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OBJECTIVE: This study assessed the health-related quality of life (HRQo) of women surviving a borderline ovarian tumor (BOT) in comparison with early-stage ovarian cancer survivors treated surgically alone and with a matched cancer-free population. METHODS: Survivors of BOT and ovarian cancer were invited in two Dutch cross-sectional, population-based studies. Ovarian cancer survivors with tumor stage I who were treated surgically only were included. A random sample from the cancer-free population was matched on sex, age and education to the sample of BOT survivors. The EORTC QLQ-C30 (version 3.0) and the EORTC QLQ-OV28 were completed by the cancer-free population and the BOT and ovarian cancer survivors in study 1 and 2. The Hospital Anxiety and Depression Scale (HADS) was only completed by the cancer-free population and the survivors of BOT and ovarian cancer in study 1. BOT survivors were compared to early-stage ovarian cancer survivors and the general population using linear regression analyses and effect sizes regarding clinical importance. RESULTS: 83 BOT (42%), 88 early-stage ovarian cancer survivors (52%), and 82 women from the general population were included. In most HRQoL domains, BOT survivors were not significantly different from early-stage ovarian cancer survivors and the cancer-free population, except that BOT survivors reported significantly less insomnia than early-stage ovarian cancer survivors and more dyspnea than the cancer-free population (small clinical difference). CONCLUSION: In general, BOT survivors' HRQoL lies between the HRQoL of early-stage ovarian cancer survivors and of the cancer-free population, but clinical effect sizes between the groups were mostly only trivial.
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Mutation spectra and mutational signatures in cancerous and non-cancerous tissues can be identified by various established techniques of massively parallel sequencing (or next-generation sequencing) including whole-exome or whole-genome sequencing, and more recently by error-corrected/duplex sequencing. One rather underexplored area has been the genome-scale analysis of mutational signatures as markers of mutagenic exposures, and their impact on cancer driver events applied to formalin-fixed or alcohol-fixed paraffin embedded archived biospecimens. This review showcases successful applications of the next-generation sequencing methodologies in archived fixed tissues, including the delineation of the specific tissue fixation-related DNA damage manifesting as artifactual signatures, distinguishable from the true signatures that arise from biological mutagenic processes. Overall, we discuss and demonstrate how next-generation sequencing techniques applied to archived fixed biospecimens can enhance our understanding of cancer causes including mutagenic effects of extrinsic cancer risk agents, and the implications for prevention efforts aimed at reducing avoidable cancer-causing exposures.
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BACKGROUND: Long-term energy balance-related factors (i.e. lifestyle and physiological factors that influence the equilibrium between energy intake and energy expenditure over an extended period) like body mass index (BMI) are linked to colorectal cancer (CRC) risk, but their impact on CRC survival is unclear. We explored associations between these long-term energy balance-related factors and survival, and examined potential differences across metabolic Warburg-subtypes. METHODS: Associations between long-term energy balance-related factors and survival in the total series of CRC patients (n=2,347) obtained from the prospective Netherlands Cohort Study, as well as according to Warburg-subtype (Warburg-low: n=652, Warburg-moderate: n=802, Warburg-high: n=797), were investigated using Cox regression analysis. RESULTS: Among the long-term energy balance-related factors studied, only increasing pre-diagnostic BMI was associated with a borderline significant poorer overall survival in CRC patients (HR5kg/m2 1.07; 95%CI 0.99-1.15). Stratified analyses showed that pre-diagnostic weight gain (HR5kg 1.06; 95%CI 1.00-1.12), and potentially increased height (HR5cm 1.04; 95%CI 0.98-1.11), were associated with poor overall survival only in patients with Warburg-high CRC. Increasing pre-diagnostic BMI was associated with poor survival only in patients with Warburg-moderate CRC (CRC-specific: HR5kg/m2 1.12; 95%CI 0.96-1.32, overall: HR5kg/m2 1.20; 95%CI 1.05-1.36). No consistent patterns were observed across energy-restriction proxies. CONCLUSIONS: Maintaining a healthy pre-diagnostic BMI may be beneficial for CRC survival. Moreover, associations between pre-diagnostic BMI, weight change, early-life energy restriction, height and CRC survival differed according to Warburg-subtype. IMPACT: Understanding the biological pathways involved in associations between energy balance-related factors and CRC survival could help refine prevention strategies in the future.
