Publications by authors named "Jonas Manjer"

282 Publications

Dietary Advanced Glycation End-Products and Colorectal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

Nutrients 2021 Sep 8;13(9). Epub 2021 Sep 8.

Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain.

Dietary advanced glycation end-products (dAGEs) have been hypothesized to be associated with a higher risk of colorectal cancer (CRC) by promoting inflammation, metabolic dysfunction, and oxidative stress in the colonic epithelium. However, evidence from prospective cohort studies is scarce and inconclusive. We evaluated CRC risk associated with the intake of dAGEs in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Dietary intakes of three major dAGEs: N-carboxy-methyllysine (CML), N-carboxyethyllysine (CEL), and N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated in 450,111 participants (median follow-up = 13 years, with 6162 CRC cases) by matching to a detailed published European food composition database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of dAGEs with CRC were computed using multivariable-adjusted Cox regression models. Inverse CRC risk associations were observed for CML (HR comparing extreme quintiles: HR. = 0.92, 95% CI = 0.85-1.00) and MG-H1 (HR. = 0.92, 95% CI = 0.85-1.00), but not for CEL (HR. = 0.97, 95% CI = 0.89-1.05). The associations did not differ by sex or anatomical location of the tumor. Contrary to the initial hypothesis, our findings suggest an inverse association between dAGEs and CRC risk. More research is required to verify these findings and better differentiate the role of dAGEs from that of endogenously produced AGEs and their precursor compounds in CRC development.
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http://dx.doi.org/10.3390/nu13093132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470201PMC
September 2021

Serum selenium, selenoprotein P and glutathione peroxidase 3 as predictors of mortality and recurrence following breast cancer diagnosis: A multicentre cohort study.

Redox Biol 2021 11 21;47:102145. Epub 2021 Sep 21.

Institute for Experimental Endocrinology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address:

The trace element selenium is of essential importance for the synthesis of a set of redox active proteins. We investigated three complementary serum selenium status biomarkers in relation to overall survival and recurrence following diagnosis of primary invasive breast cancer in a large prospective cohort study. The Sweden Cancerome Analysis Network - Breast Initiative (SCAN-B) is a prospective population-based study including multiple participating hospitals. Main analyses included 1996 patients with a new diagnosis of primary invasive breast cancer, with blood sampling at the time of diagnosis. In sera of the patients, total serum selenium, selenoprotein P (SELENOP), and glutathione peroxidase 3 (GPx3) activity was analysed. All three biomarkers showed a positive correlation (p < 0.001), supporting the high quality of samples and analytical techniques. During a total of 13,306 person years of follow-up, 310 deaths and 167 recurrent breast cancer events occurred. In fully adjusted Cox models, all three biomarkers correlated inversely with mortality (p <0.001) and compared with the lowest quintile, hazard ratios (95% confidence interval) for overall survival in the highest quintile of selenium, SELENOP and GPx3 were 0.42 (0.28-0.63), 0.51 (0.36-0.73) and 0.52 (0.36-0.75), respectively. Low GPx3 activity was associated with more recurrences (Q5 vs Q1: fully adjusted HR (95%CI); 0.57 (0.35-0.92), (p = 0.005). Patients with low selenium status according to all three biomarkers (triple deficient) had the highest mortality risk with an overall survival probability of ∼50% after 8 years, in particular as compared to those having at least one marker in the highest quintile; fully adjusted HR (95%CI); 0.30 (0.21-0.43). Prediction of mortality based on all three biomarkers outperformed established tumour characteristics like histologic grade, number of involved lymph nodes or tumour size. An assessment of Se status at breast cancer diagnosis identifies patients at exceptionally high risk for a poor prognosis.
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http://dx.doi.org/10.1016/j.redox.2021.102145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476451PMC
November 2021

Is Cadmium a Risk Factor for Breast Cancer - Results from a Nested Case-Control Study Using Data from the Malmö Diet and Cancer Study.

Cancer Epidemiol Biomarkers Prev 2021 Sep 8;30(9):1744-1752. Epub 2021 Jul 8.

Department of Occupational and Environmental Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: Some studies have shown that cadmium (Cd) is associated with breast cancer risk. One hypothesis is that Cd has estrogen-like properties. This case-control study investigated the association between breast cancer risk and blood Cd (BCd) levels.

Methods: All breast cancers in the Malmö Diet and Cancer cohort were identified through linkage to the Swedish Cancer Registry, baseline (1991-1996) through 2014. Two controls per case were selected from the same cohort. BCd was analyzed at baseline. Associations were analyzed using logistic regression.

Results: Mean BCd was 0.51 μg/L among 1,274 cases and 0.46 among 2,572 controls. There was an overall increased risk of breast cancer [OR, 1.18; 95% confidence interval (CI), 1.05-1.36] per μg/L of BCd. An increased risk was, however, only found at high BCd [OR, 1.34 (95% CI, 1.05-1.73)] for BCd more than 1.20 μg/L. The group with the highest BCd was mainly smokers. A spline indicated that at BCd less than 1.0 μg/L, the OR was not increased. The association with BCd was stronger in current smokers and at body mass index (BMI) above 25, while no modification due to receptor status was found.

