Performance of a Shotgun Prediction Model for Colorectal Cancer When Using 16S rRNA Sequencing Data.

Colorectal cancer (CRC), the third most common cancer globally, has shown links to disturbed gut microbiota. While significant efforts have been made to establish a microbial signature indicative of CRC using shotgun metagenomic sequencing, the challenge lies in validating this signature with 16S ribosomal RNA (16S) gene sequencing. The primary obstacle is reconciling the differing outputs of these two methodologies, which often lead to divergent statistical models and conclusions. In this study, we introduce an algorithm designed to bridge this gap by mapping shotgun-derived taxa to their 16S counterparts. This mapping enables us to assess the predictive performance of a shotgun-based microbiome signature using 16S data. Our results demonstrate a reduction in performance when applying the 16S-mapped taxa in the shotgun prediction model, though it retains statistical significance. This suggests that while an exact match between shotgun and 16S data may not yet be feasible, our approach provides a viable method for comparative analysis and validation in the context of CRC-associated microbiome research.

Meta-Analysis and Validation of a Colorectal Cancer Risk Prediction Model Using Deep Sequenced Fecal Metagenomes.

The gut microbiome is a potential modifiable risk factor for colorectal cancer (CRC). We re-analyzed all eight previously published stool sequencing data and conducted an MWAS meta-analysis. We used cross-validated LASSO predictive models to identify a microbiome signature for predicting the risk of CRC and precancerous lesions. These models were validated in a new study, Colorectal Cancer Screening (COLSCREEN), including 156 participants that were recruited in a CRC screening context. The MWAS meta-analysis identified 95 bacterial species that were statistically significantly associated with CRC (FDR < 0.05). The LASSO CRC predictive model obtained an area under the receiver operating characteristic curve (aROC) of 0.81 (95%CI: 0.78−0.83) and the validation in the COLSCREEN dataset was 0.75 (95%CI: 0.66−0.84). This model selected a total of 32 species. The aROC of this CRC-trained model to predict precancerous lesions was 0.52 (95%CI: 0.41−0.63). We have identified a signature of 32 bacterial species that have a good predictive accuracy to identify CRC but not precancerous lesions, suggesting that the identified microbes that were enriched or depleted in CRC are merely a consequence of the tumor. Further studies should focus on CRC as well as precancerous lesions with the intent to implement a microbiome signature in CRC screening programs.

Post-polypectomy colonoscopy surveillance: Can we improve the diagnostic yield? / Vigilancia tras resección de pólipos de colon: ¿podemos mejorar el rendimiento diagnóstico?

Although adenomas and serrated polyps are the preneoplastic lesions of colorectal cancer, only few of them will eventually progress to cancer. This review provides a comprehensive overview of the present and future of post-polypectomy colonoscopy surveillance. Post-polypectomy surveillance guidelines have recently been updated and all share the aim towards more selective and less frequent surveillance. We have examined these current guidelines and compared the recommendations of each of them. To improve the diagnostic yield of post-polypectomy surveillance it is important to find predictors of metachronous polyps that better identify high-risk individuals of developing advanced neoplasia. For this reason, we have also conducted a literature review of the molecular biomarkers of metachronous advanced colorectal polyps. Finally, we have discussed future directions of post-polypectomy surveillance and identified possible strategies to improve the use of endoscopic resources with the COVID-19 pandemic.(AU)

Aunque los adenomas y los pólipos serrados son las lesiones preneoplásicas del cáncer colorrectal, solo algunas de ellas progresarán a cáncer. Esta revisión presenta una descripción del presente y el futuro de la vigilancia endoscópica tras la resección de pólipos. Las recomendaciones de vigilancia pospolipectomía se han actualizado recientemente y todas comparten el objetivo de una vigilancia más selectiva y menos frecuente. Hemos examinado estas directrices actuales y hemos comparado las recomendaciones de cada una de ellas. Para mejorar el rendimiento diagnóstico de la vigilancia posterior a la polipectomía es importante encontrar predictores de pólipos metacrónicos que identifiquen mejor a los individuos con alto riesgo de desarrollar neoplasias avanzadas. Por este motivo, también hemos realizado una revisión de la literatura de los biomarcadores moleculares de pólipos avanzados metacrónicos. Finalmente, hemos discutido las direcciones futuras de la vigilancia endoscópica tras la resección de pólipos e identificado posibles estrategias para mejorar el uso de recursos endoscópicos con la pandemia de COVID-19.(AU)

Evaluating the Potential of Polygenic Risk Score to Improve Colorectal Cancer Screening.

