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Harbs, J., Rinaldi, S., Keski-Rahkonen, P., Liu, X., Palmqvist, R., van Guelpen, B. & Harlid, S. (2023). An epigenome-wide analysis of sex hormone levels and DNA methylation in male blood samples. Epigenetics, 18(1), Article ID 2196759.
Open this publication in new window or tab >>An epigenome-wide analysis of sex hormone levels and DNA methylation in male blood samples
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2023 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 18, no 1, article id 2196759Article in journal (Refereed) Published
Abstract [en]

Endogenous sex hormones and DNA methylation both play important roles in various diseases. However, their interplay is largely unknown. A deeper understanding of their interrelationships could provide new insights into the pathology of disease development. We, therefore, investigated associations between circulating sex hormones, sex hormone binding globulin (SHBG), and DNA methylation in blood, using samples from 77 men (65 with repeated samples), from the population-based Northern Sweden Health and Disease Study (NSHDS). DNA methylation was measured in buffy coat using the Infinium Methylation EPIC BeadChip (Illumina). Sex hormone (oestradiol, oestrone, testosterone, androstenedione, dehydroepiandrosterone, and progesterone) and SHBG concentrations were measured in plasma using a high-performance liquid chromatography tandem mass spectrometry (LC/MS-MS) method and an enzyme-linked immunoassay, respectively. Associations between sex hormones, SHBG, and DNA methylation were estimated using both linear regression and mixed-effects models. Additionally, we used the comb-p method to identify differentially methylated regions based on nearby P values. We identified one novel CpG site (cg14319657), at which DNA methylation was associated with dehydroepiandrosterone, surpassing a genome-wide significance level. In addition, more than 40 differentially methylated regions were associated with levels of sex hormones and SHBG and several of these mapped to genes involved in hormone-related diseases. Our findings support a relationship between circulating sex hormones and DNA methylation and suggest that further investigation is warranted, both for validation, further exploration and to gain a deeper understanding of the mechanisms and potential consequences for health and disease.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2023
Keywords
Sex hormones, sex hormone binding globulin, DNA methylation, men, NSHDS
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-205420 (URN)10.1080/15592294.2023.2196759 (DOI)000961068800001 ()36994855 (PubMedID)2-s2.0-85151198554 (Scopus ID)
Funder
Cancerforskningsfonden i Norrland, AMP 17-866Cancerforskningsfonden i Norrland, AMP 17-856Cancerforskningsfonden i Norrland, AMP 18-915Cancerforskningsfonden i Norrland, AMP 19-967Region Västerbotten, VLL-547711Region Västerbotten, VLL-680921Region Västerbotten, VLL58269Umeå University
Note

Originally included in thesis in manuscript form. 

Available from: 2023-03-06 Created: 2023-03-06 Last updated: 2023-09-05Bibliographically approved
Harbs, J. (2023). Circulating markers of risk and etiology in colorectal cancer. (Doctoral dissertation). Umeå: Umeå University
Open this publication in new window or tab >>Circulating markers of risk and etiology in colorectal cancer
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Cirkulerande markörer för risk och etiologi för kolorektal cancer
Abstract [en]

Background: Colorectal cancer is the third most commonly diagnosed cancer in men and women. Worldwide around 2 million individuals are diagnosed each year – a number expected to increase as colorectal cancer risk factors become more prevalent. In men and women there is a difference in incidence, which possibly could be explained by inherent differences, including sex hormone profiles. The prognosis of colorectal cancer is highly dependent on the stage at diagnosis, with individuals diagnosed at early stages having the best long-term survival. However, as onset of symptoms can be diffuse, many individuals are diagnosed at later stages when survival rates are significantly poorer. Therefore, screening and prevention strategies to detect colorectal cancer at earlier stages or remove cancer precursors such as polyps may be key to increasing survival. Commonly used screening tools today include fecal blood tests and colonoscopy, but they have modest accuracy or may not be cost-effective. Being able to identify markers in blood, either for early detection, as a complementary or alternative screening method, or for risk stratification, could aid in solving this problem. 

Aim: The overall of aim of the thesis was to improve our understanding of underlying factors contributing to CRC etiology and to find biomarkers associated with CRC that could aid in the future development of effective risk prediction models. 

