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- Harbs, Justin, 1994-
(författare)
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Circulating markers of risk and etiology in colorectal cancer
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Lu, Sai San Moon, 1988-
(författare)
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Antibiotics use in relation to colorectal cancer risk, survival and postoperative complications
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Growing evidence suggests that antibiotic-induced dysbiosis of gut microbiota potentially contributes to colorectal cancer development and oncological outcomes. However, the role of antibiotics in colorectal cancer incidence, survival and postoperative outcomes at a population level remains incompletely understood.Aims: The overall aim of the thesis is to investigate prescription antibiotics use in relation to colorectal cancer risk, survival and postoperative complications, particularly surgical site infections including anastomotic leakage.Methods: The thesis work includes matched case-control and cohort studies, leveraging complete population-based data from Swedish national registers. Paper I is a matched case-control study that consists of 40 545 colorectal cancer cases and 202 720 matched controls, aiming to investigate antibiotics use and risk of incident colorectal cancer. Multivariable conditional logistic regression was used. Paper II is a cohort study, including 47 303 colorectal cancer cases, investigating antibiotics use in relation to cancer-specific survival. Stratified Cox proportional-hazards regression was used. Paper III includes 38 839 colorectal cancer cases who had undergone abdominal tumour-resection surgery and assesses antibiotics use in relation to surgical site infections, including anastomotic leakage, within 30 days after surgery. Logistic regression with multi-level mixed-effects models was used.Results: In paper I, a dose-response association between antibiotics use and a higher risk of proximal colon cancer was found, whereas a slight inverse association with rectal cancer was observed, mainly in women. A null association was found between methenamine hippurate, assessed as a negative control due to no known effect on gut microbiome, and the risk of colorectal cancer. In paper II, the findings did not support any substantial negative effect of antibiotics on cancer-specific survival, except for very high cumulative exposure (>180 days) in stage I-III diseases. In stage IV colorectal cancer, modest inverse relationships between antibiotics use and survival were noted. In paper III, prescription antibiotics use up to 4.5 years before surgery was associated with a higher risk of surgical site infections, including anastomotic leakage, after colon cancer surgery but not rectal cancer surgery. A null association was observed between methanamine hippurate and the risk of surgical site infections. For cardiovascular and/or neurological complications, also considered as a negative control due to expected negligible or null effects of gut microbiome on these outcomes after surgery, associations were null in both colon and rectal cancer.Conclusion: These studies provided further support for antibiotics use as a modifiable risk factor for proximal colon cancer and identified antibiotics taken long before surgery as a novel risk factor for surgical site infections, including anastomotic leakage, after colon cancer surgery. In contrast, we did not find any substantial negative impact of antibiotics on cancer-specific survival. Taken together, the findings described in this thesis provide etiological insights and may contribute to strategies to prevent colon cancer and improve postoperative outcomes through prudent use of antibiotics, thereby aiding in the reduction of colorectal cancer incidence and mortality.
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