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To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of pre-cancer-associated fibroblasts. In the cancerous state, we observe T cell exhaustion, RUNX1-regulated cancer-associated fibroblasts and increasing accessibility associated with HNF4A motifs in epithelia. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.

Clinicians involved in cancer treatment often utilize somatic tumor sequencing to help tailor chemotherapy and immunotherapy. However, somatic tumor sequencing can also identify patients at risk for germline pathogenic variants causing cancer predisposition syndromes like Lynch syndrome. The extent to which clinicians realize this implication of tumor sequencing is currently unclear. We performed a retrospective chart review of Stanford Health Care patients who had somatic variant(s) in the Lynch syndrome genes or microsatellite instability identified on tumor sequencing to determine the proportion of patients who were referred to genetics. Among 6,556 patients who had tumor testing, 90 (1.37%) had findings compatible with Lynch syndrome. Of the 62 patients who had not already seen genetics, 47/62 (75.8%) were not referred to genetics for germline testing. Additionally, 26/47 (55.3%) of these individuals had a tumor type within the Lynch syndrome spectrum. Of the 10 patients who did elect germline testing after tumor sequencing, 3/10 were positive for Lynch syndrome. Our study highlights the need for specific guidelines to inform clinician referral practices on germline follow-up of somatic tumor testing and demonstrates the importance of continued research on the relationship between somatic tumor variants and germline variants to inform such guidelines.

Background: Screening reduces colorectal cancer mortality, but many persons remain unscreened. Screening with a blood test could improve screening rates. We estimated the comparative effectiveness and cost-effectiveness of colorectal cancer screening with emerging biomarkers, illustrated by a methylated Septin 9 DNA plasma assay (mSEPT9), versus established strategies.Methods: We conducted a cost-utility analysis using a validated decision analytic model comparing mSEPT9, fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), sigmoidoscopy, and colonoscopy, projecting lifetime benefits and costs.Results: In the base case, mSEPT9 decreased colorectal cancer incidence by 35% to 41% and colorectal cancer mortality by 53% to 61% at costs of $8,400 to $11,500/quality-adjusted life year gained versus no screening. All established screening strategies were more effective than mSEPT9. FIT was cost saving, dominated mSEPT9, and was preferred among all the alternatives. Screening uptake and longitudinal adherence rates over time strongly influenced the comparisons between strategies. At the population level, mSEPT9 yielded incremental benefit at acceptable costs when it increased the fraction of the population screened more than it was substituted for other strategies.Conclusions:mSEPT9 seems to be effective and cost-effective compared with no screening. To be cost-effective compared with established strategies, mSEPT9 or blood-based biomarkers with similar test performance characteristics would need to achieve substantially higher uptake and adherence rates than the alternatives. It remains to be proven whether colorectal cancer screening with a blood test can improve screening uptake or long-term adherence compared with established strategies.Impact: Our study offers insights into the potential role of colorectal cancer screening with blood-based biomarkers. Cancer Epidemiol Biomarkers Prev; 22(9); 1567–76. ©2013 AACR.

PDF file - 67K, Supplementary Figure 1. Schematic of the natural history module in the decision analytic model. Supplementary Table 1. Model inputs.