Methods: All studies included in this thesis were based on a case-control cohort nested within the Northern Sweden Health and Disease Study (NSHDS). Additionally in paper I, we also used data from the European Prospective Investigation into Cancer and Nutrition (EPIC), a large multi-center cohort study. In this paper we examined associations between sex hormones, sex hormone binding globulin (SHBG), and colon cancer in men. The study included 690 colon cancer cases and 690 matched controls. Paper II was a longitudinal study, using repeated samples from 80 men, on circulating sex hormones, SHBG, and DNA methylation in white blood cells. Papers III and IV were nested case-control studies on proteins and colorectal cancer risk with Paper III divided into a discovery and a validation phase. In the first phase, which included 69 colorectal cancer case-control pairs with repeated samples, 160 unique proteins related to inflammation and oncology were analyzed. In the second phase, 13 proteins that were significantly associated with colorectal cancer risk, together with 8 proteins identified from the literature, were measured on a custom panel, and validated in a larger material consisting of 1000 case-control pairs. In paper IV, which included 195 colorectal cancer case-control pairs, the protein analysis was extended to include 1536 proteins linked to oncology, inflammation, neurology, and metabolism. In papers using a matched case-control design, conditional i logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations. For longitudinal analyses, mixed effects models were used to estimate associations. 

Results: In paper I, we observed a statistically significant inverse association between circulating levels of testosterone and colon cancer. For SHBG there was a statistically significant inverse association prior to adjustment of testosterone and estradiol levels. In paper II, we found one novel genome-wide significant association between circulating levels of dehydroepiandrosterone and DNA methylation at the cg14319657 CpG site. In addition, we also identified more than 40 differentially methylated regions associated with levels of sex hormones and SHBG. In paper III, we first identified 13 proteins associated with CRC risk in the discovery phase. In the validation phase, however, none of the proteins remained significantly associated with colorectal cancer. When stratifying by tumor site, FGF-21 and PPY, were statically significant in colon and rectal cancer respectively, and showed some modest increase in predictive performance. In paper IV, we identified 20 proteins surpassing a significance threshold of 0.005. One protein, TFF3 (Trefoil Factor 3), which was positively associated with colorectal, also withstood strict Bonferroni correction. In addition, we validated several proteins, including AREG, CEA, and LGALS4, which were identified as biomarker candidates in previous studies. 

Conclusions: Our results support the hypothesis that circulating sex hormones play a role in male colon cancer etiology and that this may partly explain the difference in colorectal cancer incidence between men and women. Furthermore, our findings suggest a possible link between circulating sex hormones, SHBG and DNA methylation, which could be of interest in the etiology of colorectal cancer as well as other hormone-dependent diseases. Finally, we also identified several proteins associated with colorectal cancer, some of which have shown potential as screening markers. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2023. p. 60
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2232
Keywords
Colorectal cancer, CRC, sex hormones, colon cancer, DNA methylation, proteomics, risk, etiology
National Category
Cancer and Oncology
Research subject
Cancer Epidemiology
Identifiers
urn:nbn:se:umu:diva-205431 (URN)978-91-8070-006-1 (ISBN)978-91-8070-005-4 (ISBN)
Public defence
2023-03-31, Betula, Byggnad 6M, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2023-03-10 Created: 2023-03-06 Last updated: 2023-03-13Bibliographically approved
Bodén, S., Harbs, J., Sundkvist, A., Fuchs, K., Myte, R., Gylling, B., . . . van Guelpen, B. (2023). Plasma concentrations of gut hormones acyl ghrelin and peptide YY and subsequent risk of colorectal cancer and molecular tumor subtypes. Cancer Prevention Research, 16(2), 75-87
Open this publication in new window or tab >>Plasma concentrations of gut hormones acyl ghrelin and peptide YY and subsequent risk of colorectal cancer and molecular tumor subtypes
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2023 (English)In: Cancer Prevention Research, ISSN 1940-6207, E-ISSN 1940-6215, Vol. 16, no 2, p. 75-87Article in journal (Refereed) Published
Abstract [en]