BACKGROUND: Colorectal cancer has high incidence and associated mortality worldwide. Screening programs are recommended for men and women over 50. Intermediate screens such as fecal immunochemical testing (FIT) select patients for colonoscopy with suboptimal sensitivity. Additional biomarkers could improve the current scenario. METHODS: We included 2,893 individuals with a positive FIT test. They were classified as cases when a high-risk lesion for colorectal cancer was detected after colonoscopy, whereas the control group comprised individuals with low-risk or no lesions. 65 colorectal cancer risk genetic variants were genotyped. Polygenic risk score (PRS) and additive models for risk prediction incorporating sex, age, FIT value, and PRS were generated. RESULTS: Risk score was higher in cases compared with controls [per allele OR = 1.04; 95% confidence interval (CI), 1.02-1.06; P < 0.0001]. A 2-fold increase in colorectal cancer risk was observed for subjects in the highest decile of risk alleles (≥65), compared with those in the first decile (≤54; OR = 2.22; 95% CI, 1.59-3.12; P < 0.0001). The model combining sex, age, FIT value, and PRS reached the highest accuracy for identifying patients with a high-risk lesion [cross-validated area under the ROC curve (AUROC): 0.64; 95% CI, 0.62-0.66]. CONCLUSIONS: This is the first investigation analyzing PRS in a two-step colorectal cancer screening program. PRS could improve current colorectal cancer screening, most likely for higher at-risk subgroups. However, its capacity is limited to predict colorectal cancer risk status and should be complemented by additional biomarkers. IMPACT: PRS has capacity for risk stratification of colorectal cancer suggesting its potential for optimizing screening strategies alongside with other biomarkers.

Diagnostic Performance of a Fecal Immunochemical Test-Based Colorectal Cancer Screening Program According to Ambient Temperature and Humidity.

Exposure of the fecal immunochemical test (FIT) to different ambient temperatures and humidity is unavoidable in population-based screening programs in Southern European countries, and it could lead to a decrease in target colorectal lesions. The objective was to evaluate the effect of ambient temperature and humidity on the FIT sensitivity in a population-based screening program for colorectal cancer (CRC) using an ecological design. The retrospective cohort included individuals aged 50−69 years who participated in CRC screening (Barcelona) from 2010−2015, and were followed until 2017 to identify interval CRCs. The positivity rate, and detection rates for advanced polyps and CRC were compared according to ambient temperature, humidity, and quarters of the year. A positive FIT was defined as the detection of ≥20 µg Hb/g in feces. The monthly ambient temperature and humidity were recorded on the day that the FIT was performed. In total, 92,273 FIT results from 53,860 participants were analyzed. The FIT positivity rate was lower at >24 °C than at ≤24 °C (p = 0.005) but was not affected by humidity. The temperature's impact on positivity did not lead to a decrease in the FIT detection rate for advanced neoplasia or the interval cancer detection rate in a program where the samples were refrigerated until the analysis and screening invitations were discontinued in July and August.

Transcriptome-Wide Association Study for Inflammatory Bowel Disease Reveals Novel Candidate Susceptibility Genes in Specific Colon Subsites and Tissue Categories.

