Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.
- MeSH
- Aspirin terapeutické užití MeSH
- celogenomová asociační studie MeSH
- dieta MeSH
- genotypizační techniky MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory krev epidemiologie genetika prevence a kontrola MeSH
- kyselina salicylová aplikace a dávkování krev MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- rizikové faktory MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
One of the principal mechanisms of chemotherapy resistance in highly frequent solid tumors, such as colorectal cancer (CRC), is the decreased activity of drug transport into tumor cells due to low expression of important membrane proteins, such as solute carrier (SLC) transporters. Sequence complementarity is a major determinant for target gene recognition by microRNAs (miRNAs). Single-nucleotide polymorphisms (SNPs) in target sequences transcribed into messenger RNA may therefore alter miRNA binding to these regions by either creating a new site or destroying an existing one. miRSNPs may explain the modulation of expression levels in association with increased/decreased susceptibility to common diseases as well as in chemoresistance and the consequent inter-individual variability in drug response. In the present study, we investigated whether miRSNPs in SLC transporter genes may modulate CRC susceptibility and patient's survival. Using an in silico approach for functional predictions, we analyzed 26 miRSNPs in 9 SLC genes in a cohort of 1368 CRC cases and 698 controls from the Czech Republic. After correcting for multiple tests, we found several miRSNPs significantly associated with patient's survival. SNPs in SLCO3A1, SLC22A2 and SLC22A3 genes were defined as prognostic factors in the classification and regression tree analysis. In contrast, we did not observe any significant association between miRSNPs and CRC risk. To the best of our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to SLC transporter genes and their impact on CRC susceptibility or patient's prognosis.
- MeSH
- 3' nepřekládaná oblast genetika MeSH
- adjuvantní chemoterapie MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory krev genetika mortalita terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru epidemiologie prevence a kontrola MeSH
- messenger RNA krev genetika MeSH
- mikro RNA krev metabolismus MeSH
- následné studie MeSH
- přenašeče organických aniontů genetika MeSH
- prognóza MeSH
- proteiny přenášející organické kationty genetika MeSH
- regulace genové exprese u nádorů MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- transportér organických kationtů 2 genetika MeSH
- vazebná místa genetika MeSH
- výpočetní biologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
BACKGROUND & AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. CONCLUSIONS: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.
- MeSH
- hodnocení rizik metody MeSH
- IGFBP-3 krev genetika MeSH
- incidence MeSH
- insulinu podobný růstový faktor I analýza genetika MeSH
- insulinu podobný růstový faktor II analýza MeSH
- jednonukleotidový polymorfismus MeSH
- kolorektální nádory krev epidemiologie genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- nádorové biomarkery krev genetika MeSH
- následné studie MeSH
- registrace statistika a číselné údaje MeSH
- rizikové faktory MeSH
- senioři MeSH
- sexuální faktory MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
- Geografické názvy
- Spojené království MeSH
S100 proteins are involved in biological events related to colorectal carcinogenesis. Aim of this prospective study was to assess serum concentration of S100A6, A8, A9 and A11 proteins in patients with colorectal neoplasia. Eighty-four subjects were enrolled: 20 controls (average risk population with normal findings on colonoscopy; 7 men, 13 women, age 23-74, mean 55 ± 14), 20 patients with non-advanced colorectal adenoma (non-AA, 10 men, 10 women, age 41-82, mean 62 ± 11), 22 with advanced colorectal adenoma (AA, 15 men, 7 women, age 49-80, mean 64 ± 8) and 22 with colorectal cancer (CRC, 12 men, 10 women, age 49-86, mean 69 ± 10). Peripheral venous blood was obtained. Serum S100 proteins were investigated by enzyme immunoassay technique. Serum S100A6 was significantly lower in CRC (mean 8530 ± 4743 ng/L), p = .035 compared to controls (mean 11308 ± 2968 ng/L). Serum S100A8 was significantly higher in AA (median 11955 ng/L, IQR 2681-34756 ng/L), p = .009 and in CRC (median 27532 ng/L, IQR 6794-35092 ng/L), p < .001 compared to controls (median 2513 ng/L, IQR 2111-4881 ng/L). Serum S100A9 concentrations did not differ between any tested group and controls, p > .05. Serum concentration of S100A11 was significantly lower in non-AA (mean 3.5 ± 2.4 μg/L), p = .004 and in CRC (mean 3.4 ± 2.4 μg/L), p = .002 compared to controls (mean 5.9 ± 2.5 μg/L). Sensitivity and specificity for S100A8 protein in patients with CRC were 94% and 73%; positive predictive value 68% and negative predictive value 95%. Patients with colorectal neoplasia have significantly lower serum S100A6 and S100A11 levels, significantly higher S100A8 and unaltered serum S100A9 levels.