Obesity and metabolic dysfunction are implicated in colorectal cancer development. Appetite-regulating gut hormones might have a role in colorectal cancer risk. We investigated whether circulating levels of the gut hormones ghrelin (analyzed as acyl ghrelin) and Peptide YY (PYY) were associated with subsequent colorectal cancer risk, including clinical and molecular tumor subtypes. We also provide descriptive data on these hormones in relation to background participant characteristics and metabolic biomarkers. This population-based study included 1,010 matched case-control pairs with a median of 12.3 years of follow-up. Acyl ghrelin and PYY were measured by multiplex immunoassay. Data on KRAS and BRAF mutations and microsatellite instability (MSI) status were available for 704 and 708 cases, respectively. Conditional logistic regression models estimated association to colorectal cancer risk. Partial correlation and linear regression were used to investigate relationships between background and metabolic variables and variation in plasma gut hormone concentrations. Acyl ghrelin was not clearly associated with colorectal cancer risk (multivariable OR per 1 SD increase: 1.11; 95% CI, 1.00-1.23). Positive associations were observed for specific subtypes, in particular BRAF-mutated colorectal cancer and right-sided colon cancer, although with nonsignificant heterogeneity. PYY was not related to colorectal cancer risk (multivariable OR per 1 SD: 1.04; 95% CI, 0.95-1.14) or any tumor subtype. In the control participants, ghrelin was inversely correlated with BMI, and PYY was positively correlated with C-peptide and insulin levels. These findings provide limited support for a possible role for ghrelin in colorectal cancer development, primarily in specific anatomical and molecular tumor subtypes.

PREVENTION RELEVANCE: The findings of this study do not support a major role for the metabolic gut hormones ghrelin and PYY in colorectal cancer development but suggest the possibility of an involvement for ghrelin in specific tumor subtypes. Elucidating subtype-specific risk factors and mechanisms of carcinogenesis may have implications for precision prevention.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-204740 (URN)10.1158/1940-6207.CAPR-22-0325 (DOI)000928164800001 ()36367526 (PubMedID)2-s2.0-85147457884 (Scopus ID)
Funder
Region VästerbottenUmeå UniversitySwedish Cancer Society, 2017/ 581Swedish Cancer Society, 2014/780Swedish Cancer Society, 2012/0501Cancerforskningsfonden i Norrland, AMP 21-1039Cancerforskningsfonden i Norrland, AMP 20-1015Cancerforskningsfonden i Norrland, AMP 19-984Knut and Alice Wallenberg Foundation
Available from: 2023-02-22 Created: 2023-02-22 Last updated: 2023-09-05Bibliographically approved
Nimptsch, K., Aleksandrova, K., Pham, T. T., Papadimitriou, N., Janke, J., Christakoudi, S., . . . Pischon, T. (2023). Prospective and Mendelian randomization analyses on the association of circulating fatty acid binding protein 4 (FABP-4) and risk of colorectal cancer. BMC Medicine, 21(1), Article ID 391.
Open this publication in new window or tab >>Prospective and Mendelian randomization analyses on the association of circulating fatty acid binding protein 4 (FABP-4) and risk of colorectal cancer
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2023 (English)In: BMC Medicine, E-ISSN 1741-7015, Vol. 21, no 1, article id 391Article in journal (Refereed) Published
Abstract [en]

Background: Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach.

Methods: The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry.

Results: In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37).

Conclusions: Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Colorectal cancer, FABP-4, Mendelian randomization
National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-215878 (URN)10.1186/s12916-023-03104-1 (DOI)37833736 (PubMedID)2-s2.0-85174314339 (Scopus ID)
Funder
Swedish Cancer SocietySwedish Research CouncilRegion SkåneRegion Västerbotten
Available from: 2023-10-31 Created: 2023-10-31 Last updated: 2023-10-31Bibliographically approved
Harbs, J., Rinaldi, S., Gicquiau, A., Keski-Rahkonen, P., Mori, N., Liu, X., . . . Harlid, S. (2022). Circulating Sex Hormone Levels and Colon Cancer Risk in Men: A Nested Case–Control Study and Meta-Analysis. Cancer Epidemiology, Biomarkers and Prevention, 31(4), 793-803
Open this publication in new window or tab >>Circulating Sex Hormone Levels and Colon Cancer Risk in Men: A Nested Case–Control Study and Meta-Analysis
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2022 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 31, no 4, p. 793-803Article in journal (Refereed) Published
Abstract [en]

Background: Endogenous sex hormones may contribute to higher colorectal cancer incidence rates in men compared with women, but despite an increased number of studies, clear evidence is lacking.

