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Colorectal cancer (CRC) is the fourth most common cancer amongst men and women. Between 3 and 6% of all CRCs are attributed to well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), and several hamartomatous polyposis conditions. Identification of these patients through family history and appropriate genetic testing can provide estimates of cancer risk that inform appropriate cancer screening, surveillance and/or preventative interventions. This narrative review examines the hereditary colorectal cancer and polyposis syndromes, their genetic basis, clinical management, and evidence supporting cancer screening.

We performed meta-analysis to estimate pooled prevalence, risk factors, and outcomes of interval colorectal cancers (CRCs). Systematic literature search through October 2013, identified population-based studies, reporting prevalence of interval CRCs (CRCs diagnosed within 6-36 months of colonoscopy). We estimated the pooled prevalence, patient, endoscopist, and tumor-related risk factors, as well as outcomes of interval CRCs, as compared with detected CRCs (CRCs diagnosed at or within 6 months of colonoscopy). Twelve studies reporting on 7,912 interval CRCs were included. Pooled prevalence of interval CRCs was 3.7% (95% confidence interval (CI)=2.8-4.9%). These cancers were 2.4 times more likely to arise in the proximal colon (6.5%; 95% CI=4.9-8.6%) as compared with distal colon (2.9%; 95% CI=2.0-4.2%). Patients with interval CRCs were older (age >65-70 years vs. <65-70 years: odds ratio (OR)=1.15; 95% CI=1.02-1.30), have more comorbidities (high Charlson comorbidity index: OR=2.00; 95% CI=1.77-2.27), and have diverticular disease (OR=4.25; 95% CI=2.58-7.00). There was a nonsignificant time trend of declining prevalence of interval CRCs from 4.8% in 1990s to 4.2% between 2000 and 2005 and 3.7% beyond 2005. Patients with interval CRCs were less likely to present at an advanced stage (OR=0.79; 95% CI=0.67-0.94), although there was no survival benefit. Considerable heterogeneity was observed in most of the analyses. Based on meta-analysis, approximately 1 in 27 CRCs are interval CRCs, although the confidence in these estimates is low because of the heterogeneity among the studies. These are more likely to arise in the proximal colon and are diagnosed in older patients, patients with comorbidities or diverticular disease.

There are limited recent data on the characteristics of inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) and the use of colonoscopy prior to CRC diagnosis among persons with IBD. We analyzed IBD-CRC characteristics, survival after IBD-CRC diagnosis and the use of colonoscopy prior to IBD-CRC diagnosis over time. We identified individuals with and without IBD from the University of Manitoba IBD Epidemiology Database and CRC from linkage to the Manitoba Cancer Registry. We compared characteristics of IBD-CRC and sporadic-CRC using logistic regression and survival after CRC diagnosis using Cox regression analysis. We assessed rate and predictors of colonoscopy use 5 years to 6 months prior to IBD-CRC. 1,262 individuals with CRC were included (212 IBD-CRC). IBD was associated with an increased risk of death after CRC diagnosis in 2004-2011 (HR 1.89; 95% CI 1.25-2.88) but not in 2012-2017 (HR = 1.002; CI 0.50-2.03). In the 5 years to 6 months prior to IBD-CRC (1989-2018), 51% underwent colonoscopy, which was very similar to IBD without CRC and contrasted to 9% among sporadic CRCs. Exposure to colonoscopy pre IBD-CRC remained stable through the study period (1989-2002 OR = 1.25; CI 0.77-2.01; 2003-2011 OR = 1.21; CI 0.56-1.70; reference 2012-2018). Exposure to colonoscopy pre-IBD-CRC was not associated with improved post-CRC survival. The risk of death following CRC diagnosis is not impacted by a diagnosis of IBD in recent years. There is a very high proportion of post colonoscopy CRC among IBD-CRC, which has not changed over the years and needs detailed root-cause analysis and interventions.