- MeSH
- adenom krev diagnóza genetika patologie MeSH
- dospělí MeSH
- ELISA MeSH
- exprese genu MeSH
- kalgranulin A krev genetika MeSH
- kalgranulin B krev genetika MeSH
- karcinogeneze genetika metabolismus patologie MeSH
- kolorektální nádory krev diagnóza genetika patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery krev genetika MeSH
- prospektivní studie MeSH
- protein S100A6 krev genetika MeSH
- proteiny buněčného cyklu krev genetika MeSH
- proteiny S100 krev genetika MeSH
- senioři MeSH
- senzitivita a specificita MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
The circulating human transcriptome, which includes both coding and non-coding RNA (ncRNA) molecules, represents a rich source of potential biomarkers for colorectal cancer (CRC) that has only recently been explored. In particular, the release of RNA-containing extracellular vesicles (EVs), in a multitude of different in vitro cell systems and in a variety of body fluids, has attracted wide interest. The role of RNA species in EVs is still not fully understood, but their capacity to act as a form of distant communication between cells and their higher abundance in association with cancer demonstrated their relevance. In this review, we report the evidence from both in vitro and human studies on microRNAs (miRNAs) and other ncRNA profiles analysed in EVs in relation to CRC as diagnostic, prognostic and predictive markers. The studies so far highlighted that, in exosomes, the most studied category of EVs, several miRNAs are able to accurately discriminate CRC cases from controls as well as to describe the progression of the disease and its prognosis. Most of the time, the in vitro findings support the miRNA profiles detected in human exosomes. The expression profiles measured in exosomes and other EVs differ and, interestingly, there is a variability of expression also among different subsets of exosomes according to their proteic profile. On the other hand, evidence is still limited for what concerns exosome miRNAs as early diagnostic and predictive markers of treatment. Several other ncRNAs that are carried by exosomes, mostly long ncRNAs and circular RNAs, seem also to be dysregulated in CRC. Besides various technical challenges, such as the standardisation of EVs isolation methods and the optimisation of methodologies to characterise the whole spectrum of RNA molecules in exosomes, further studies are needed in order to elucidate their relevance as CRC markers.