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BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.
Subject(s)
Endometrial Neoplasms , Hypertension , Humans , Female , Endometrial Neoplasms/epidemiology , Risk Factors , Hypertension/epidemiology , Middle Aged , Case-Control Studies , Aged , Adult , IncidenceABSTRACT
Data on the role of circadian related factors in the etiology of endometrial cancer are scarce. We collected individual data on night shift work or daily sleep duration from 7,207 cases and 22,027 controls participating in 11 studies from the Epidemiology of Endometrial Cancer Consortium (E2C2). Main analyses were performed among postmenopausal women: 6,335 endometrial cancer cases and 18,453 controls. Using individual data, study-specific odd ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated with logistic regression and pooled analyses were conducted using random-effects meta-analyses. A non-significant inverse association was observed between endometrial cancer and night shift work (OR=0.89, 95%CI=0.72-1.09; I2=0.0%, Pheterogeneity=0.676). Associations did not vary by shift type (permanent or rotating), or duration of night work. Categorizations of short (<7h) or long (≥9h) sleep duration were not associated with endometrial cancer risk (ORshort=1.02, 95%CI=0.95-1.10; I2=55.3%, Pheterogeneity=0.022; ORlong=0.93, 95%CI=0.81-1.06; I2=11.5%, Pheterogeneity=0.339). No associations were observed per 1-h increment of sleep (OR=0.98, 95%CI=0.95-1.01; I2=46.1%, Pheterogeneity=0.063), but an inverse association was identified among obese women (OR=0.93, 95%CI=0.89-0.98 per 1-h increment; I2=12.7%, Pheterogeneity=0.329). Overall, these pooled analyses provide evidence that night shift work and sleep duration are not strong risk factors for endometrial cancer in postmenopausal women.
Subject(s)
Endometrial Neoplasms , Shift Work Schedule , Female , Humans , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/etiology , Risk Factors , Shift Work Schedule/adverse effects , Sleep , Sleep Duration , Work Schedule ToleranceABSTRACT
Autopsy rates are declining, while major discrepancies between autopsies and clinical diagnoses remain. Still, little is known about the impact of suspected underlying diseases, for example, a diagnosis of cancer, on the autopsy rate. The aim of this study was to investigate the relation between the clinical cause of death, a history of cancer, and the medical autopsy rate using data from the Netherlands Cohort Study on Diet and Cancer (NLCS), a large prospective cohort study with a long follow-up. The NLCS is a prospective study initiated in 1986 and includes 120,852 persons (58,279 males and 62,573 females), 55-69 years of age at the time of enrollment. The NLCS was linked with the Dutch Nationwide Pathology Databank (PALGA), the Dutch Population Register (GBA), the Netherlands Cancer Registry, and the causes of death registry (Statistics Netherlands). If applicable, the 95% confidence intervals were calculated. During the follow-up of the NLCS, 59,760 deaths were recorded by linkage with the GBA from 1991 until 2009. Of these, a medical autopsy was performed on 3736 deceased according to linkage with PALGA, resulting in an overall autopsy rate of 6.3%. Major variations in the autopsy rate were observed according to the cause of death. The autopsy rate increased according to the number of contributing causes of death. Lastly, a diagnosis of cancer affected the autopsy rate. The clinical cause of death and a history of cancer both influenced the medical autopsy rate in a large national cohort. The insight this study provides may help clinicians and pathologists counteracting the further downfall of the medical autopsy.
Subject(s)
Neoplasms , Male , Female , Humans , Aged , Autopsy , Prospective Studies , Cohort Studies , Cause of Death , Retrospective StudiesABSTRACT
Cancer of Unknown Primary (CUP) is metastatic cancer with an unidentifiable primary tumour origin during life. It remains difficult to study the occurrence and aetiology of CUP. Hitherto, it is unclear whether risk factors are associated with CUP, yet identifying these factors could reveal whether CUP is a specific entity or a cluster of metastasised cancers from various primary tumour origins. Epidemiological studies on possible CUP risk factors were systematically searched in PubMed and Web of Science on February 1st, 2022. Studies, published before 2022, were included if they were observational human-based, provided relative risk estimates, and investigated possible CUP risk factors. A total of 5 case-control and 14 cohort studies were included. There appears to be an increased risk for smoking in relation to CUP. However, limited suggestive evidence was found to link alcohol consumption, diabetes mellitus, and family history of cancer as increased risks for CUP. No conclusive associations could be made for anthropometry, food intake (animal or plant-based), immunity disorders, lifestyle (overall), physical activity, or socioeconomic status and CUP risk. No other CUP risk factors have been studied. This review highlights smoking, alcohol consumption, diabetes mellitus and family history of cancer as CUP risk factors. Yet, there remains insufficient epidemiological evidence to conclude that CUP has its own specific risk factor profile.