BACKGROUND AND AIMS: Genome-wide association studies [GWAS] for inflammatory bowel disease [IBD] have identified 240 risk variants. However, the benefit of understanding the genetic architecture of IBD remains to be exploited. Transcriptome-wide association studies [TWAS] associate gene expression with genetic susceptibility to disease, providing functional insight into risk loci. In this study, we integrate relevant datasets for IBD and perform a TWAS to nominate novel genes implicated in IBD genetic susceptibility. METHODS: We applied elastic net regression to generate gene expression prediction models for the University of Barcelona and University of Virginia RNA sequencing project [BarcUVa-Seq] and correlated expression and disease association research [CEDAR] datasets. Together with Genotype-Tissue Expression project [GTEx] data, and GWAS results from about 60 000 individuals, we employed Summary-PrediXcan and Summary-MultiXcan for single and joint analyses of TWAS results, respectively. RESULTS: BarcUVa-Seq TWAS revealed 39 novel genes whose expression in the colon is associated with IBD genetic susceptibility. They included expression markers for specific colon cell types. TWAS meta-analysis including all tissues/cell types provided 186 novel candidate susceptibility genes. Additionally, we identified 78 novel susceptibility genes whose expression is associated with IBD exclusively in immune (N = 19), epithelial (N = 25), mesenchymal (N = 22) and neural (N = 12) tissue categories. Associated genes were involved in relevant molecular pathways, including pathways related to known IBD therapeutics, such as tumour necrosis factor signalling. CONCLUSION: These findings provide insight into tissue-specific molecular processes underlying IBD genetic susceptibility. Associated genes could be candidate targets for new therapeutics and should be prioritized in functional studies.

Post-polypectomy colonoscopy surveillance: Can we improve the diagnostic yield?

Although adenomas and serrated polyps are the preneoplastic lesions of colorectal cancer, only few of them will eventually progress to cancer. This review provides a comprehensive overview of the present and future of post-polypectomy colonoscopy surveillance. Post-polypectomy surveillance guidelines have recently been updated and all share the aim towards more selective and less frequent surveillance. We have examined these current guidelines and compared the recommendations of each of them. To improve the diagnostic yield of post-polypectomy surveillance it is important to find predictors of metachronous polyps that better identify high-risk individuals of developing advanced neoplasia. For this reason, we have also conducted a literature review of the molecular biomarkers of metachronous advanced colorectal polyps. Finally, we have discussed future directions of post-polypectomy surveillance and identified possible strategies to improve the use of endoscopic resources with the COVID-19 pandemic.

Polygenic risk score across distinct colorectal cancer screening outcomes: from premalignant polyps to colorectal cancer.

BACKGROUND: Different risk-based colorectal cancer (CRC) screening strategies, such as the use of polygenic risk scores (PRS), have been evaluated to improve effectiveness of these programs. However, few studies have previously assessed its usefulness in a fecal immunochemical test (FIT)-based screening study. METHODS: A PRS of 133 single nucleotide polymorphisms was assessed for 3619 participants: population controls, screening controls, low-risk lesions (LRL), intermediate-risk (IRL), high-risk (HRL), CRC screening program cases, and clinically diagnosed CRC cases. The PRS was compared between the subset of cases (n = 648; IRL+HRL+CRC) and controls (n = 956; controls+LRL) recruited within a FIT-based screening program. Positive predictive values (PPV), negative predictive values (NPV), and the area under the receiver operating characteristic curve (aROC) were estimated using cross-validation. RESULTS: The overall PRS range was 110-156. PRS values increased along the CRC tumorigenesis pathway (Mann-Kendall P value 0.007). Within the screening subset, the PRS ranged 110-151 and was associated with higher risk-lesions and CRC risk (ORD10vsD1 1.92, 95% CI 1.22-3.03). The cross-validated aROC of the PRS for cases and controls was 0.56 (95% CI 0.53-0.59). Discrimination was equal when restricted to positive FIT (aROC 0.56), but lower among negative FIT (aROC 0.55). The overall PPV among positive FIT was 0.48. PPV were dependent on the number of risk alleles for positive FIT (PPVp10-p90 0.48-0.57). CONCLUSIONS: PRS plays an important role along the CRC tumorigenesis pathway; however, in practice, its utility to stratify the general population or as a second test after a FIT positive result is still doubtful. Currently, PRS is not able to safely stratify the general population since the improvement on PPV values is scarce.

Positive impact of a faecal-based screening programme on colorectal cancer mortality risk.