While prior studies have largely focused on family communication of diagnostic single-gene test results or specific types of cancer testing results, far less work has investigated family communication of cancer-related genetic results that include multi-gene panels, a broad array of cancer types/stages, and participants without family history of cancer. The study we report here examined individuals’ anticipated barriers and benefits to sharing genetic information with family members. An 80+ gene panel was performed on participants recruited from Mayo Clinic, diagnosed with different cancer types, who did not have a family history suggestive of an inherited risk. Participants completed a 49-item survey before receiving genetic test results. Family variant testing was provided to family members at no cost, allowing factors influencing intent to share to be examined in the absence of financial burdens. In all, 1721 of 2984 individuals who received genetic testing completed the survey (57.7% completion rate). Participants’ intent to share with parents, siblings, and children was inversely related to the number of anticipated barriers to sharing and directly related to the number of anticipated benefits to sharing. Of those participants who did not intend to share with parents, siblings, and adult children, 64.8%, 30.3%, and 67.6% reported that there were no barriers, while 17.1%, 24.5%, and 40.2.% reported there were no benefits. Findings indicate that barriers to sharing genetic information with family members vary across family member types, and an inability to identify at least one benefit of sharing with family members is a predictor of intent not to share.

A polygenic risk score (PRS) is used to quantify the combined disease risk of many genetic variants. For complex human traits there is interest in determining whether the PRS modifies, i.e. interacts with, important environmental (E) risk factors. Detection of a PRS by environment (PRS x E) interaction may provide clues to underlying biology and can be useful in developing targeted prevention strategies for modifiable risk factors. The standard PRS may include a subset of variants that interact with E but a much larger subset of variants that affect disease without regard to E. This latter subset will dilute the underlying signal in former subset, leading to reduced power to detect PRS x E interaction. We explore the use of pathway-defined PRS (pPRS) scores, using state of the art tools to annotate subsets of variants to genomic pathways. We demonstrate via simulation that testing targeted pPRS x E interaction can yield substantially greater power than testing overall PRS x E interaction. We also analyze a large study (N = 78,253) of colorectal cancer (CRC) where E = non-steroidal anti-inflammatory drugs (NSAIDs), a well-established protective exposure. While no evidence of overall PRS x NSAIDs interaction (p = 0.41) is observed, a significant pPRS x NSAIDs interaction (p = 0.0003) is identified based on SNPs within the TGF-β/ gonadotropin releasing hormone receptor (GRHR) pathway. NSAIDS is protective (OR=0.84) for those at the 5 th percentile of the TGF-β/GRHR pPRS (low genetic risk, OR), but significantly more protective (OR=0.70) for those at the 95 th percentile (high genetic risk). From a biological perspective, this suggests that NSAIDs may act to reduce CRC risk specifically through genes in these pathways. From a population health perspective, our result suggests that focusing on genes within these pathways may be effective at identifying those for whom NSAIDs-based CRC-prevention efforts may be most effective.

Colonoscopy is widely recommended for colorectal cancer (CRC) screening, but evidence to guide the optimal frequency of repeat screening examination is limited. We examined the duration and magnitude of the risk of developing CRC, following a negative colonoscopy in those at average risk and those with a first-degree family history of CRC. A cohort of Utah residents aged 50-80 years who had a negative colonoscopy between 1 January 2001 and 31 December 2011 was identified using the Utah Population Database. Patients were followed from the time of the index colonoscopy until diagnosis of CRC, death, migration out of state, repeat colonoscopy, or end of the study period. CRC incidence after the index colonoscopy was compared with that of the state population by standardized incidence ratios (SIRs). A cohort of 131,349 individuals at average risk with a negative colonoscopy was identified. Compared with the state population, a negative colonoscopy was associated with SIRs of 0.15 (95% confidence interval (CI): 0.08-0.23) at 1 year, 0.26 (95% CI: 0.19-0.32) at 2-5 years, 0.33 (95% CI: 0.22-0.43) at 5-6 years, and 0.60 (95% CI: 0.44-0.76) at 7-10 years for CRC following the index colonoscopy. In a secondary analysis involving only patients with a first-degree relative with CRC, patients had a significantly lower incidence of CRC only for the first 5 years of follow-up (SIR 0.39, 95% CI: 013-0.64). There was also a difference in the risk of proximal (SIR 0.72, 95% CI: 0.45-0.98) and distal (SIR 0.51, 95% CI: 0.30-0.72) colon cancers at 7-10 years following a negative colonoscopy. The risk of developing CRC remains decreased for at least 10 years following the performance of a negative colonoscopy. However, the lower incidence of CRC in those with a family history of CRC differed in magnitude and timing being limited primarily to the first 5 years of follow-up and of lesser magnitude than that in the overall cohort.