Subject(s)
Diabetes Mellitus , Neoplasms, Unknown Primary , Humans , Neoplasms, Unknown Primary/pathology , Risk Factors , Smoking , Alcohol DrinkingABSTRACT
The aim of the present study was to re-evaluate 457 renal cell carcinoma (RCC) cases from the Netherlands Cohort Study on Diet and Cancer (NLCS), a large population-based cohort, according to the new 2022 ISUP, Genitourinary Pathology Society and World Health Organisation (WHO) classifications to assess whether newly recognized subtypes of RCC could be found among these cases. These cases were initially evaluated according to the 2004 WHO classification, the Fuhrman grading system and the 3rd version of the Tumor-Node-Metastasis (TNM). Data on tumor size, laterality and date of diagnosis, among other clinicopathological characteristics, were obtained through record linkage with the Netherlands Cancer Registry and the Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief. Digital slides from the NLCS were reviewed by two urogenital pathologists according to the new ISUP grading and the 2022 WHO classification (5th edition). Immunohistochemistry staining for carbonic anhydrase IX was performed on cases with ambiguous morphology. A total of 373 cases of clear cell RCC (ccRCC), 61 cases of papillary RCC (pRCC), 13 cases of chromophobe RCC, 3 cases of collecting duct carcinoma and 4 cases of oncocytoma were identified. The subtyping showed no discrepancy with the previous diagnoses. A comparison of the WHO/ISUP grading to the original Fuhrman grading showed a similar grading in 245 (56.5%) cases of the total ccRCC and pRCC cases. The staging according to the novel TNM classification 8th edition showed a restaging in 286 cases (65.5%). Lymphovascular (microvascular) invasion (LVI) and tumor necrosis (TN) were present in 14.4% and 33.5% of the total number of cases, respectively. Furthermore, the presence of sarcomatoid differentiation in 5.1% and rhabdoid differentiation in 4.2% of the cases was observed. In conclusion, none of the newly accepted and emerging/provisional RCC entities were identified in the NLCS cases, which could be attributed to the high mean age (71.4 years) at diagnosis of the patients included in the present study. A restaging of the NLCS cases using the TNM 8th edition and regrading using ISUP grading was performed, which showed that it is possible to report on newer features, such as sarcomatoid differentiation and LVI, even in an old sample collection.
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BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology. MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk. RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade. CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.
Subject(s)
Endometrial Neoplasms , Fatty Acids, Omega-3 , Humans , Female , Prospective Studies , Overweight , Diet , Obesity/epidemiology , Obesity/complications , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/prevention & control , Endometrial Neoplasms/etiology , Logistic Models , Risk FactorsABSTRACT
PURPOSE: Tumor location and tumor node metastasis (TNM) stage guide treatment decisions in colorectal cancer (CRC) patients. However, patients with the same disease stage do not benefit equally from adjuvant therapy. Hence, there remains an urgent clinical need to identify prognostic and/or predictive biomarker(s) to personalize treatment decisions. In this exploratory study, we investigated whether our previously defined metabolic Warburg-subtypes can predict which CRC patients might derive survival benefit from adjuvant therapy. METHODS: Information regarding treatment (surgery only: n = 1451; adjuvant radiotherapy: n = 82; or adjuvant chemotherapy: n = 260) and Warburg-subtype (Warburg-low: n = 485, -moderate: n = 641, or -high: n = 667) was available for 1793 CRC patients from the Netherlands Cohort Study (NLCS). Kaplan-Meier curves and Cox regression models were used to investigate survival benefit from adjuvant therapy compared to surgery-only for the different Warburg-subtypes. RESULTS: Patients with Warburg-moderate CRC (HRCRC-specific 0.64; 95% CI 0.47-0.86, HRoverall 0.61; 95% CI 0.47-0.80), and possibly Warburg-high CRC (HRCRC-specific 0.86; 95% CI 0.65-1.14, HRoverall 0.82; 95% CI 0.64-1.05), had survival benefit from adjuvant therapy. No survival benefit was observed for patients with Warburg-low CRC (HRCRC-specific 1.07; 95% CI 0.76-1.52, HRoverall 0.95; 95% CI 0.70-1.30). There was a significant interaction between Warburg-subtype and adjuvant therapy for CRC-specific survival (p = 0.049) and overall survival (p = 0.035). CONCLUSION: Our results suggest that Warburg-subtypes may predict survival benefit from adjuvant therapy in CRC patients. A survival benefit from adjuvant therapy was observed for patients with Warburg-moderate and possibly Warburg-high CRC, but not for patients with Warburg-low CRC. Future prospective studies are necessary to validate our findings.