Methods: We conducted a comprehensive nested case–control study of circulating concentrations of sex hormones, sex hormone precursors, and sex hormone binding globulin (SHBG) in relation to subsequent colon cancer risk in European men. Concentrations were measured using liquid LC/MS-MS in prospectively collected plasma samples from 690 cases and 690 matched controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). In addition, we conducted a meta-analysis of previous studies on men.

Results: Circulating levels of testosterone (OR, 0.68; 95% CI, 0.51–0.89) and SHBG (OR, 0.77; 95% CI, 0.62–0.96) were inversely associated with colon cancer risk. For free testosterone, there was a nonsignificant inverse association (OR, 0.83; 95% CI, 0.58–1.18). In a dose–response meta-analysis of endogenous sex hormone levels, inverse associations with colorectal/colon cancer risk were found for testosterone [relative risks (RR) per 100 ng/dL ¼ 0.98; 95% CI, 0.96–1.00; I2 ¼ 22%] and free testosterone (RR per 1 ng/dL ¼ 0.98; 95% CI, 0.95–1.00; I2 ¼ 0%).

Conclusions: Our results provide suggestive evidence for the association between testosterone, SHBG, and male colon cancer development.

Impact: Additional support for the involvement of sex hormones in male colon cancer.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2022
National Category
Cancer and Oncology Endocrinology and Diabetes
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-194638 (URN)10.1158/1055-9965.EPI-21-0996 (DOI)000796549600001 ()35086823 (PubMedID)2-s2.0-85128993260 (Scopus ID)
Funder
Region SkåneRegion VästerbottenSwedish Research Council, 2017-00650Cancerforskningsfonden i Norrland, AMP 17-856Cancerforskningsfonden i Norrland, AMP 18-915Cancerforskningsfonden i Norrland, AMP 19-967Swedish Cancer Society
Available from: 2022-05-12 Created: 2022-05-12 Last updated: 2023-09-05Bibliographically approved
Pham, T.-T., Nimptsch, K., Aleksandrova, K., Jenab, M., Reichmann, R., Wu, K., . . . Pischon, T. (2022). Pre-diagnostic circulating resistin concentrations are not associated with colorectal cancer risk in the european prospective investigation into cancer and nutrition study. Cancers, 14(22), Article ID 5499.
Open this publication in new window or tab >>Pre-diagnostic circulating resistin concentrations are not associated with colorectal cancer risk in the european prospective investigation into cancer and nutrition study
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2022 (English)In: Cancers, ISSN 2072-6694, Vol. 14, no 22, article id 5499Article in journal (Refereed) Published
Abstract [en]