Conclusions: The results indicated increased risk of breast cancer only for high Cd exposure, which occurred mainly among smokers. This made it difficult to disentangle the effects of smoking and Cd, despite inclusion of smoking habits in the models.

Impact: This study provides support for reducing Cd exposure through smoking cessation and dietary choice. On the population level, preventive measures against Cd pollution are warranted.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0181DOI Listing
September 2021

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.

Sci Rep 2021 07 5;11(1):13805. Epub 2021 Jul 5.

Duke - NUS Medical School, Singapore, Singapore.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.
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http://dx.doi.org/10.1038/s41598-021-93214-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257595PMC
July 2021

Serum zinc and dietary intake of zinc in relation to risk of different breast cancer subgroups and serum levels as a marker of intake: a prospective nested case-control study.

Breast Cancer Res Treat 2021 Sep 5;189(2):571-583. Epub 2021 Jul 5.

Department of Surgery, Skåne University Hospital Malmö, Lund University, 20501, Malmö, Sweden.

Purpose: Zinc has been suggested to be protective against breast cancer, but the evidence remains inconclusive. One reason for inconsistent findings in previous studies may be that zinc only influences the risk of developing certain subtypes of breast cancer. Our study is the first study assessing zinc levels in relation to the risk of different breast cancer subgroups, defined by their tumor characteristics. In addition, we analyze serum zinc as a marker of dietary intake.

Methods: The Malmö Diet and Cancer Study is a population-based cohort study that took place 1991-1996 in Malmö, Sweden. Until end of follow-up, 31 December 2013, 1186 incident cases were identified and matched to an equal number of controls. Odds ratios (ORs) for breast cancer, and having a certain tumor characteristic, were estimated in quartiles of baseline serum zinc and zinc intake and adjusted for potential confounders.

Results: No associations were found between zinc, measured in serum or diet pre-diagnostically, and breast cancer risk. The adjusted OR for breast cancer in serum zinc Q4 compared to Q1 was 1.09 (0.85-1.41) and in zinc intake Q4 versus Q1 was 0.97 (0.77-1.23). Moreover, there were no clear associations between zinc and any breast cancer characteristics. The kappa value, 0.025 (P = 0.022), showed poor agreement between serum zinc and zinc intake.

Conclusion: Our findings indicate that there is no clear association between zinc and overall breast cancer risk or risk of different breast cancer subgroups. Finally, our results suggest that serum zinc is a poor marker of zinc intake.
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http://dx.doi.org/10.1007/s10549-021-06318-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357733PMC
September 2021

The Inverse Association of Body Mass Index with Lung Cancer: Exploring Residual Confounding, Metabolic Aberrations and Within-Person Variability in Smoking.

Cancer Epidemiol Biomarkers Prev 2021 Aug 22;30(8):1489-1497. Epub 2021 Jun 22.

Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

Background: The inverse observational association between body mass index (BMI) and lung cancer risk remains unclear. We assessed whether the association is explained by metabolic aberrations, residual confounding, and within-person variability in smoking, and compared against other smoking-related cancers.

Methods: We investigated the association between BMI, and its combination with a metabolic score (MS) of mid-blood pressure, glucose, and triglycerides, with lung cancer and other smoking-related cancers in 778,828 individuals. We used Cox regression, adjusted and corrected for within-person variability in smoking (status/pack-years), calculated from 600,201 measurements in 221,958 participants.

Results: Over a median follow-up of 20 years, 20,242 smoking-related cancers (6,735 lung cancers) were recorded. Despite adjustment and correction for substantial within-person variability in smoking, BMI remained inversely associated with lung cancer [HR per standard deviation increase, 0.87 (95% confidence interval 0.85-0.89)]. Individuals with BMI less than 25 kg/m and high MS had the highest risk [HR 1.52 (1.44-1.60) vs. BMI ≥25 with low MS]. These associations were weaker and nonsignificant among nonsmokers. Similar associations were observed for head and neck cancers and esophageal squamous cell carcinoma, whereas for other smoking-related cancers, we generally observed positive associations with BMI.

Conclusions: The increased lung cancer risk with low BMI and high MS is unlikely due to residual confounding and within-person variability in smoking. However, similar results for other cancers strongly related to smoking suggest a remaining, unknown, effect of smoking.

Impact: Extensive smoking-adjustments may not capture all the effects of smoking on the relationship between obesity-related factors and risk of smoking-related cancers.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0058DOI Listing
August 2021

Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Nutrients 2021 May 28;13(6). Epub 2021 May 28.

Office of the Director, International Agency for Research on Cancer, CEDEX 08, 69372 Lyon, France.

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992-2000 and December 2013-December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.
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http://dx.doi.org/10.3390/nu13061843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228096PMC
May 2021

Risk of breast cancer in relation to dietary intake of selenium and serum selenium as a marker of dietary intake: a prospective cohort study within The Malmö Diet and Cancer Study.