Subject(s)
Colorectal Neoplasms , Humans , Cohort Studies , Prospective Studies , Chemotherapy, Adjuvant , Prognosis , Colorectal Neoplasms/drug therapy , Neoplasm StagingABSTRACT
BACKGROUND: Diet, alcohol, cigarette smoking, physical inactivity, and body mass index have been studied as risk factors for renal cell cancer (RCC). The joint effects of these lifestyle factors, captured as Healthy Lifestyle Index (HLI), were examined in one previous study. This study aims to investigate the association between HLI score and RCC risk in the prospective Netherlands Cohort Study (NLCS). METHODS: A case-cohort analysis (3,767 subcohort members, 485 cases) was conducted using NLCS data (n = 120,852). Data on aforementioned risk factors was used to calculate HLI score, ranging 0-20, with higher scores reflecting healthier lifestyles. RCC occurrence was obtained by record linkage to cancer registries. Multivariable-adjusted proportional hazard models were used to calculate Hazard Ratios (HR) and 95% Confidence Intervals (95%CI). RESULTS: Compared to participants in the unhealthiest HLI category, participants within the healthiest category had a lower RCC risk (HR = 0.79, 95%CI = 0.56-1.10, p for trend 0.045). A standard deviation (± 3-unit) increase in HLI score was not statistically significantly associated with a lower RCC risk (HR = 0.92, 95%CI = 0.83-1.01). This association was stronger after excluding diet or alcohol from the score, although confidence intervals overlap. CONCLUSIONS: Adherence to a healthy lifestyle was weakly, though not statistically significantly, associated with a lower RCC risk.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Humans , Cohort Studies , Carcinoma, Renal Cell/epidemiology , Prospective Studies , Netherlands/epidemiology , Risk Factors , Healthy Lifestyle , Kidney Neoplasms/epidemiology , Kidney Neoplasms/etiologyABSTRACT
BACKGROUND: Previous research suggests that Warburg-subtypes are related to potentially important survival differences in colorectal cancer (CRC) patients. In the present study, we investigated whether mutational subgroups based on somatic mutations in RAS, BRAF, PIK3CA, and MET, which are known to promote the Warburg-effect, as well as mismatch repair (MMR) status, hold prognostic value in CRC. In addition, we investigated whether Warburg-subtypes provide additional prognostic information, independent of known prognostic factors like TNM stage. METHODS: CRC patients (n = 2344) from the prospective Netherlands Cohort Study (NLCS) were classified into eight mutually exclusive mutational subgroups, based on observed mutations in RAS, BRAF, PIK3CA, and MET, and MMR status: All-wild-type + MMRproficient , KRASmut + MMRproficient , KRASmut + PIK3CAmut + MMRproficient , PIK3CAmut + MMRproficient , BRAFmut + MMRproficient , BRAFmut + MMRdeficient , other + MMRproficient , and other + MMRdeficient . Kaplan-Meier curves and Cox regression models were used to investigate associations between mutational subgroups and survival, as well as associations between our previously established Warburg-subtypes and survival within these mutational subgroups. RESULTS: Compared to patients with all-wild-type + MMRproficient CRC, patients with KRASmut + MMRproficient , KRASmut + PIK3CAmut + MMRproficient , BRAFmut + MMRproficient , or other + MMRproficient CRC had a statistically significant worse survival (HRCRC-specific ranged from 1.29 to 1.88). In contrast, patients with other + MMRdeficient CRC had the most favorable survival (HRCRC-specific 0.48). No statistically significant survival differences were observed for the Warburg-subtypes within mutational subgroups. CONCLUSION: Our results highlight the prognostic potential of mutational subgroups in CRC. Warburg-subtypes did not provide additional prognostic information within these mutational subgroups. Future larger-scale prospective studies are necessary to validate our findings and to examine the potential clinical utility of CRC subtyping based on mutational subgroups.
