The Colorectal cancer Study of Austria (CORSA) is comprised more than 13,500 newly diagnosed colorectal cancer (CRC) patients, patients with high- and low-risk adenomas as well as population-based ...controls. The recruitment for the CORSA biobank is performed in close cooperation with the invited two-stage CRC screening project "Burgenland PREvention trial of colorectal Disease with ImmunologiCal Testing" (B-PREDICT). Annually, more than 150,000 inhabitants of the Austrian federal state Burgenland aged between 40 and 80 are invited to participate using FIT-tests as an initial screening. FIT-positive tested participants are offered a diagnostic colonoscopy and are asked to take part in CORSA, sign a written informed consent, complete questionnaires concerning dietary and lifestyle habits and provide an ethylenediaminetetraacetic acid (EDTA) blood sample as well as a stool sample. Additional CRC cases have been recruited at four hospitals in Vienna and a hospital in lower Austria. A major strength of CORSA is the population-based controls who are FIT-positive and colonoscopy-confirmed to be free of polyps and/or CRC.
The colorectal cancer (CRC) screening program B-PREDICT is a population based invited two stage screening project using a faecal immunochemical test (FIT) for initial screening followed by a ...colonoscopy for those with a positive FIT. B-PREDICT was compared with the opportunistic screening colonoscopy (OPP-COL), performed in course of the nationwide screening program.
Within B-PREDICT all residents of the Austrian federal state Burgenland, aged between 40 and 80 are annually invited to FIT testing. All individuals who underwent initial colonoscopy in Burgenland between 01/2003 and 12/2014, were included in this study. Individuals from the FIT-triggered invited screening program B-PREDICT were compared with those from the non-FIT triggered OPP-COL.
15 133 individuals from B-PREDICT were compared to 10 045 individuals with OPP-COL. CRC detection rates were 1.34% (CI-95%, 1.15; 1.52) in B-PREDICT compared to 0.54% in OPP-COL (95%-CI, 0.39; 0.68 p < 0.001). The decrease in the age standardized incidence rates of CRC was more pronounced in the population screened with FIT than in the general population screened with colonoscopy. Changes in incidence rates per year were -4.4% (95%-CI, -5.1; -3.7) vs. -1.8% (95%-CI, -1.9; -1.6 p < 0.001).
B-PREDICT shows a two-fold higher detection rate of CRC as well as HRA compared to OPP-COL.
The colorectal cancer (CRC) screening program B-PREDICT is an invited two-stage screening project using a fecal immunochemical test (FIT) for initial screening followed by a colonoscopy for those ...with a positive FIT. Since the gut microbiome likely plays a role in the etiology of CRC, microbiome-based biomarkers in combination with FIT could be a promising tool for optimizing CRC screening. Therefore, we evaluated the usability of FIT cartridges for microbiome analysis and compared it to Stool Collection and Preservation Tubes. Corresponding FIT cartridges as well as Stool Collection and Preservation Tubes were collected from participants of the B-PREDICT screening program to perform 16S rRNA gene sequencing. We calculated intraclass correlation coefficients (ICCs) based on center log ratio transformed abundances and used ALDEx2 to test for significantly differential abundant taxa between the two sample types. Additionally, FIT and Stool Collection and Preservation Tube triplicate samples were obtained from volunteers to estimate variance components of microbial abundances. FIT and Preservation Tube samples produce highly similar microbiome profiles which cluster according to subject. Significant differences between the two sample types can be found for abundances of some bacterial taxa (e.g. 33 genera) but are minor compared to the differences between the subjects. Analysis of triplicate samples revealed slightly worse repeatability of results for FIT than for Preservation Tube samples. Our findings indicate that FIT cartridges are appropriate for gut microbiome analysis nested within CRC screening programs.
