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Circulating Sex Hormone Levels and Colon Cancer Risk in Men: A Nested Case–Control Study and Meta-Analysis
Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.ORCID-id: 0000-0002-4759-2643
International Agency for Research on Cancer, World Health Organization, Lyon, France.
International Agency for Research on Cancer, World Health Organization, Lyon, France.
International Agency for Research on Cancer, World Health Organization, Lyon, France.
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2022 (Engelska)Ingår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 31, nr 4, s. 793-803Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
American Association for Cancer Research , 2022. Vol. 31, nr 4, s. 793-803
Nationell ämneskategori
Cancer och onkologi Endokrinologi och diabetes
Forskningsämne
onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-194638DOI: 10.1158/1055-9965.EPI-21-0996ISI: 000796549600001PubMedID: 35086823Scopus ID: 2-s2.0-85128993260OAI: oai:DiVA.org:umu-194638DiVA, id: diva2:1657886
Forskningsfinansiär
Region SkåneRegion VästerbottenVetenskapsrådet, 2017-00650Cancerforskningsfonden i Norrland, AMP 17-856Cancerforskningsfonden i Norrland, AMP 18-915Cancerforskningsfonden i Norrland, AMP 19-967CancerfondenTillgänglig från: 2022-05-12 Skapad: 2022-05-12 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
Ingår i avhandling
1. Circulating markers of risk and etiology in colorectal cancer
Öppna denna publikation i ny flik eller fönster >>Circulating markers of risk and etiology in colorectal cancer
2023 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[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. 

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2023. s. 60
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2232
Nyckelord
Colorectal cancer, CRC, sex hormones, colon cancer, DNA methylation, proteomics, risk, etiology
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
cancerepidemiologi
Identifikatorer
urn:nbn:se:umu:diva-205431 (URN)978-91-8070-006-1 (ISBN)978-91-8070-005-4 (ISBN)
Disputation
2023-03-31, Betula, Byggnad 6M, NUS, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2023-03-10 Skapad: 2023-03-06 Senast uppdaterad: 2023-03-13Bibliografiskt granskad

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Harbs, JustinLiu, Xijiavan Guelpen, BethanyHarlid, Sophia

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Harbs, JustinLiu, Xijiavan Guelpen, BethanyHarlid, Sophia
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