Subject(s)
Colorectal Neoplasms , Proto-Oncogene Proteins B-raf , Humans , Proto-Oncogene Proteins B-raf/genetics , Prospective Studies , Cohort Studies , Proto-Oncogene Proteins p21(ras)/genetics , Prognosis , Mutation , Colorectal Neoplasms/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , DNA Mutational AnalysisABSTRACT
KRAS mutations (KRASmut ), PIK3CAmut , BRAFmut , and deficient DNA mismatch repair (dMMR) have been associated with the Warburg effect. We previously reported differential associations between early-life energy balance-related factors (height, energy restriction, body mass index [BMI]) and colorectal cancer (CRC) subtypes based on the Warburg effect. We now investigated associations of early-life energy balance-related factors and the risk of CRC subgroups based on mutation and MMR status. Data from the Netherlands Cohort Study was used. KRASmut , PIK3CAmut, BRAFmut, and MMR status were available for 2349 CRC cases, and complete covariate data for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox regression was used to estimate associations of height, energy restriction proxies (exposure to Dutch Hunger Winter, Second World War, Economic Depression), and early adult BMI (age 20 years) with risk of CRC based on individual molecular features and combinations thereof (all-wild-type+MMR-proficient [pMMR]; any-mutation/dMMR). Height was positively associated with any-mutation/dMMR CRC but not all-wild-type+pMMR CRC, with the exception of rectal cancer in men, and with heterogeneity in associations observed for colon cancer in men (p-heterogeneity = 0.049) and rectal cancer in women (p-heterogeneity = 0.014). Results on early-life energy restriction proxies in relation to the risk of CRC subgroups did not show clear patterns. Early adult BMI was positively, but not significantly, associated with KRASmut colon cancer in men and with BRAFmut and dMMR colon cancer in women. Our results suggest a role of KRASmut , PIK3CAmut , BRAFmut , and dMMR in the etiological pathway between height and CRC risk. KRASmut might potentially play a role in associations of early adult BMI with colon cancer risk in men, and BRAFmut and dMMR in women.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , DNA Mismatch Repair , Rectal Neoplasms , Adolescent , Adult , Female , Humans , Male , Young Adult , Class I Phosphatidylinositol 3-Kinases/genetics , Cohort Studies , Colonic Neoplasms/epidemiology , Colonic Neoplasms/genetics , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Mutation , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Rectal Neoplasms/epidemiology , Rectal Neoplasms/genetics , ChildABSTRACT
BACKGROUND: Epidemiologic studies suggest that coffee consumption may be inversely associated with risk of endometrial cancer (EC), the most common gynecological malignancy in developed countries. Furthermore, coffee consumption may lower circulating concentrations of estrogen and insulin, hormones implicated in endometrial carcinogenesis. Antioxidants and other chemopreventive compounds in coffee may have anticarcinogenic effects. Based on available meta-analyses, the World Cancer Research Fund (WCRF) concluded that consumption of coffee probably protects against EC. OBJECTIVES: Our main aim was to examine the association between coffee consumption and EC risk by combining individual-level data in a pooled analysis. We also sought to evaluate potential effect modification by other risk factors for EC. METHODS: We combined individual-level data from 19 epidemiologic studies (6 cohort, 13 case-control) of 12,159 EC cases and 27,479 controls from the Epidemiology of Endometrial Cancer Consortium (E2C2). Logistic regression was used to calculate ORs and their corresponding 95% CIs. All models were adjusted for potential confounders including age, race, BMI, smoking status, diabetes status, study design, and study site. RESULTS: Coffee drinkers had a lower risk of EC than non-coffee drinkers (multiadjusted OR: 0.87; 95% CI: 0.79, 0.95). There was a dose-response relation between higher coffee consumption and lower risk of EC: compared with non-coffee drinkers, the adjusted pooled ORs for those who drank 1, 2-3, and >4 cups/d were 0.90 (95% CI: 0.82, 1.00), 0.86 (95% CI: 0.78, 0.95), and 0.76 (95% CI: 0.66, 0.87), respectively (P-trend < 0.001). The inverse association between coffee consumption and EC risk was stronger in participants with BMI > 25 kg/m2. CONCLUSIONS: The results of the largest analysis to date pooling individual-level data further support the potentially beneficial health effects of coffee consumption in relation to EC, especially among females with higher BMI.