Cancer Causes Control 2021 Aug 29;32(8):815-826. Epub 2021 Apr 29.

Department of Surgery, Skåne University Hospital Malmö, Lund University, 20501, Malmö, Sweden.

Purpose: Selenium has been suggested to be protective against breast cancer, but the evidence remains inconclusive. Hence, it is important to further examine the potential protective effect. This prospective cohort study investigates pre-diagnostic selenium intake in relation to breast cancer risk. In addition, we analyze serum selenium as a marker of dietary intake.

Methods: This study includes 17,035 women in the Malmö Diet and Cancer cohort. Dietary assessment and serum samples were collected at baseline (1991-1996). During 344,584 person-years of follow-up, 1,427 incident cases were retrieved. Cox regression analysis examined breast cancer risks adjusted for potential confounding factors. In addition, odds ratios (ORs) were estimated for 1186 cases and an equal number of controls in relation to quartiles (Q) of selenium intake and groups consisting of a combination of intake and serum selenium levels.

Results: No overall association between selenium intake, or a combination of intake and serum levels, and breast cancer risk was found. The adjusted relative risk for breast cancer in selenium intake Q4 versus Q1 was 0.96 (0.83-1.12) (P = 0.65). Similarly, adjusted the OR for breast cancer in selenium intake for Q4 versus Q1 was 0.97 (0.76-1.23). The kappa value, 0.096 (p = 0.001), showed poor agreement between serum selenium and selenium intake.

Conclusion: Our findings suggest that there is no overall association between selenium intake, or a combination of intake and serum levels, and breast cancer risk. Finally, our results showed a poor correlation between estimated selenium intake and serum selenium.
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http://dx.doi.org/10.1007/s10552-021-01433-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236480PMC
August 2021

A comparison of complementary measures of vitamin B6 status, function, and metabolism in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Am J Clin Nutr 2021 07;114(1):338-347

Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.

Background: Vitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5'-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health.

Objectives: We explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics.

Medthods: Dietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP.

Results: In total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers.

Conclusions: We found that 5 different markers, capturing different aspects of vitamin B6-related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors.
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http://dx.doi.org/10.1093/ajcn/nqab045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246608PMC
July 2021

Prognostic implications of the expression levels of different immunoglobulin heavy chain-encoding RNAs in early breast cancer.

NPJ Breast Cancer 2020 6;6:28. Epub 2020 Jul 6.

Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

The extent and composition of the immune response in a breast cancer is one important prognostic factor for the disease. The aim of the current work was to refine the analysis of the humoral component of an immune response in breast tumors by quantifying mRNA expression of different immunoglobulin classes and study their association with prognosis. We used RNA-Seq data from two local population-based breast cancer cohorts to determine the expression of and immunoglobulin heavy (IGH) chain-encoding RNAs. The association with prognosis was investigated and public data sets were used to corroborate the findings. Except for and , mRNAs encoding heavy chains were generally detected at substantial levels and correlated with other immune-related genes. High mRNA was associated with factors related to poor prognosis such as estrogen receptor negativity, HER2 amplification, and high grade, whereas high mRNA levels were primarily associated with lower age at diagnosis. High and mRNA levels were associated with a more favorable prognosis both in univariable and multivariable Cox models. When adjusting for other prognostic factors, high mRNA levels were positively associated with improved prognosis. To our knowledge, these results are the first to demonstrate that expression of individual Ig class types has prognostic implications in breast cancer.
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http://dx.doi.org/10.1038/s41523-020-0170-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338507PMC
July 2020

Serum Iodine and Breast Cancer Risk: A Prospective Nested Case-Control Study Stratified for Selenium Levels.

Cancer Epidemiol Biomarkers Prev 2020 07 26;29(7):1335-1340. Epub 2020 May 26.

Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.

Background: Iodine has been suggested to protect against breast cancer, but there are no epidemiologic studies on individual risk. An interesting finding is that in areas where the exposure to both selenium and iodine are high (e.g., Japan), the risk of breast cancer is lower than in areas where selenium is high and iodine low (e.g., United States), or in areas where both are low (e.g., Northern Europe). The aim of this study was to investigate the association between prediagnostic serum iodine levels and subsequent breast cancer risk, and to investigate if this potential association was modified by selenium levels.

Methods: The Malmö Diet and Cancer Study provided prediagnostic serum samples and the current analysis included 1,159 breast cancer cases and 1,136 controls. Levels of baseline serum iodine and selenium were analyzed. A logistic regression analysis yielded ORs with 95% confidence intervals adjusted for potential confounders.

Results: There was no evidence of an overall association between iodine levels and risk of breast cancer. Among women with high selenium levels (above the median), high iodine levels were associated with a lower risk of breast cancer; the OR for above versus below the median was 0.75 (0.57-0.99). The corresponding OR for women with low selenium was 1.15 (0.87-1.50), and the was 0.06.

Conclusions: The combination of high serum iodine levels and high selenium levels was associated with a lower risk of breast cancer.