- MeSH
- exozómy genetika metabolismus MeSH
- extracelulární vezikuly genetika metabolismus MeSH
- kolorektální nádory krev diagnóza genetika metabolismus MeSH
- lidé MeSH
- mikro RNA genetika metabolismus MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nekódující RNA genetika metabolismus MeSH
- progrese nemoci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: One of the most notable applications for circulating tumor DNA (ctDNA) detection in peripheral blood of patients with metastatic colorectal cancer (mCRC) is a long-term postoperative follow-up. Sometimes referred to as a "liquid (re)biopsy" it is a minimally invasive procedure and can be performed repeatedly at relatively short intervals (months or even weeks). The presence of the disease and the actual extent of the tumor burden (tumor mass) within the patient's body can be monitored. This is of particular importance, especially when evaluating radicality of surgical treatment as well as for early detection of disease progression or recurrence. AIM: To confirm the radicality of surgery using ctDNA and compare available methods for detection of recurrence in metastatic colorectal cancer. METHODS: A total of 47 patients with detected ctDNA and indications for resection of mCRC were enrolled in the multicenter study involving three surgical centers. Standard postoperative follow-ups using imaging techniques and the determination of tumor markers were supplemented by ctDNA sampling. In addition to the baseline ctDNA testing prior to surgery, a postoperative observation was conducted by evaluating ctDNA presence up to a week after surgery and subsequently at approximately three-month intervals. The presence of ctDNA was correlated with radicality of surgical treatment and the actual clinical status of the patient. RESULTS: Among the monitored patients, the R0 (curative) resection correlated with postoperative ctDNA negativity in 26 out of 28 cases of surgical procedures (26/28, 93%). In the remaining cases of R0 surgeries that displayed ctDNA, both patients were diagnosed with a recurrence of the disease after 6 months. In 7 patients who underwent an R1 resection, 4 ctDNA positivities (4/7, 57%) were detected after surgery and associated with the confirmation of early disease recurrence (after 3 to 7 months). All 15 patients (15/15, 100%) undergoing R2 resection remained constantly ctDNA positive during the entire follow-up period. In 22 cases of recurrence, ctDNA positivity was detected 22 times (22/22, 100%) compared to 16 positives (16/22, 73%) by imaging methods and 15 cases (15/22, 68%) of elevated tumor markers. CONCLUSION: ctDNA detection in patients with mCRC is a viable tool for early detection of disease recurrence as well as for confirmation of the radicality of surgical treatment.
- MeSH
- časná detekce nádoru metody MeSH
- cirkulující nádorová DNA krev izolace a purifikace MeSH
- dospělí MeSH
- kolektomie MeSH
- kolorektální nádory krev patologie chirurgie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru krev diagnóza epidemiologie prevence a kontrola MeSH
- nádorové biomarkery krev izolace a purifikace MeSH
- nádory jater krev diagnóza epidemiologie sekundární MeSH
- následné studie MeSH
- pooperační období MeSH
- progrese nemoci MeSH
- prospektivní studie MeSH
- resekční okraje MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie proveditelnosti MeSH
- tekutá biopsie metody MeSH
- tumor burden MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: In a prospective study with long-term follow-up, we analyzed circulating T cell subsets in patients with metastatic colorectal cancer (mCRC) in the context of primary tumor sidedness, KRAS status, and clinical outcome. Our primary goal was to investigate whether baseline levels of circulating T cell subsets serve as a potential biomarker of clinical outcome of mCRC patients treated with an anti-VEGF-based regimen. METHODS: The study group consisted of 36 patients with colorectal adenocarcinoma who started first-line chemotherapy with bevacizumab for metastatic disease. We quantified T cell subsets including Tregs and CD8+ T cells in the peripheral blood prior to therapy initiation. Clinical outcome was evaluated as progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). RESULTS: 1) mCRC patients with KRAS wt tumors had higher proportions of circulating CD8+ cytotoxic T cells among all T cells but also higher measures of T regulatory (Treg) cells such as absolute count and a higher proportion of Tregs in the CD4+ subset. 2) A low proportion of circulating Tregs among CD4+ cells, and a high CD8:Treg ratio at initiation of VEGF-targeting therapy, were associated with favorable clinical outcome. 3) In a subset of patients with primarily right-sided mCRC, superior PFS and OS were observed when the CD8:Treg ratio was high. CONCLUSIONS: The baseline level of circulating immune cells predicts clinical outcome of 1st-line treatment with the anti-VEGF angio/immunomodulatory agent bevacizumab. Circulating immune biomarkers, namely the CD8:Treg ratio, identified patients in the right-sided mCRC subgroup with favorable outcome following treatment with 1st-line anti-VEGF treatment.