Subject(s)
Endometrial Neoplasms , Female , Humans , Risk Factors , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/etiology , Endometrial Neoplasms/prevention & control , Logistic Models , Case-Control Studies , Data CollectionABSTRACT
BACKGROUND: Several reproductive and hormonal factors, like age at menarche, parity, age at menopause, use of oral contraceptives and postmenopausal treatment, have been associated with the risk of renal cell cancer (RCC) in women, but results have not always been consistent. We therefore investigated the association between these factors and the risk of RCC in postmenopausal women participating in the Netherlands Cohort Study on Diet and Cancer. METHODS: Information on reproductive history, exogenous hormone use and gynecological surgery was obtained through a self-administered questionnaire at baseline in 1986. After 20.3 years of follow-up, 204 cases and 2280 subcohort members were available for case-cohort analysis. Multivariable hazard ratios (HR) were calculated using Cox Proportional Hazard analysis. RESULTS: Women who reported a hysterectomy had an increased RCC risk compared to women who did not (HR, 1.42, 95%CI, 1.01-2.00). Women with a natural age at menopause between 45 and 49 years compared to 50-54 years had an increased RCC risk (HR, 1.61; 95%CI, 1.10-2.35). RCC risk was slightly and not statistically significant increased among parous women with three or more children and age at first birth before 25 years compared to nulliparous women (HR, 1.36; 95% confidence interval (CI), 0.84-2.20). No associations were observed with RCC risk for age at menarche, use of oral contraceptives and use of hormonal replacement therapy. CONCLUSION: Hysterectomy and age at natural menopause were associated with an increased RCC risk. Other hormonal and reproductive factors and RCC risk were not increased. Further studies are required to establish the mechanism(s) that explain the observed association.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Carcinoma, Renal Cell/epidemiology , Carcinoma, Renal Cell/etiology , Child , Cohort Studies , Contraceptives, Oral/adverse effects , Female , Humans , Kidney Neoplasms/epidemiology , Kidney Neoplasms/etiology , Menarche , Menopause , Middle Aged , Netherlands/epidemiology , Pregnancy , Reproductive History , Risk FactorsABSTRACT
INTRODUCTION: KRAS mutations (KRASmut), PIK3CAmut, BRAFmut, and mismatch repair deficiency (dMMR) have been associated with the Warburg-effect. We previously observed differential associations between energy balance-related factors (BMI, clothing-size, physical activity) and colorectal cancer (CRC) subtypes based on the Warburg-effect. We now investigated whether associations between energy balance-related factors and risk of CRC differ between subgroups based on mutation and MMR status. METHODS: Information on molecular features was available for 2349 incident CRC cases within the Netherlands Cohort Study (NLCS), with complete covariate data available for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox-regression was used to estimate associations of energy balance-related factors with risk of CRC based on individual molecular features (KRASmut; PIK3CAmut; BRAFmut; dMMR) and combinations thereof (all-wild-type + MMR-proficient (pMMR); any-mutation/dMMR). RESULTS: In men, BMI and clothing-size were positively associated with risk of colon, but not rectal cancer, regardless of molecular features subgroups; the strongest associations were observed for PIK3CAmut colon cancer. In women, however, BMI and clothing-size were only associated with risk of KRASmut colon cancer (p-heterogeneityKRASmut versus all-wild-type+pMMR = 0.008). Inverse associations of non-occupational physical activity with risk of colon cancer were strongest for any-mutation/dMMR tumors in men and women, and specifically for PIK3CAmut tumors in women. Occupational physical activity was inversely associated with both combination subgroups of colon cancer in men. CONCLUSION: In men, associations did not vary according to molecular features. In women, a role of KRAS mutations in the etiological pathway between adiposity and colon cancer is suggested, and of PIK3CA mutations between physical activity and colon cancer.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Class I Phosphatidylinositol 3-Kinases/genetics , Cohort Studies , Colonic Neoplasms/pathology , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , DNA Mismatch Repair , Female , Humans , Male , Mutation , Neoplasm Staging , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/geneticsABSTRACT