Impact: A high iodine and selenium exposure may decrease the risk of breast cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0122DOI Listing
July 2020

Protein-altering germline mutations implicate novel genes related to lung cancer development.

Nat Commun 2020 05 11;11(1):2220. Epub 2020 May 11.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10) and replication (adjusted OR = 2.93, P = 2.22 × 10) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
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http://dx.doi.org/10.1038/s41467-020-15905-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214407PMC
May 2020

Prediagnostic serum selenium levels in relation to breast cancer survival and tumor characteristics.

Int J Cancer 2020 11 18;147(9):2424-2436. Epub 2020 May 18.

Department of Surgery, Skåne University Hospital Malmö, Lund University, Malmö, Sweden.

Women with lower levels of serum selenium (Se) may have a worse survival in breast cancer than women with higher levels, despite no difference in incidence of the disease. Our study was conducted to test whether Se is associated with the aggressiveness of breast tumors. Both the risk of having a tumor characteristic associated with worse prognosis, as well as the overall and breast cancer-specific mortality, were studied. We identified breast cancer cases and controls within the Malmö Diet and Cancer Study, a population-based cohort with 17 035 women recruited between 1991 and 1996. Inclusion criteria were incident breast cancer. Exclusion criteria were carcinoma in situ and bilateral breast cancer. Controls were selected among breast cancer-free women both from matching (n = 694) as well as randomization (n = 492). After exclusion, 1066 cases remained and were compared to controls regarding their prediagnostic serum Se levels and subsequent risk of having a certain tumor characteristic or intrinsic subtype. We also followed breast cancer patients regarding overall and breast cancer-specific mortality, comparing different Se quartiles. No association between serum Se quartile and any tumor characteristic or intrinsic subtype was found. Lower overall mortality was found among women in the highest Se quartile compared to the lowest using an adjusted Cox proportional hazards model, hazard ratio 0.63 (95% confidence interval: 0.44-0.89). Similar results were seen for breast cancer-specific mortality, 0.60 (0.37-0.98). The results of our study support that Se is associated with a lower mortality in breast cancer, not related to established prognostic factors.
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http://dx.doi.org/10.1002/ijc.33031DOI Listing
November 2020

Sociodemographic and Lifestyle Factors in relation to Overweight Defined by BMI and "Normal-Weight Obesity".

J Obes 2020 7;2020:2070297. Epub 2020 Jan 7.

Lund University, Skane University Hospital, Department of Surgery, Malmö, Sweden.

Sociodemographic factors and lifestyle habits affect body weight and body composition. A new syndrome, called normal-weight obesity (NWO), is found in individuals with normal weight and excess body fat in contrast to lean and overweight individuals. The aim of the present study was to explore the associations between sociodemographic factors and smoking and alcohol habits and lower versus higher BMI (≥25 kg/m) and to examine whether categorization into lean, NWO, and overweight leads to further information about sociodemographic and lifestyle associations, compared with the common categorization defined by BMI. A cohort of 17,724 participants (9,936 females, 56.1%) from the EpiHealth study, with a median age of 61 (53-67) years, was examined. The participants answered a questionnaire about lifestyle, and weight and fat percentage were measured. Associations between sociodemographic factors and lifestyle habits and lower versus higher BMI, and lean versus NWO or lean and NWO versus overweight were calculated by binary logistic regression. Male sex, age, sick leave/disability, married/cohabitating, divorced/widowed, former smoking, and a high alcohol consumption were associated with higher BMI, whereas higher education and frequent alcohol consumption were inversely associated (all < 0.001). The associations were similar to associations with lean versus overweight and NWO versus overweight, except for age in the latter case. Associations with lean versus NWO differed from those of lower versus higher BMI, with an association with retirement, an inverse association with male sex (OR, 0.664; 95% confidence interval, 0.591-0.746), and no associations with marital status, smoking, and alcohol consumption frequency. Associations with age and occupation were sex dependent, in contrast to other variables examined. Thus, sociodemographic and lifestyle habits showed similar associations with lower versus higher BMI as with lean and NWO versus overweight, whereas lean versus NWO showed different directions of associations regarding sex, marital status, occupation, smoking, and frequency of alcohol consumption.
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http://dx.doi.org/10.1155/2020/2070297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969981PMC
May 2021

Patient-reported outcome after oncoplastic breast surgery compared with conventional breast-conserving surgery in breast cancer.

Breast Cancer Res Treat 2020 Feb 27;180(1):247-256. Epub 2020 Jan 27.

Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.

Introduction: Oncoplastic breast surgery (OBS) has developed as an extension of breast-conserving surgery (BCS) in an effort to improve esthetic and functional outcome following surgery for breast cancer. The aim of the present study was to evaluate the possible benefits of OBS, as compared with BCS, with regard to health-related quality of life (HRQoL), using patient-reported outcome measures (PROMs).