DNA repair processes are involved in both the onset and treatment efficacy of colorectal cancer (CRC). A change of a single nucleotide causing an amino acid substitution in the corresponding protein ...may alter the efficiency of DNA repair, thus modifying the CRC susceptibility and clinical outcome. We performed a candidate gene approach in order to analyze the association of non-synonymous single nucleotide polymorphisms (nsSNPs) in the genes covering the main DNA repair pathways with CRC risk and clinical outcome modifications. Our candidate polymorphisms were selected according to the foremost genomic and functional prediction databases. Sixteen nsSNPs in 12 DNA repair genes were evaluated in cohorts from the Czech Republic and Austria. Apart from the tumor-node-metastasis (TNM) stage, which occurred as the main prognostic factor in all of the performed analyses, we observed several significant associations of different nsSNPs with survival and clinical outcomes in both cohorts. However, only some of the genes (
,
and
) were prominently defined as prediction factors in the classification and regression tree analysis; therefore, the study suggests their association for patient survival. In summary, we provide observational and bioinformatics evidence that even subtle alterations in specific proteins of the DNA repair pathways may contribute to CRC susceptibility and clinical outcome.
Aside from genetic alterations, epigenetic tumor-specific changes including DNA methylation are measurable in ctDNA and CTCs and their potential as diagnostic, prognostic and predictive epigenetic ...biomarkers has been demonstrated in a large number of studies although only few have made it into clinical practice, yet 7. Next, the 92 analyzed marker candidates were used for prediction model calculations by inputting PMR values for class prediction models based on different algorithms including Diagonal Linear Discriminant Analysis (DLDA), Nearest Centroid Predictor, k-Nearest-Neighbor Predictor, Support Vector Machines and (Bayesian) Compound Covariate Predictor (BCCP/CCP). Together, these data suggest that mCRPC can be identified based on methylation signatures with high accuracy, whereas organ-confined PCa with Gleason scores lower than 9 cannot be differentiated from benign samples, most likely due to limited amounts of ctDNA, which was also described in other studies analyzing DNA methylation in localized PCa patients using digital droplet PCR 11, 12. When performing fragment analysis of a subset of benign, localized PCa and mCRPC plasma samples (n=20 per group), we observed a significant shift of the mean cfDNA fragment size from 175 bp in benign and localized PCa (range 168 - 183bp) to 168 bp in mCRPC (range 145 – 179 bp) samples (Figure S2I). ...our markers might be suitable to identify high risk patients, who have already developed micrometastases, which cannot be detected by regular computed tomography (CT).
Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host ...genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.
PurposeThe overarching goal of the FOCUS (biomarkers related to folate-dependent one-carbon metabolism in colorectal cancer (CRC) recurrence and survival) Consortium is to unravel the effect of ...folate and folate-mediated one-carbon metabolism (FOCM) biomarkers on CRC prognosis to provide clinically relevant advice on folate intake to cancer patients and define future tertiary prevention strategies.ParticipantsThe FOCUS Consortium is an international, prospective cohort of 2401 women and men above 18 years of age who were diagnosed with a primary invasive non-metastatic (stages I–III) CRC. The consortium comprises patients from Austria, two sites from the Netherlands, Germany and two sites from the USA. Patients are recruited after CRC diagnosis and followed at 6 and 12 months after enrolment. At each time point, sociodemographic data, data on health behaviour and clinical data are collected, blood samples are drawn.Findings to dateAn increased risk of cancer recurrences was observed among patients with higher compared with lower circulating folic acid concentrations. Furthermore, specific folate species within the FOCM pathway were associated with both inflammation and angiogenesis pathways among patients with CRC. In addition, higher vitamin B6 status was associated with better quality of life at 6 months post-treatment.Future plansBetter insights into the research on associations between folate and FOCM biomarkers and clinical outcomes in patients with CRC will facilitate the development of guidelines regarding folate intake in order to provide clinically relevant advice to patients with cancer, health professionals involved in patient care, and ultimately further tertiary prevention strategies in the future. The FOCUS Consortium offers an excellent infrastructure for short-term and long-term research projects and for combining additional biomarkers and data resulting from the individual cohorts within the next years, for example, microbiome data, omics and multiomics data or CT-quantified body composition data.