BACKGROUND: DNA methylation biomarkers for early detection, risk stratification and treatment response in cancer have been of great interest over the past decades. Nevertheless, clinical implementation of these biomarkers is limited, as only < 1% of the identified biomarkers is translated into a clinical or commercial setting. Technical factors such as a suboptimal genomic location of the assay and inefficient primer or probe design have been emphasized as important pitfalls in biomarker research. Here, we use eleven diagnostic DNA methylation biomarkers for colorectal cancer (ALX4, APC, CDKN2A, MGMT, MLH1, NDRG4, SDC2, SFRP1, SFRP2, TFPI1 and VIM), previously described in a systematic literature search, to evaluate these pitfalls. RESULTS: To assess the genomic assay location, the optimal genomic locations according to TCGA data were extracted and compared to the genomic locations used in the published assays for all eleven biomarkers. In addition, all primers and probes were technically evaluated according to several criteria, based on literature and expert opinion. Both assay location and assay design quality varied widely among studies. CONCLUSIONS: Large variation in both assay location and design hinders the development of future DNA methylation biomarkers as well as inter-study comparability.
Subject(s)
Colorectal Neoplasms , DNA Methylation , Biomarkers, Tumor/genetics , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Humans , Polymerase Chain ReactionABSTRACT
BACKGROUND: Cancer of Unknown Primary (CUP) is a metastatic cancer for which the primary lesion remains unidentifiable during life and little is also known about the modifiable risk factors that contribute to its development. This study investigates whether vegetables and fruits are associated with CUP risk. METHODS: We used data from the prospective Netherlands Cohort Study on Diet and Cancer which includes 120,852 participants aged between 55 and 69 years in 1986. All participants completed a self-administered questionnaire on cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. As a result, 867 incident CUP cases and 4005 subcohort members were available for case-cohort analyses after 20.3 years of follow-up. Multivariable adjusted hazard ratios were calculated using proportional hazards models. RESULTS: We observed no associations between total vegetable and fruit consumption (combined or as separate groups) and CUP risk. However, there appeared to be an inverse association between the consumption of raw leafy vegetables and CUP. With respect to individual vegetable and fruit items, we found neither vegetable nor fruit items to be associated with CUP risk. CONCLUSIONS: Overall, vegetable and fruit intake were not associated with CUP incidence within this cohort.
Subject(s)
Neoplasms, Unknown Primary , Vegetables , Aged , Cohort Studies , Diet , Fruit , Humans , Incidence , Middle Aged , Netherlands/epidemiology , Prospective Studies , Risk Factors , Surveys and QuestionnairesABSTRACT
In this study, we investigate the influence of the seven genes (VHL, PBRM1, SETD2, BAP1, KDM5C, MTOR and TP53) most frequently mutated in clear cell renal cell cancer (ccRCC) on cancer-specific survival (CSS) in the prospective Netherlands Cohort Study on diet and cancer. DNA isolated from routinely archived formalin-fixed paraffin-embedded tumour blocks from 252 incident ccRCC cases was available for targeted next generation sequencing. Based on the sequencing quality and the completeness of information on clinical characteristics and follow-up, we could use 110 cases for survival analysis. The association with CSS for each mutated gene in these cases was tested using multivariable Cox proportional hazards models to estimate hazards ratios (HR) and confidence intervals (CIs), and we observed mutations in one or more of the seven genes in 64 out of 110 cases (58%). In the multivariable-adjusted analyses, mutations in VHL and PBRM1 were associated with better CSS (HRs (95% CI) 0.34 (0.13â0.89) and 0.17 (0.04-0.66), respectively), although these results were not statistically significant after multiple testing correction. No association was observed for the other five genes, which may be attributable to limited power.