INTRODUCTION: The effectiveness of colorectal cancer (CRC) screening programs is directly related to participation and the number of interval CRCs. The objective was to analyse specific-mortality in a cohort of individuals invited to a CRC screening program according to type of CRC diagnosis (screen-detected cancers, interval cancers, and cancers among the non-uptake group). MATERIAL AND METHODS: Retrospective cohort that included invitees aged 50-69 years of a CRC screening program (target population of 85,000 people) in Catalonia (Spain) from 2000-2015 with mortality follow-up until 2020. A screen-detected CRC was a cancer diagnosed after a positive faecal occult blood test (guaiac or immunochemical); an interval cancer was a cancer diagnosed after a negative test result and before the next invitation to the program (≤24 months); a non-uptake cancer was a cancer in subjects who declined screening. RESULTS: A total of 624 people were diagnosed with CRC (n = 265 screen-detected, n = 103 interval cancers, n = 256 non-uptake). In the multivariate analysis, we observed a 74% increase in mortality rate in the group with interval CRC compared to screen-detected CRC adjusted for age, sex, location and stage (HR: 1.74%, 95% CI:1.08-2.82, P = 0.02). These differences were found even when we restricted for advanced-cancers participants. In the stratified analysis for type of faecal occult blood test, a lower mortality rate was only observed among FIT screen-detected CRCs. CONCLUSION: CRC screening with the FIT was associated with a significant reduction in CRC mortality.

Future Prospects of Colorectal Cancer Screening: Characterizing Interval Cancers.

Tumors that are not detected by screening tests are known as interval cancers and are diagnosed clinically after a negative result in the screening episode but before the next screening invitation. Clinical characteristics associated with interval colorectal cancers have been studied, but few molecular data are available that describe interval colorectal cancers. A better understanding of the clinical and biological characteristics associated with interval colorectal cancer may provide new insights into how to prevent this disease more effectively. This review aimed to summarize the current literature concerning interval colorectal cancer and its epidemiological, clinical, and molecular features.

Genetic Effects on Transcriptome Profiles in Colon Epithelium Provide Functional Insights for Genetic Risk Loci.

BACKGROUND & AIMS: The association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait-associated loci and may suggest novel genes implicated in disease. Here, our aims were as follows: (1) to generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse, and descending), (2) to identify expression and splicing quantitative trait loci (QTLs), (3) to find traits for which identified QTLs contribute to single-nucleotide polymorphism (SNP)-based heritability, (4) to propose candidate effector genes, and (5) to provide a web-based visualization resource. METHODS: We collected colonic mucosal biopsy specimens from 485 healthy adults and performed bulk RNA sequencing. We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses. RESULTS: We provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate effector genes for multiple phenotypes. Finally, we provided the Colon Transcriptome Explorer web application. CONCLUSIONS: We provide a large characterization of gene expression and splicing across colon subsites. Our findings provide greater etiologic insight into complex traits and diseases influenced by transcriptomic changes in colon tissue.

Text messaging as a tool to improve cancer screening programs (M-TICS Study): A randomized controlled trial protocol.

BACKGROUND: Short message service (SMS) based interventions are widely used in healthcare and have shown promising results to improve cancer screening programs. However, more research is still needed to implement SMS in the screening process. We present a study protocol to assess the impact on health and economics of three targeted SMS-based interventions in population-based cancer screening programs. METHODS/DESIGN: The M-TICs study is a randomized controlled trial with a formal process evaluation. Participants aged 50-69 years identified as eligible from the colorectal cancer (CRC) and breast cancer (BC) screening program of the Catalan Institute of Oncology (Catalonia, Spain) will be randomly assigned to receive standard invitation procedure (control group) or SMS-based intervention to promote participation. Two interventions will be conducted in the CRC screening program: 1) Screening invitation reminder: Those who do not participate in the CRC screening within 6 weeks of invite will receive a reminder (SMS or letter); 2) Reminder to complete and return fecal immunochemical test (FIT) kit: SMS reminder versus no intervention to individuals who have picked up a FIT kit at the pharmacy and they have not returned it after 14 days. The third intervention will be performed in the BC screening program. Women who had been screened previously will receive an SMS invitation or a letter invitation to participate in the screening. As a primary objective we will assess the impact on participation for each intervention. The secondary objectives will be to analyze the cost-effectiveness of the interventions and to assess participants' perceptions. EXPECTED RESULTS: The results from this randomized controlled trial will provide important empirical evidence for the use of mobile phone technology as a tool for improving population-based cancer screening programs. These results may influence the cancer screening invitation procedure in future routine practice. TRIAL REGISTRATION: Registry: NCT04343950 (04/09/2020); clinicaltrials.gov.