Resistin is a polypeptide implicated in inflammatory processes, and as such could be linked to colorectal carcinogenesis. In case-control studies, higher resistin levels have been found in colorectal cancer (CRC) patients compared to healthy individuals. However, evidence for the association between pre-diagnostic resistin and CRC risk is scarce. We investigated pre-diagnostic resistin concentrations and CRC risk within the European Prospective Investigation into Cancer and Nutrition using a nested case-control study among 1293 incident CRC-diagnosed cases and 1293 incidence density-matched controls. Conditional logistic regression models controlled for matching factors (age, sex, study center, fasting status, and women-related factors in women) and potential confounders (education, dietary and lifestyle factors, body mass index (BMI), BMI-adjusted waist circumference residuals) were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for CRC. Higher circulating resistin concentrations were not associated with CRC (RR per doubling resistin, 1.11; 95% CI 0.94–1.30; p = 0.22). There were also no associations with CRC subgroups defined by tumor subsite or sex. However, resistin was marginally associated with a higher CRC risk among participants followed-up maximally two years, but not among those followed-up after more than two years. We observed no substantial correlation between baseline circulating resistin concentrations and adiposity measures (BMI, waist circumference), adipokines (adiponectin, leptin), or metabolic and inflammatory biomarkers (C-reactive protein, C-peptide, high-density lipoprotein cholesterol, reactive oxygen metabolites) among controls. In this large-scale prospective cohort, there was little evidence of an association between baseline circulating resistin concentrations and CRC risk in European men and women.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
colorectal cancer, inflammation, pre-diagnostic resistin, prospective, risk
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-201416 (URN)10.3390/cancers14225499 (DOI)000887169800001 ()2-s2.0-85142501335 (Scopus ID)
Funder
NordForskSwedish Cancer SocietySwedish Research CouncilRegion SkåneRegion Västerbotten
Available from: 2022-12-01 Created: 2022-12-01 Last updated: 2023-09-05Bibliographically approved
Harlid, S., Harbs, J., Myte, R., Brunius, C., Gunter, M. J., Palmqvist, R., . . . van Guelpen, B. (2021). A two-tiered targeted proteomics approach to identify pre-diagnostic biomarkers of colorectal cancer risk. Scientific Reports, 11(1), Article ID 5151.
Open this publication in new window or tab >>A two-tiered targeted proteomics approach to identify pre-diagnostic biomarkers of colorectal cancer risk
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2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 5151Article in journal (Refereed) Published
Abstract [en]

Colorectal cancer prognosis is dependent on stage, and measures to improve early detection are urgently needed. Using prospectively collected plasma samples from the population-based Northern Sweden Health and Disease Study, we evaluated protein biomarkers in relation to colorectal cancer risk. Applying a two-tiered approach, we analyzed 160 proteins in matched sequential samples from 58 incident colorectal cancer case–control pairs. Twenty-one proteins selected from both this discovery phase and the literature were then analyzed in a validation set of 450 case–control pairs. Odds ratios were estimated by conditional logistic regression. LASSO regression and ROC analysis were used for multi-marker analyses. In the main validation analysis, no proteins retained statistical significance. However, exploratory subgroup analyses showed associations between FGF-21 and colon cancer risk (multivariable OR per 1 SD: 1.23 95% CI 1.03–1.47) as well as between PPY and rectal cancer risk (multivariable OR per 1 SD: 1.47 95% CI 1.12–1.92). Adding protein markers to basic risk predictive models increased performance modestly. Our results highlight the challenge of developing biomarkers that are effective in the asymptomatic, prediagnostic window of opportunity for early detection of colorectal cancer. Distinguishing between cancer subtypes may improve prediction accuracy. However, single biomarkers or small panels may not be sufficient for effective precision screening.

Place, publisher, year, edition, pages
Springer Nature, 2021
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-181726 (URN)10.1038/s41598-021-83968-6 (DOI)000626139000041 ()2-s2.0-85102182478 (Scopus ID)
Available from: 2021-03-24 Created: 2021-03-24 Last updated: 2023-09-05Bibliographically approved
Dimou, N., Mori, N., Harlid, S., Harbs, J., Martin, R. M., Smith-Byrne, K., . . . Murphy, N. (2021). Circulating levels of testosterone, sex hormone binding globulin and colorectal cancer risk: Observational and mendelian randomization analyses. Cancer Epidemiology, Biomarkers and Prevention, 30(7), 1336-1348
Open this publication in new window or tab >>Circulating levels of testosterone, sex hormone binding globulin and colorectal cancer risk: Observational and mendelian randomization analyses
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2021 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 30, no 7, p. 1336-1348Article in journal (Refereed) Published
Abstract [en]

Background: Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses.

Methods: The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR.

Results: In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational andMRanalyses.

Conclusions: Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development.