- MeSH
- adenokarcinom krev farmakoterapie mortalita patologie MeSH
- bevacizumab aplikace a dávkování terapeutické užití MeSH
- cytotoxické T-lymfocyty metabolismus MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- inhibitory angiogeneze aplikace a dávkování terapeutické užití MeSH
- kolorektální nádory krev farmakoterapie mortalita patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů farmakoterapie MeSH
- míra přežití MeSH
- nádorové biomarkery metabolismus MeSH
- následné studie MeSH
- počet lymfocytů MeSH
- prospektivní studie MeSH
- protoonkogenní proteiny p21(ras) analýza MeSH
- regulační T-lymfocyty metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vaskulární endoteliální růstový faktor A antagonisté a inhibitory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
New non-invasive approaches that can complement and improve on current strategies for colorectal cancer (CRC) screening and management are urgently needed. A growing number of publications have documented that components of tumors, which are shed into the circulation, can be detected in the form of liquid biopsies and can be used to detect CRC at early stages, to predict response to certain therapies and to detect CRC recurrence in a minimally invasive way. The analysis of circulating tumor DNA (ctDNA), tumor-derived cells (CTC, circulating tumor cells) or circulating microRNA (miRNA) in blood and other body fluids, have a great potential to improve different aspects of CRC management. The challenge now is to find which types of components, biofluids and detection methods would be the most suitable to be applied in the different steps of CRC detection and treatment. This chapter will provide an up to date review on ctDNA, CTCs and circulating miRNAs as new biomarkers for CRC, either for clinical management or early detection, highlighting their advantages and limitations.
- MeSH
- časná detekce nádoru MeSH
- cirkulující mikroRNA MeSH
- cirkulující nádorová DNA MeSH
- kolorektální nádory krev diagnóza etiologie terapie MeSH
- lidé MeSH
- management nemoci MeSH
- nádorové biomarkery krev MeSH
- nádorové cirkulující buňky MeSH
- prognóza MeSH
- tekutá biopsie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Dietary selenium (Se) intake is essential for synthesizing selenoproteins that are important in countering oxidative and inflammatory processes linked to colorectal carcinogenesis. However, there is limited knowledge on the selenoprotein expression in colorectal adenoma (CRA) and colorectal cancer (CRC) patients, or the interaction with Se status levels. We studied the expression of seventeen Se pathway genes (including fifteen of the twenty-five human selenoproteins) in RNA extracted from disease-normal colorectal tissue pairs, in the discovery phase of sixty-two CRA/CRC patients from Ireland and a validation cohort of a hundred and five CRC patients from the Czech Republic. Differences in transcript levels between the disease and paired control mucosa were assessed by the Mann-Whitney U-test. GPX2 and TXNRD3 showed a higher expression and GPX3, SELENOP, SELENOS, and SEPHS2 exhibited a lower expression in the disease tissue from adenomas and both cancer groups (p-values from 0.023 to <0.001). In the Czech cohort, up-regulation of GPX1, SELENOH, and SOD2 and down-regulation of SELENBP1, SELENON, and SELENOK (p-values 0.036 to <0.001) was also observed. We further examined the correlation of gene expression with serum Se status (assessed by Se and selenoprotein P, SELENOP) in the Irish patients. While there were no significant correlations with both Se status markers, SELENOF, SELENOK, and TXNRD1 tumor tissue expression positively correlated with Se, while TXNRD2 and TXNRD3 negatively correlated with SELENOP. In an analysis restricted to the larger Czech CRC patient cohort, Cox regression showed no major association of transcript levels with patient survival, except for an association of higher SELENOF gene expression with both a lower disease-free and overall survival. Several selenoproteins were differentially expressed in the disease tissue compared to the normal tissue of both CRA and CRC patients. Altered selenoprotein expression may serve as a marker of functional Se status and colorectal adenoma to cancer progression.
- MeSH
- adenom krev genetika MeSH
- genetické markery MeSH
- glutathionperoxidasa genetika metabolismus MeSH
- kohortové studie MeSH
- kolorektální nádory krev genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- proporcionální rizikové modely MeSH
- regulace genové exprese MeSH
- selen krev MeSH
- selenoprotein P genetika metabolismus MeSH
- selenoproteiny genetika metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- thioredoxin-disulfidreduktasa genetika metabolismus MeSH
- thioredoxinreduktasa 1 genetika metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Irsko MeSH
