands, and Norway. Adjustment for chemotherapy did not alter the observed associations. Stratified analyses by tumor location showed mostly similar results with the findings in all patients with non-metastatic GaCs regarding the associations between year of diagnosis and survival. CONCLUSIONS: OS of patients with non-metastatic GaC mostly did not improve in selected European countries and was even worsened in Sweden, while it was slightly increased in the US in the early 21st century. Progress in OS of patients with non-metastatic GaC seems to have been impeded to a large extent by decreasing rates of resection.


Assuntos
Adenocarcinoma , Adenocarcinoma/epidemiologia , Adenocarcinoma/cirurgia , Estudos de Coortes , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Sistema de Registros
19.
JNCI Cancer Spectr ; 6(4)2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35642982

RESUMO

BACKGROUND: Hormone-replacement therapy (HRT) is associated with lower colorectal cancer (CRC) risk among postmenopausal women. However, little is known about the effects of lifetime exposure of women to varying levels of estrogen and progesterone through reproductive factors such as parity, use of oral contraceptives (OC), breastfeeding, and menstruation on CRC risk. METHODS: We assessed associations between reproductive factors and CRC risk among 2650 female CRC patients aged 30+ years and 2175 matched controls in a population-based study in Germany, adjusting for potential confounders by multiple logistic regression. RESULTS: Inverse associations with CRC risk were found for numbers of pregnancies (odds ratio [OR] per pregnancy = 0.91, 95% confidence interval [CI] = 0.86 to 0.97), breastfeeding for 12 months and longer (OR = 0.74, 95% CI = 0.61 to 0.90), and use of either OC or HRT (OR = 0.75, 95% CI = 0.64 to 0.87) or both (OR = 0.58, 95% CI = 0.48 to 0.70). Similar results were found for postmenopausal women only and when adjusting for number of pregnancies and for all reproductive factors analyzed together. Breastfeeding duration of 12 months and longer was associated with lower risk of cancer only in the proximal colon (OR = 0.58, 95% CI = 0.45 to 0.74). CONCLUSIONS: Several reproductive factors were associated with lower CRC risk in women, including number of pregnancies, breastfeeding duration, and use of OC and HRT. This suggests that women's exposure to female reproductive hormones plays a key role in the difference in CRC risk between women and men and in site-specific CRC risk.


Assuntos
Neoplasias Colorretais , História Reprodutiva , Estudos de Casos e Controles , Neoplasias Colorretais/induzido quimicamente , Anticoncepcionais Orais/efeitos adversos , Feminino , Humanos , Masculino , Razão de Chances , Gravidez , Fatores de Risco
20.
J Natl Cancer Inst ; 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35723569

RESUMO

BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER) positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23,353 cases, and 71,072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared to nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46; for multiparous women with luminal A-like tumors 20-<25 years after last birth and 45-<50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95%CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95%CI = 0.79 to 1.34, for multiparous women 25 to < 30 years after last birth). Older age at first birth (P-heterogeneity<.001 for triple-negative compared to luminal-A like) and breastfeeding (P-heterogeneity<.001 for triple-negative compared to luminal-A like) were associated with lower risk of triple-negative but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like. CONCLUSION: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared to other subtypes, with implications for the understanding of disease etiology and risk prediction.

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