Patients And Methods: Patients treated with OBS (n = 200) and BCS (n = 1304) in the period 1 January 2008 to 31 December 2013 were identified in a research database and in the Danish Breast Cancer Cooperative Group (DBCG) registry. Data on patient, tumor, and treatment characteristics were retrieved from the DBCG registry. Patients were sent a survey including the Breast-Q™ BCT postoperative module and a study-specific questionnaire (SSQ) in 2016. A good outcome in the Breast-Q module was defined as above the median. OBS was compared to BCS using a logistic regression analysis, and then adjusted for potential confounders, yielding odds ratios (OR) with 95% confidence intervals.

Results: There was a statistically significant better outcome considering the HRQoL domain "Psychosocial Well-being " for patients treated with OBS as compared with BCS (OR 2.15: 1.25-3.69). No statistically significant differences were found for the domains "Physical Well-being" (0.83: 0.50-1.39), "Satisfaction with Breast" (0.95: 0.57-1.59), or "Sexual Well-being" (1.42: 0.78-2.58).

Conclusion: The present study indicates better outcomes of HRQoL for breast cancer patients treated with OBS as compared to patients treated with BCS. There was no increase in physical discomfort among OBS patients despite more extensive surgery.
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http://dx.doi.org/10.1007/s10549-020-05544-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031405PMC
February 2020

Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: a multinational cohort study.

BMC Med 2020 01 10;18(1). Epub 2020 Jan 10.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases.

Methods: In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs.

Results: During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and women with healthy lifestyles.

Conclusion: Pre-diagnostic healthy lifestyle behaviours were strongly inversely associated with the risk of cancer and cardiometabolic diseases, and with the prognosis of these diseases by reducing risk of multimorbidity.
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http://dx.doi.org/10.1186/s12916-019-1474-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953215PMC
January 2020

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility.

Nat Commun 2020 01 7;11(1):27. Epub 2020 Jan 7.

BC Cancer Agency, Vancouver, BC, Canada.

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV: r = 0.098, p = 2.3 × 10) and the ratio of FEV to forced vital capacity (FEV/FVC: r = 0.137, p = 2.0 × 10). Mendelian randomization analyses demonstrate that reduced FEV increases squamous cell carcinoma risk (odds ratio (OR) = 1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV/FVC increases the risk of adenocarcinoma (OR = 1.17, 1.01-1.35) and lung cancer in never smokers (OR = 1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.
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http://dx.doi.org/10.1038/s41467-019-13855-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946810PMC
January 2020

Investigating the risk of breast cancer among women exposed to chemicals: a nested case-control study using improved exposure estimates.

Int Arch Occup Environ Health 2020 02 24;93(2):261-269. Epub 2019 Oct 24.

Unit of Occupational Medicine, Institute of Environmental Medicine, Karolinska Institutet, Solnavägen 4, 113 65, Stockholm, Sweden.

Purpose: The aim of this study was to examine if exposures to chemicals at the workplace were associated with an increased risk of postmenopausal breast cancer, using improved exposure estimates.

Methods: The design is a case-control study, nested within a cohort of women from the Malmö Diet and Cancer Study. The study comprised 2400 women, 731 cases and 1669 matched controls, born 1923-1950 and living in Malmö, Sweden between 1991 and 1996. An occupational hygienist reclassified the probability for exposure given by a job-exposure matrix, using individual data on work tasks. First-time diagnoses of invasive breast cancer were identified through the Swedish Cancer Registry.

Results: Women exposed to chemicals in their occupational environment had a statistically significantly increased risk (OR 1.59, 95% CI 1.11-2.29) of breast cancer, and the risk correlated positively with duration of exposure but not with exposure intensity. Women exposed to chlorinated hydrocarbon solvents for more than 10 years had a significant higher risk of breast cancer (OR 3.06, 95% CI 1.18-7.96) as well as women exposed to oil mist for more than 10 years (OR 3.08, 95% CI 1.12-8.49).

Conclusions: This study gives some support to the hypothesis that exposure to organic solvents as well as oil mist is associated with increased risk of breast cancer.
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http://dx.doi.org/10.1007/s00420-019-01479-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007902PMC
February 2020

BMI and weight changes and risk of obesity-related cancers: a pooled European cohort study.

Int J Epidemiol 2019 12;48(6):1872-1885

Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.

Background: Obesity is an established risk factor for several cancers. Adult weight gain has been associated with increased cancer risk, but studies on timing and duration of adult weight gain are relatively scarce. We examined the impact of BMI (body mass index) and weight changes over time, as well as the timing and duration of excess weight, on obesity- and non-obesity-related cancers.

Methods: We pooled health data from six European cohorts and included 221 274 individuals with two or more height and weight measurements during 1972-2014. Several BMI and weight measures were constructed. Cancer cases were identified through linkage with national cancer registries. Hazard ratios (HRs) of cancer with 95% confidence intervals (CIs) were derived from time-dependent Cox-regression models.

Results: During follow-up, 27 881 cancer cases were diagnosed; 9761 were obesity-related. The HR of all obesity-related cancers increased with increasing BMI at first and last measurement, maximum BMI and longer duration of overweight (men only) and obesity. Participants who were overweight before age 40 years had an HR of obesity-related cancers of 1.16 (95% CI 1.02, 1.32) and 1.15 (95% CI 1.04, 1.27) in men and women, respectively, compared with those who were not overweight. The risk increase was particularly high for endometrial (70%), male renal-cell (58%) and male colon cancer (29%). No positive associations were seen for cancers not regarded as obesity-related.

