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Circulating markers of risk and etiology in colorectal cancer
Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.ORCID-id: 0000-0002-4759-2643
2023 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)Alternativ titel
Cirkulerande markörer för risk och etiologi för kolorektal cancer (Svenska)
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 [en]
Colorectal cancer, CRC, sex hormones, colon cancer, DNA methylation, proteomics, risk, etiology
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
cancerepidemiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-205431ISBN: 978-91-8070-006-1 (digital)ISBN: 978-91-8070-005-4 (tryckt)OAI: oai:DiVA.org:umu-205431DiVA, id: diva2:1741526
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
Delarbeten
1. Circulating Sex Hormone Levels and Colon Cancer Risk in Men: A Nested Case–Control Study and Meta-Analysis
Öppna denna publikation i ny flik eller fönster >>Circulating Sex Hormone Levels and Colon Cancer Risk in Men: A Nested Case–Control Study and Meta-Analysis
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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
Nationell ämneskategori
Cancer och onkologi Endokrinologi och diabetes
Forskningsämne
onkologi
Identifikatorer
urn:nbn:se:umu:diva-194638 (URN)10.1158/1055-9965.EPI-21-0996 (DOI)000796549600001 ()35086823 (PubMedID)2-s2.0-85128993260 (Scopus ID)
Forskningsfinansiär
Region SkåneRegion VästerbottenVetenskapsrådet, 2017-00650Cancerforskningsfonden i Norrland, AMP 17-856Cancerforskningsfonden i Norrland, AMP 18-915Cancerforskningsfonden i Norrland, AMP 19-967Cancerfonden
Tillgänglig från: 2022-05-12 Skapad: 2022-05-12 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
2. An epigenome-wide analysis of sex hormone levels and DNA methylation in male blood samples
Öppna denna publikation i ny flik eller fönster >>An epigenome-wide analysis of sex hormone levels and DNA methylation in male blood samples
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2023 (Engelska)Ingår i: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 18, nr 1, artikel-id 2196759Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Taylor & Francis Group, 2023
Nyckelord
Sex hormones, sex hormone binding globulin, DNA methylation, men, NSHDS
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-205420 (URN)10.1080/15592294.2023.2196759 (DOI)000961068800001 ()36994855 (PubMedID)2-s2.0-85151198554 (Scopus ID)
Forskningsfinansiär
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 universitet
Anmärkning

Originally included in thesis in manuscript form. 

Tillgänglig från: 2023-03-06 Skapad: 2023-03-06 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
3. A two-tiered targeted proteomics approach to identify pre-diagnostic biomarkers of colorectal cancer risk
Öppna denna publikation i ny flik eller fönster >>A two-tiered targeted proteomics approach to identify pre-diagnostic biomarkers of colorectal cancer risk
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2021 (Engelska)Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, nr 1, artikel-id 5151Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Springer Nature, 2021
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-181726 (URN)10.1038/s41598-021-83968-6 (DOI)000626139000041 ()2-s2.0-85102182478 (Scopus ID)
Tillgänglig från: 2021-03-24 Skapad: 2021-03-24 Senast uppdaterad: 2023-09-05Bibliografiskt granskad
4. Identifying prediagnostic colorectal cancer biomarkers using a targeted proteomics platform with extensive coverage
Öppna denna publikation i ny flik eller fönster >>Identifying prediagnostic colorectal cancer biomarkers using a targeted proteomics platform with extensive coverage
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:umu:diva-205426 (URN)
Tillgänglig från: 2023-03-06 Skapad: 2023-03-06 Senast uppdaterad: 2023-03-06

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