Proton-pump inhibitors are associated with a high false-positivity rate in faecal immunochemical testing.

BACKGROUND: False-positivity rates in faecal immunochemical test (FIT) can be affected by drug exposure. We aimed to assess the association between proton pump inhibitors (PPI) consumption and false positive (FP) results in a colorectal cancer (CRC) screening programme using electronic prescription records. METHODS: A retrospective cohort study within a population-based screening program for CRC from 2010 to 2016 was performed. Participants with a conclusive FIT result and with prescription electronic data were included. An FP result was defined as having a positive FIT (≥ 20 µg haemoglobin/g faeces) and a follow-up colonoscopy without intermediate or high-risk lesions or CRC. Screening data were anonymously linked to the public data analysis program for health research and innovation (PADRIS) database that recorded patient diseases history and reimbursed medication. PPI exposure was defined as having retrieved at least one dispensation of PPI three months prior to the FIT. RESULTS: A total of 89,199 tests (of 46,783 participants) were analysed, 4824 (5.4%) tested positive and the proportion of FP was 53.5%. Overall, 17,544 participants (19.7%) were PPI users prior to FIT performance. PPI exposure increased the probability of obtaining an FP FIT result from 50.4 to 63.3% (adjusted OR 1.39; 95% CI 1.18-1.65). Nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, antibiotics, and laxatives were also associated with an FP result. The effect of PPI was independent and showed a synergistic interaction with nonsteroidal anti-inflammatory drugs. CONCLUSION: PPIs increase FIT positivity at the expense of FP results. The recommendation to avoid their use before FIT performance could reduce up to 3% of colonoscopies and 9% of FP results.

Identifying environmental risk factors for inflammatory bowel diseases: a Mendelian randomization study.

Several studies have examined environmental factors and inflammatory bowel diseases (IBD) using traditional approaches; however, provided results are still conflicting. Our aim was to determine whether lifestyle and nutrient exposures, related to IBD in observational meta-analyses, influence IBD risk using a Mendelian randomization (MR) approach. A two-sample MR approach was applied on summary-level genome-wide association results. Genetic variants strongly associated with measures of tobacco smoking, obesity and fat distribution, physical activity, and blood levels of vitamins and fatty acids were evaluated on genetic data from international IBD consortia including a total of 25,042 IBD cases (12,194 cases of Crohn's disease (CD) and 12,366 cases of ulcerative colitis (UC)) and 34,915 controls. Our results indicated that, among lifestyle exposures, being a smoker was positively associated with CD (OR 1.13, P = 0.02), but it was not associated with UC risk (OR 0.99, P = 0.88). Body-mass index (BMI) and body fat percentage were positively associated with CD (OR 1.11, P = 0.02, per standard deviation (SD) of 4.6 kg/m2; and OR 1.50, P = 3 × 10-10, per SD of 6.6%; respectively); while for UC, BMI was inversely associated (OR 0.85, P = 5 × 10-5; per SD) and body fat percentage showed a OR of 1.11 (P = 0.11; per SD). Additionally, among nutrient exposures, omega-3 fatty acids levels were inversely associated with CD (OR 0.67, P = 2 × 10-6). Our MR results did not support a protective effect for being a smoker on UC risk; however, they are compatible with a risk effect for higher body fat proportion and a protective role for higher levels of omega-3 fatty acids on CD etiology.

Chondroitin Sulphate and Glucosamine Use Depend on Nonsteroidal Anti-inflammatory Drug Use to Modify the Risk for Colorectal Cancer.