Conclusions: Adult weight gain was associated with increased risk of several major cancers. The degree, timing and duration of overweight and obesity also seemed to be important. Preventing weight gain may reduce the cancer risk.
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http://dx.doi.org/10.1093/ije/dyz188DOI Listing
December 2019

Vitamin D receptor expression in invasive breast tumors and breast cancer survival.

Breast Cancer Res 2019 07 29;21(1):84. Epub 2019 Jul 29.

Department of Surgery, Lund University, Skåne University Hospital, SE-205 02, Malmö, Sweden.

Background: Vitamin D has been suggested to prevent and improve the prognosis of several cancers, including breast cancer. We have previously shown a U-shaped association between pre-diagnostic serum levels of vitamin D and risk of breast cancer-related death, with poor survival in patients with the lowest and the highest levels respectively, as compared to the intermediate group. Vitamin D exerts its functions through the vitamin D receptor (VDR), and the aim of the current study was to investigate if the expression of VDR in invasive breast tumors is associated with breast cancer prognosis.

Methods: VDR expression was evaluated in a tissue microarray of 718 invasive breast tumors. Covariation between VDR expression and established prognostic factors for breast cancer was analyzed, as well as associations between VDR expression and breast cancer mortality.

Results: We found that positive VDR expression in the nuclei and cytoplasm of breast cancer cells was associated with favorable tumor characteristics such as smaller size, lower grade, estrogen receptor positivity and progesterone receptor positivity, and lower expression of Ki67. In addition, both intranuclear and cytoplasmic VDR expression were associated with a low risk of breast cancer mortality, hazard ratios 0.56 (95% CI 0.34-0.91) and 0.59 (0.30-1.16) respectively.

Conclusions: This study found that high expression of VDR in invasive breast tumors is associated with favorable prognostic factors and a low risk of breast cancer death. Hence, a high VDR expression is a positive prognostic factor.
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http://dx.doi.org/10.1186/s13058-019-1169-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664551PMC
July 2019

Oncoplastic Breast Surgery Compared to Conventional Breast-Conserving Surgery With Regard to Oncologic Outcome.

Clin Breast Cancer 2019 12 7;19(6):423-432.e5. Epub 2019 Jun 7.

Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; Department of Surgery, Skåne University Hospital, Malmö, Sweden.

Introduction: Oncoplastic breast surgery (OBS) has been implemented with increasing frequency in the treatment of breast cancer. The aim of this study was to compare the oncologic outcome after OBS to the outcome after conventional breast-conserving surgery (BCS) in patients with invasive breast cancer.

Patients And Methods: In all, 197 patients treated with OBS were compared to 1399 patients treated with conventional BCS from 2008 to 2013. We evaluated nonradical primary tumor excision, time to initiation of adjuvant therapy, disease-free survival (risk of recurrent disease), and survival (cause specific and overall). Identification of patients and follow-up were made using the Danish Breast Cancer Cooperative Group registry and the Danish Cause of Death registry. Multivariate logistic regression and the Cox proportional hazard analysis were used to obtain odds ratios and hazard ratios with 95% confidence intervals (CI).

Results: There was a lower risk for nonradical primary tumor excision for patients undergoing OBS versus conventional BCS (adjusted odds ratio:95% CI, 0.50:0.29-0.84). No significant differences were found with regard to a delay in initiation of adjuvant chemotherapy (adjusted hazard ratio:95% CI, 1.14:0.89-1.45) or radiotherapy (0.91:0.71-1.16), disease-free survival (1.23:0.61-2.47), breast cancer as cause of death (1.46:0.52-4.09), breast cancer as underlying or multiple cause of death (0.90:0.34-2.37), or overall survival (0.90:0.51-1.60).

Conclusion: We found no significant differences in oncologic outcome comparing OBS to conventional BCS. However, a lower risk of nonradical primary tumor excision was found for patients treated with OBS. These results indicate that OBS is a safe procedure.
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http://dx.doi.org/10.1016/j.clbc.2019.05.016DOI Listing
December 2019

Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3).

Int J Cancer 2020 05 22;146(9):2394-2405. Epub 2019 Jul 22.

Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN.

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all p < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.
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http://dx.doi.org/10.1002/ijc.32555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960354PMC
May 2020

Determinants for non-sentinel node metastases in primary invasive breast cancer: a population-based cohort study of 602 consecutive patients with sentinel node metastases.

BMC Cancer 2019 Jun 25;19(1):626. Epub 2019 Jun 25.

Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.