Place, publisher, year, edition, pages
AACR Publications, 2021
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-185900 (URN)10.1158/1055-9965.EPI-20-1690 (DOI)000675844700008 ()2-s2.0-85109097818 (Scopus ID)
Funder
NIH (National Institute of Health)EU, FP7, Seventh Framework Programme
Available from: 2021-07-12 Created: 2021-07-12 Last updated: 2023-09-05Bibliographically approved
Mori, N., Keski-Rahkonen, P., Gicquiau, A., Rinaldi, S., Dimou, N., Harlid, S., . . . Murphy, N. (2021). Endogenous Circulating Sex Hormone Concentrations and Colon Cancer Risk in Postmenopausal Women: A Prospective Study and Meta-Analysis. JNCI cancer spectrum, 5(6), Article ID pkab084.
Open this publication in new window or tab >>Endogenous Circulating Sex Hormone Concentrations and Colon Cancer Risk in Postmenopausal Women: A Prospective Study and Meta-Analysis
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2021 (English)In: JNCI cancer spectrum, ISSN 2515-5091, Vol. 5, no 6, article id pkab084Article in journal (Refereed) Published
Abstract [en]

Background: Observational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk, but epidemiologic studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results.

Methods: We investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone-binding globulin (SHBG) with colon cancer risk in a nested case-control study of 1028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were noncurrent users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios and 95% confidence intervals to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided.

Results: In the multivariable model, a nonstatistically significantly positive relationship was found between circulating estrone and colon cancer risk (odds ratio per log2 1-unit increment=1.17 [95% confidence interval=1.00 to 1.38]; odds ratioquartile4-quartile1 =1.33 [95% confidence interval=0.89 to 1.97], P trend =.20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the dose-response meta-analysis, no clear evidence of associations were found between circulating estradiol and estrone concentrations with colorectal, colon, and rectal cancer risk.

Conclusion: Our observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex hormones and colon or rectal cancer in postmenopausal women.

Place, publisher, year, edition, pages
Oxford University Press, 2021
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-193621 (URN)10.1093/jncics/pkab084 (DOI)000744512900004 ()34805742 (PubMedID)2-s2.0-85126288006 (Scopus ID)
Available from: 2022-04-07 Created: 2022-04-07 Last updated: 2023-09-05Bibliographically approved
Singleton, R. K., Heath, A. K., Clasen, J. L., Scelo, G., Johansson, M., Le Calvez-Kelm, F., . . . Muller, D. C. (2021). Risk prediction for renal cell Carcinoma: Results from the European Prospective Investigation into Cancer and nutrition (EPIC) prospective cohort study. Cancer Epidemiology, Biomarkers and Prevention, 30(3), 507-512
Open this publication in new window or tab >>Risk prediction for renal cell Carcinoma: Results from the European Prospective Investigation into Cancer and nutrition (EPIC) prospective cohort study
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2021 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 30, no 3, p. 507-512Article in journal (Refereed) Published
Abstract [en]

Background: Early detection of renal cell carcinoma (RCC) has the potential to improve disease outcomes. No screening program for sporadic RCC is in place. Given relatively low incidence, screening would need to focus on people at high risk of clinically meaningful disease so as to limit overdiagnosis and screen-detected false positives. Methods: Among 192,172 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (including 588 incident RCC cases), we evaluated a published RCC risk prediction model (including age, sex, BMI, and smoking status) in terms of discrimination (C-statistic) and calibration (observed probability as a function of predicted probability). We used a flexible parametric survival model to develop an expanded model including age, sex, BMI, and smoking status, with the addition of self-reported history of hypertension and measured blood pressure. Results: The previously published model yielded well-calibrated probabilities and good discrimination (C-statistic [95% CI]: 0.699 [0.679–0.721]). Our model had slightly improved discrimination (0.714 [0.694–0.735], bootstrap optimism-corrected C-statistic: 0.709). Despite this good performance, predicted risk was low for the vast majority of participants, with 70% of participants having 10-year risk less than 0.0025. Conclusions: Although the models performed well for the prediction of incident RCC, they are currently insufficiently powerful to identify individuals at substantial risk of RCC in a general population. Impact: Despite the promising performance of the EPIC RCC risk prediction model, further development of the model, possibly including biomarkers of risk, is required to enable risk stratification of RCC.

Place, publisher, year, edition, pages
AACR, 2021
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-181725 (URN)10.1158/1055-9965.EPI-20-1438 (DOI)000627591100013 ()2-s2.0-85102127616 (Scopus ID)
Available from: 2021-03-25 Created: 2021-03-25 Last updated: 2023-09-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-4759-2643

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