BACKGROUND: A safe and effective colorectal cancer chemoprevention agent remains to be discovered. There is little evidence regarding the protective effect of chondroitin sulphate and glucosamine on colorectal cancer. We aimed to assess the association between colorectal cancer risk and the use of chondroitin sulphate and glucosamine using a large cohort with dispensed data. METHODS: We performed a population-based case-control study in Catalonia using primary care reimbursed medication records (SIDIAP database). The study included 25,811 cases with an incident diagnosis of colorectal cancer and 129,117 matched controls between 2010 and 2015. RESULTS: The prevalence of ever use was 9.0% (n = 13,878) for chondroitin sulphate, 7.3% (n = 11,374) for glucosamine, and 35% for regular use of nonsteroidal anti-inflammatory drugs (NSAID; n = 45,774). A decreased risk of colorectal cancer was observed among chondroitin sulphate use [OR: 0.96; 95% confidence interval (CI), 0.91-1.01], glucosamine use (OR: 0.92; 95% CI, 0.87-0.97), and concurrent use of chondroitin sulphate and glucosamine (OR: 0.83; 95% CI, 0.70-0.98). Especially for glucosamine, there was a dose-response association regarding duration and cumulative dose. The analysis stratified by simultaneous use with other NSAIDs showed that these drugs used without other NSAIDs do not reduce risk (OR: 1.06; 95% CI, 0.74-1.51). However, they may have a synergistic protective effect when used with other NSAIDs (OR: 0.80; 95% CI, 0.72-0.88). CONCLUSIONS: This study does not provide strong support for an independent protective association of chondroitin sulphate or glucosamine on colorectal cancer risk in our population. However, these drugs may have a synergistic beneficial effect among NSAID users. IMPACT: Chondroitin sulphate or glucosamine may contribute to the protective effect of NSAID use in colorectal cancer.

Gut microbiome diversity detected by high-coverage 16S and shotgun sequencing of paired stool and colon sample.

The gut microbiome has a fundamental role in human health and disease. However, studying the complex structure and function of the gut microbiome using next generation sequencing is challenging and prone to reproducibility problems. Here, we obtained cross-sectional colon biopsies and faecal samples from nine participants in our COLSCREEN study and sequenced them in high coverage using Illumina pair-end shotgun (for faecal samples) and IonTorrent 16S (for paired feces and colon biopsies) technologies. The metagenomes consisted of between 47 and 92 million reads per sample and the targeted sequencing covered more than 300 k reads per sample across seven hypervariable regions of the 16S gene. Our data is freely available and coupled with code for the presented metagenomic analysis using up-to-date bioinformatics algorithms. These results will add up to the informed insights into designing comprehensive microbiome analysis and also provide data for further testing for unambiguous gut microbiome analysis.

The use of faecal immunochemical testing in the decision-making process for the endoscopic investigation of iron deficiency anaemia.

Background Blood loss from the gastrointestinal (GI) tract is the most common cause of iron deficiency anaemia (IDA) in adult men and postmenopausal women. Gastroduodenal endoscopy (GDE) and colonoscopy are frequently recommended, despite uncertainty regarding the coexistence of lesions in the upper and lower GI tract. The faecal immunochemical test (FIT) measures the concentration of faecal haemoglobin (f-Hb) originating only from the colon or rectum. We aimed to assess whether the FIT was able to select the best endoscopic procedure for detecting the cause of IDA. Methods A prospective study of 120 men and postmenopausal women referred for a diagnostic study of IDA were evaluated with an FIT, GDE and colonoscopy. The endoscopic finding of a significant upper lesion (SUL) or a significant bowel lesion (SBL) was considered to be the cause of the IDA. Results The diagnoses were 35.0% SUL and 20.0% SBL, including 13.3% GI cancer. In the multivariate analysis, the concentration of blood haemoglobin (b-Hb) <9 g/dL (OR: 2.60; 95% CI 1.13-6.00; p = 0.025) and non-steroidal anti-inflammatory drugs NSAIDs (2.56; 1.13-5.88; p = 0.024) were associated with an SUL. Age (0.93; 0.88-0.99; p = 0.042) and f-Hb ≥ 15 µg Hb/g faeces (38.53; 8.60-172.50; p < 0.001) were associated with an SBL. A "FIT plus gastroscopy" strategy, in which colonoscopy is performed only when f-Hb ≥15 µg Hb/g faeces, would be able to detect 92.4% of lesions and be 100% accurate in the detection of cancer while avoiding 71.6% of colonoscopies. Conclusions The FIT is an accurate method for selecting the best endoscopy study for the evaluation of IDA. An FIT-based strategy is more cost-effective than the current bidirectional endoscopy-based strategy and could improve endoscopic resource allocation.

Risk of colorectal cancer in users of bisphosphonates: analysis of population-based electronic health records.