Sporadic colorectal cancer is characterized by a multistep progression from normal epithelium to precancerous low-risk and high-risk adenomas to invasive cancer. Yet, the underlying molecular ...mechanisms of colorectal carcinogenesis are not completely understood. Within the "Metabolomic profiles throughout the continuum of colorectal cancer" (MetaboCCC) consortium we analyzed data generated by untargeted, mass spectrometry-based metabolomics using plasma from 88 colorectal cancer patients, 200 patients with high-risk adenomas and 200 patients with low-risk adenomas recruited within the "Colorectal Cancer Study of Austria" (CORSA). Univariate logistic regression models comparing colorectal cancer to adenomas resulted in 442 statistically significant molecular features. Metabolites discriminating colorectal cancer patients from those with adenomas in our dataset included acylcarnitines, caffeine, amino acids, glycerophospholipids, fatty acids, bilirubin, bile acids and bacterial metabolites of tryptophan. The data obtained discovers metabolite profiles reflecting metabolic differences between colorectal cancer and colorectal adenomas and delineates a potentially underlying biological interpretation.
Most genome-wide association studies (GWAS) were analyzed using single marker tests in combination with stringent correction procedures for multiple testing. Thus, a substantial proportion of ...associated single nucleotide polymorphisms (SNPs) remained undetected and may account for missing heritability in complex traits. Model selection procedures present a powerful alternative to identify associated SNPs in high-dimensional settings. In this GWAS including 1060 colorectal cancer cases, 689 cases of advanced colorectal adenomas and 4367 controls we pursued a dual approach to investigate genome-wide associations with disease risk applying both, single marker analysis and model selection based on the modified Bayesian information criterion, mBIC2, implemented in the software package MOSGWA. For different case-control comparisons, we report models including between 1-14 candidate SNPs. A genome-wide significant association of rs17659990 (P=5.43×10
,
, chromosome 3p21.2) with colorectal cancer risk was observed. Furthermore, 56 SNPs known to influence susceptibility to colorectal cancer and advanced adenoma were tested in a hypothesis-driven approach and several of them were found to be relevant in our Austrian cohort. After correction for multiple testing (α=8.9×10
), the most significant associations were observed for SNPs rs10505477 (P=6.08×10
) and rs6983267 (P=7.35×10
) of
, rs3802842 (P=8.98×10
,
), and rs12953717 (P=4.64×10
,
). All previously unreported SNPs demand replication in additional samples. Reanalysis of existing GWAS datasets using model selection as tool to detect SNPs associated with a complex trait may present a promising resource to identify further genetic risk variants not only for colorectal cancer.
The tryptophan-kynurenine pathway has been linked to cancer aetiology and survivorship, and diet potentially affects metabolites of this pathway, but evidence to date is scarce. Among 247 stage I-III ...CRC survivors, repeated measurements were performed at 6 weeks, 6 months, and 1 year post-treatment. Adherence to the World Cancer Research Fund/ American Institute for Cancer Research (WCRF) and Dutch Healthy Diet (DHD) recommendations was operationalized using seven-day dietary records. Plasma kynurenines of nine metabolites were analysed. Longitudinal associations of adherence to these dietary patterns and plasma kynurenines were analysed using confounder-adjusted linear mixed-models. In general, higher adherence to the dietary WCRF/AICR and DHD recommendations was associated with lower concentrations of kynurenines with pro-oxidative, pro-inflammatory, and neurotoxic properties (3-hydroxykynurenine (HK) and quinolinic acid (QA)), and higher concentrations of kynurenines with anti-oxidative, anti-inflammatory, and neuroprotective properties (kynurenic acid (KA) and picolinic acid (Pic)), but associations were weak and not statistically significant. Statistically significant positive associations between individual recommendations and kynurenines were observed for: nuts with kynurenic-acid-to-quinolinic-acid ratio (KA/QA); alcohol with KA/QA, KA, and xanthurenic acid (XA); red meat with XA; and cheese with XA. Statistically significant inverse associations were observed for: nuts with kynurenine-to-tryptophan ratio (KTR) and hydroxykynurenine ratio; alcohol with KTR; red meat with 3-hydroxyanthranilic-to-3-hydroxykynurenine ratio; ultra-processed foods with XA and KA/QA; and sweetened beverages with KA/QA. Our findings suggest that CRC survivors might benefit from adhering to the dietary WCRF and DHD recommendations in the first year after treatment, as higher adherence to these dietary patterns is generally, but weakly associated with more favourable concentrations of kynurenines and their ratios. These results need to be validated in other studies.
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