Background: Sentinel node biopsy (SNB) is the standard procedure for axillary staging in patients with clinically lymph node negative invasive breast cancer. Completion axillary lymph node dissection (c-ALND) may not be necessary for all patients as a significant number of patients have no further metastases in non-sentinel nodes (non-SN) and c-ALND may not improve survival. The first aim of our study is to identify clinicopathological determinants associated with non-SN metastases. The second aim is to determine the impact of the number of sentinel node (SN) with macro-metastases and the type of SN metastases on metastatic involvement in non-SN.

Methods: This is a retrospective study of 602 patients with primary invasive breast cancer operated on with SNB and c-ALND in Lund and Malmö during 2008-2013. All these patients had micro- and/or macro-metastases in SNs. Information was retrieved from the national Information Network for Cancer Care (INCA). The risk of metastases to non-SNs were analyzed in relation to clinicopathological determinants such as age, screening mammography, tumour size, tumour type, histological grade, estrogen status, progesterone status, HER2 status, multifocality and lymphovascular invasion. Additionally, we compared the association between the number of the SN and the type of metastases in SN with the risk of metastases to non-SNs. Binary logistic regression was used, yielding odds ratios (OR) with 95% confidence intervals (CI).

Results: We found that 211 patients (35%) had metastases in non-SNs and 391 patients (65%) had no metastases in non-SNs. Lobular type (18%) of breast cancer (1.73; 1.0 1-2.97) and multifocal (31.3%) tumours (2.20; 1.41-3.44) had a high risk of non-SNs metastases. As compared to only micro-metastases, the presence of macro-metastases in SNs was associated with a high risk of metastases to non-SNs (4.91; 3.01-8.05). The number of SN with macro-metastases, regardless of the number of SNs removed by surgery, increases the risk of finding non-SNs with metastases. The total number of SN removed by surgery had no impact on diagnosis of metastases in non-SNs. No statistically significant associations were observed regarding other studied determinants.

Conclusion: We conclude in the present study that lobular cancer and multifocal tumours were associated with a high risk of non-SN involvement. The presence of the macro-metastases in SNs and the number of SN with macro-metastases has a positive association with presence of metastases in non-SNs. The total number of SNs removed by surgery had no impact on finding metastases in non-SNs. These factors may be valuable considering whether or not to omit c-ALND.
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http://dx.doi.org/10.1186/s12885-019-5823-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593584PMC
June 2019

Postmenopausal breast cancer and occupational exposure to chemicals.

Scand J Work Environ Health 2019 11 8;45(6):642-650. Epub 2019 Apr 8.

Institute of Environmental Medicine, Unit of Occupational medicine, Karolinska Institutet, Solnavägen 4, 113 65 Stockholm.

Objectives The aim of this study was to investigate if exposure to chemicals in the workplace was associated with an increased risk of postmenopausal breast cancer. Methods The study comprised women born 1923-1950 living in Malmö city, Sweden, 1991-1996, and enrolled for a prospective population cohort study. Occupational exposure to various chemicals was assessed from job-exposure matrices. An extensive set of individual data on hormonal breast cancer risk factors were collected via a baseline questionnaire and used for confounding control. First time diagnoses of invasive breast cancer were identified through the Swedish Cancer Registry until end of follow-up on 31 December 2013. Results Of 16 084 women, 1011 were diagnosed with breast cancer. Women exposed to chemicals in their occupational environment had a statistically significant increased risk [adjusted hazard ratio (HR ) 1.26, 95% confidence interval (CI) 1.02-1.54] of breast cancer, and the risk correlated with duration of exposure. Investigation of risk in association with specific chemicals showed a non-significantly elevated risk after exposure to organic solvents. More than ten years of exposure to diesel exhaust was associated with an increased risk (HR 1.69, 95% CI 1.01-2.82). Occupational chemical exposures account for 2% of the breast cancer cases in this population. Conclusions Occupational exposure to chemicals in general was associated with an elevated risk of breast cancer. A slight elevation of risk was seen after exposure to organic solvents. A statistically significant elevation of risk after >10 years of exposure to diesel exhaust was an unexpected finding.
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http://dx.doi.org/10.5271/sjweh.3822DOI Listing
November 2019

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development.

Oncotarget 2019 Mar 5;10(19):1760-1774. Epub 2019 Mar 5.

Department of Epidemiology and Prevention, N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation.

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in (OR=0.44, value=3.27x10 in overall lung cancer and OR=0.41, value=9.71x10 in non-small cell lung cancer), (OR=0.73, value=1.01x10 in adenocarcinoma) and (OR=1.82, value=7.62x10 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.
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http://dx.doi.org/10.18632/oncotarget.26678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442994PMC
March 2019

The triglyceride-glucose index as a measure of insulin resistance and risk of obesity-related cancers.

Int J Epidemiol 2020 02;49(1):193-204

Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Innsbruck, Austria.

Background: The role of insulin resistance as a mediator in the association of body mass index (BMI) with site-specific cancer risk has, to our knowledge, never been systematically quantified.

Methods: Altogether 510 471 individuals from six European cohorts, with a mean age of 43.1 years, were included. We used the triglyceride glucose product (TyG index) as a surrogate measure for insulin resistance. We fitted Cox models, adjusted for relevant confounders, to investigate associations of TyG index with 10 common obesity-related cancers, and quantified the proportion of the effect of BMI mediated through TyG index on the log-transformed hazard ratio (HR) scale.