Background Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach. Methods The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n  = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Results In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37). Conclusions Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further.

The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37–0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.

Background and Aims The molecular, endoscopic, and histological features of IBD-associated CRC differ from sporadic CRC. The objective of this study was to describe the prevalence, clinical features, and prognosis of IBD-associated CRC compared to patients with sporadic CRC in a US statewide population-based cohort. Methods All newly diagnosed cases of CRC between 1996 and 2011 were obtained from Utah Cancer Registry. IBD was identified using a previously validated algorithm, from statewide databases of Intermountain Healthcare, University of Utah Health Sciences, and the Utah Population Database. Logistic regression was performed to identify risk factors associated with IBD-associated cancer and Cox regression for differences in survival. Results Among 12,578 patients diagnosed with CRC, 101 (0.8%) had a prior history of IBD (61 ulcerative colitis and 40 Crohn’s disease). The mean age at CRC diagnosis was greater for patients without IBD than those with IBD (67.1 vs 52.8 years, P  < 0.001). Individuals with IBD-associated CRC were more likely to be men (odds ratio [OR] 1.90, 95% CI 1.23–2.92), aged less than 65 years (OR 6.77, 95% CI 4.06–11.27), and have CRC located in the proximal colon (OR 2.79, 95% CI 1.85–4.20) than those with sporadic CRC. Nearly 20% of the IBD-associated CRCs had evidence of primary sclerosing cholangitis. After adjustment for age, gender, and stage at diagnosis, the excess hazard of death after CRC diagnosis was 1.7 times higher in IBD than in non-IBD patients (95% CI 1.27–2.33). Conclusions The features of patients with CRC and IBD differ significantly from those without IBD and may be associated with increased mortality.

Purpose Tracking patient-reported outcomes (PROs) and quality-of-life response rates is essential for clinical trials. Historically, rates are monitored through scheduled reports, which can require gathering, merging, and cleaning data from multiple databases. At the end of this process, if gaps are found, new data are entered and the cycle repeats, leaving a trail of reports that are not up-to-date or immediately accessible to the investigator. The financial and person-hour cost of utilizing clinical research staff for this purpose is impractical. Online dashboards are continuously updated to monitor data, providing on-demand access to promote successful research. Methods Dashboard implementation utilizes R, an open-source statistical programming language, RMarkdown, a markup language, Flexdashboard, which creates structural elements, and Shiny, allowing investigators the ability to interact with data within the dashboard. By leveraging these four elements, powerful, cost-effective interactive dashboards can be built. Results Numerous dashboards have been utilized to identify potentially missing data and increase protocol adherence. Immediate patient consultation can occur to retrieve protocol-related forms, reducing research staff and patient burden while improving trial effectiveness. Dashboards can monitor PROs, enrollment, demographics, toxicity, and biomarker data, clinical outcomes, and implemented predictive models, creating a single hub for on-demand clinical trial monitoring. Conclusion By employing a set of freely available tools, the burden of utilizing study staff to continuously monitor trials is greatly reduced. These tools allow users to rapidly build and deploy dynamic dashboards capable of meeting the research needs of any investigator while limiting missing data through simplified monitoring of protocol adherence.