The use of bisphosphonates has been associated with a decrease in the risk of colorectal cancer (CRC) in observational studies, but with controversial results and difficult to interpret because of routine concomitant use of calcium and vitamin D. We aimed to assess the association between CRC risk and outpatient exposure to antiosteoporotic drugs using a large cohort with prescription data in Catalonia. A case-control study was performed using the Information System for Development of Primary Care Research (SIDIAP) which is a primary care medical record database that has linked data on reimbursed medication. The study included 25,836 cases with an incident diagnosis of CRC between 2010 and 2015 and 129,117 matched controls by age (± 5 years), sex and healthcare region. A multivariable model was built adjusting for known risk factors and comorbidities that were significantly associated to CRC in the dataset, and a propensity score for bisphosphonates. Tests for interaction for multiple drug use and stratified analysis for tumour location were prospectively planned. Overall 18,230 individuals (11.5%) were users of bisphosphonates. A significant but modest protective effect on CRC was observed for bisphosphonates (OR 0.95, 95% CI 0.91-0.99), that was no longer significant when adjusted for calcium and vitamin D (OR 0.98, 95% CI 0.93-1.03). Bisphosphonates, however, showed a dose-response effect with duration of use even when adjusted for calcium and vitamin D (OR for use > 40 months: 0.90, 95% CI 0.81-1.00, P value for trend: 0.018). The use of bisphosphonates was associated with a modest decrease in the risk of CRC, but this effect was essentially explained by concomitant use of calcium or vitamin D. The observed protective effect was stronger for long durations of use, which deserves further study.

Mendelian randomization analysis rules out disylipidaemia as colorectal cancer cause.

Dyslipidemia and statin use have been associated with colorectal cancer (CRC), but prospective studies have shown mixed results. We aimed to determine whether dyslipidemia is causally linked to CRC risk using a Mendelian randomization approach and to explore the association of statins with CRC. A case-control study was performed including 1336 CRC cases and 2744 controls (MCC-Spain). Subjects were administered an epidemiological questionnaire and were genotyped with an array which included polymorphisms associated with blood lipids levels, selected to avoid pleiotropy. Four genetic lipid scores specific for triglycerides (TG), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), or total cholesterol (TC) were created as the count of risk alleles. The genetic lipid scores were not associated with CRC. The ORs per 10 risk alleles, were for TG 0.91 (95%CI: 0.72-1.16, p = 0.44), for HDL 1.14 (95%CI: 0.95-1.37, p = 0.16), for LDL 0.97 (95%CI: 0.81-1.16, p = 0.73), and for TC 0.98 (95%CI: 0.84-1.17, p = 0.88). The LDL and TC genetic risk scores were associated with statin use, but not the HDL or TG. Statin use, overall, was a non-significant protective factor for CRC (OR 0.84; 95%CI: 0.70-1.01, p = 0.060), but lipophilic statins were associated with a CRC risk reduction (OR 0.78; 95%CI 0.66-0.96, p = 0.018). Using the Mendelian randomization approach, our study does not support the hypothesis that lipid levels are associated with the risk of CRC. This study does not rule out, however, a possible protective effect of statins in CRC by a mechanism unrelated to lipid levels.

Statin use and the risk of colorectal cancer in a population-based electronic health records study.

There is extensive debate regarding the protective effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on colorectal cancer (CRC). We aimed to assess the association between CRC risk and exposure to statins using a large cohort with prescription data. We carried out a case-control study in Catalonia using the System for Development of Primary Care Research (SIDIAP) database that recorded patient diseases history and linked data on reimbursed medication. The study included 25 811 cases with an incident diagnosis of CRC between 2010 and 2015 and 129 117 frequency-matched controls. Subjects were classified as exposed to statins if they had ever been dispensed statins. Analysis considering mean daily defined dose, cumulative duration and type of statin were performed. Overall, 66 372 subjects (43%) were exposed to statins. There was no significant decrease of CRC risk associated to any statin exposure (OR = 0.98; 95% CI: 0.95-1.01). Only in the stratified analysis by location a reduction of risk for rectal cancer was observed associated to statin exposure (OR = 0.87; 95% CI: 0.81-0.92). This study does not support an overall protective effect of statins in CRC, but a protective association with rectal cancer merits further research.