Results: During a median follow-up of 17.2 years, 16 052 individuals developed obesity-related cancers. TyG index was associated with the risk of cancers of the kidney HR per one standard deviation increase 1.13, 95% confidence interval: 1.07 to 1.20], liver (1.13, 1.04 to 1.23), pancreas (1.12, 1.06 to 1.19), colon (1.07, 1.03 to 1.10) and rectum (1.09, 1.04 to 1.14). Substantial proportions of the effect of BMI were mediated by TyG index for cancers of the pancreas (42%), rectum (34%) and colon (20%); smaller proportions for kidney (15%) and liver (11%). Little or no mediation was observed for breast (postmenopausal), endometrial and ovarian cancer. Results were similar for males and females, except for pancreatic cancer where the proportions mediated were 20% and 91%, respectively.

Conclusions: The TyG index was associated with increased risk of cancers of the digestive system and substantially mediated the effect of BMI, suggesting that insulin resistance plays a promoting role in the pathogenesis of gastrointestinal cancers.
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http://dx.doi.org/10.1093/ije/dyz053DOI Listing
February 2020

Linear age-course effects on the associations between body mass index, triglycerides, and female breast and male liver cancer risk: An internal replication study of 800,000 individuals.

Int J Cancer 2020 01 18;146(1):58-67. Epub 2019 Mar 18.

Department of Clinical Sciences in Lund, Lund University, Lund, Sweden.

Apart from the consistently observed differential association between obesity and breast cancer risk by menopausal status, the associations between obesity and other metabolic imbalances with risks of cancers have not been systematically investigated across the age-course. We created two random 50-50% cohorts from six European cohorts comprising 813,927 individuals. In the "discovery cohort", we used Cox regression with attained age as time-scale and tested interactions between body mass index (BMI), blood pressure, plasma glucose, triglycerides and cholesterol, and attained age in relation to cancer risk. Results with a p-value below 0.05 were additionally tested in the "replication cohort" where a replicated result was considered evidence of a linear interaction with attained age. These findings were investigated by flexible parametric survival models for any age-plateaus in their shape of associations with cancer risk across age. Consistent with other studies, BMI was negatively related to breast cancer risk (n cases = 11,723) among younger (premenopausal) women. However, the association remained negative for several years after menopause and, although gradually weakening over age, the association became positive only at 62 years of age. This linear and positive age-interaction was also found for triglycerides and breast cancer, and for BMI and triglycerides in relation to liver cancer among men (n cases = 444). These findings are unlikely to be due to chance owing to the replication. The linear age-interactions in breast cancer may suggest an influence by other age-related factors than menopause; however, further investigation of age-related effect modifiers in both breast and liver cancer is needed.
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http://dx.doi.org/10.1002/ijc.32240DOI Listing
January 2020

Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis.

Cancer Epidemiol Biomarkers Prev 2019 05 30;28(5):935-942. Epub 2019 Jan 30.

Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear.

Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk.

Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings.

Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention.

Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075698PMC
May 2019

Systematic analyses of regulatory variants in DNase I hypersensitive sites identified two novel lung cancer susceptibility loci.

Carcinogenesis 2019 05;40(3):432-440

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.
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http://dx.doi.org/10.1093/carcin/bgy187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783905PMC
May 2019

Coffee and tea drinking in relation to the risk of differentiated thyroid carcinoma: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Eur J Nutr 2019 Dec 10;58(8):3303-3312. Epub 2018 Dec 10.

Department of Community Medicine, Faculty of Health Sciences, UiT, The Arctic University of Tromsø, Tromsö, Norway.

Purpose: Coffee and tea constituents have shown several anti-carcinogenic activities in cellular and animal studies, including against thyroid cancer (TC). However, epidemiological evidence is still limited and inconsistent. Therefore, we aimed to investigate this association in a large prospective study.

Methods: The study was conducted in the EPIC (European Prospective Investigation into Cancer and Nutrition) cohort, which included 476,108 adult men and women. Coffee and tea intakes were assessed through validated country-specific dietary questionnaires.

Results: During a mean follow-up of 14 years, 748 first incident differentiated TC cases (including 601 papillary and 109 follicular TC) were identified. Coffee consumption (per 100 mL/day) was not associated either with total differentiated TC risk (HR 1.00, 95% CI 0.97-1.04) or with the risk of TC subtypes. Tea consumption (per 100 mL/day) was not associated with the risk of total differentiated TC (HR 0.98, 95% CI 0.95-1.02) and papillary tumor (HR 0.99, 95% CI 0.95-1.03), whereas an inverse association was found with follicular tumor risk (HR 0.90, 95% CI 0.81-0.99), but this association was based on a sub-analysis with a small number of cancer cases.

Conclusions: In this large prospective study, coffee and tea consumptions were not associated with TC risk.
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http://dx.doi.org/10.1007/s00394-018-1874-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850907PMC
December 2019
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