The rates of serious cardiac, neurologic, and pulmonary events attributable to colonoscopy are poorly characterized, and background event rates are usually not accounted for.We performed a multistate population-based study using changepoint analysis to determine the rates and timing of serious gastrointestinal and nongastrointestinal adverse events associated with screening/surveillance colonoscopy, including analyses by age (45 to55, 55 to65, 65 to75, and ≥75 years). Among 4.5 million persons in the Ambulatory Surgery and Services Databases of California, Florida, and New York who underwent screening/surveillance colonoscopy in 2005-2015, we ascertained serious postcolonoscopy events in excess of background rates in Emergency Department (SEDD) and Inpatient Databases (SID).Most serious nongastrointestinal postcolonoscopy events were expected based on the background rate and not associated with colonoscopy itself. However, associated nongastrointestinal events predominated over gastrointestinal events at ages ≥65 years, including more myocardial infarctions plus ischemic strokes than perforations at ages ≥75 years (361 [95% confidence intervals {CI} 312-419] plus 1,279 [95% CI 1,182-1,384] vs 912 [95% CI 831-1,002] per million). At all ages, the observed-to-expected ratios for days 0-7, 0-30, and 0-60 after colonoscopy were substantially1 for gastrointestinal bleeding and perforation, but minimally1 for most nongastrointestinal complications. Risk periods ranged from 1 to 125 days depending on complication type and age. No excess postcolonoscopy in-hospital deaths were observed.Although crude counts substantially overestimate nongastrointestinal events associated with colonoscopy, nongastrointestinal complications exceed bleeding and perforation risk in older persons. The inability to ascertain modifications to antiplatelet therapy was a study limitation. Our results can inform benefit-to-risk determinations for preventive colonoscopy.

A 35-year-old Filipino woman presented with epigastric pain and was found to have two large jejunal and ileal inflammatory fibroid polyps (IFPs) and dozens of subcentimeter small bowel submucosal nodules. Targeted exon sequencing of PDGFRA on the resected jejunum IFP identified a variant c.1664A>G that was subsequently confirmed in the germline. Family history was striking for three relatives with confirmed IFPs, including one with small bowel intussusception on five occasions. All relatives with IFPs were confirmed to have the same PDGFRA germline likely pathogenic variant, all were female, and all had IFPs by age 50 years that necessitated surgery. Two obligate carriers were reported to have had a similar phenotype while at least one obligate male carrier had no reported history of IFPs. This is the sixth reported family with a germline PDGFRA pathogenic variant and history of IFPs or gastrointestinal stromal tumor (GIST). This is the second report of the c.1664A>G likely pathogenic variant in a family that is unrelated to, and of different ethnic origin than, the first family. This second family exhibited a striking history of multiple IFPs without any reported GISTs, suggesting a possible genotype/phenotype association for this variant, and a possible female gender penetrance bias.

Among the characteristics of high-risk adenomas (HRA), some may predict a higher risk of metachronous advanced lesions. Our aim was to assess which HRA characteristics are associated with high risk of metachronous colorectal cancer (CRC) or advanced adenomas (AA).We systematically searched Pubmed, EMBASE and Cochrane for cohort studies and clinical trials of CRC or AA incidence at surveillance stratified by baseline lesion size, histology, and multiplicity. We calculated pooled relative risks (RR) using a random-effects model. Heterogeneity was assessed with the IFifty-five studies were included, with 936,540 patients. CRC incidence per 1,000 person-years was 2.6 (2.1-3.0) for adenomas ≥20mm, 2.7 (2.2-3.2) for high-grade dysplasia (HGD), 2.0 (1.8-2.3) for villous component, 0.8 (0.1-1.4) for ≥5 adenomas, 1.0 (0.7-1.2) for ≥3 adenomas. Metachronous CRC risk was higher in adenomas ≥20mm vs 10-19mm (RR 2.08, 95%CI 1.20-3.61), HGD vs low-grade dysplasia (RR 2.89, 95%CI 1.88-4.44), villous vs tubular (RR 1.75, 95%CI 1.33-2.31). No significant differences in CRC risk were found in ≥3 adenomas vs 1-2 (RR 1.24, 95%CI 0.84-1.83), nor in ≥5 adenomas vs 3-4 (RR 0.79, 95%CI 0.30-2.11). Compared to normal colonoscopy, RR for CRC risk was 2.61 (95%CI 2.06-3.32) for ≥10mm, 6.62 (95%CI 4.60-9.52) for HGD, 3.58 (95%CI 2.24-5.73) for villous component, 2.03 (95%CI 1.40-2.94) for ≥3 adenomas. Similar trends were seen for metachronous AA.Metachronous CRC risk is highest in patients with baseline adenomas with ≥20mm or HGD. Multiplicity does not seem to be associated with substantially higher CRC risk.

Although 3D genome architecture is essential for long-range gene regulation, the significance of distal regulatory chromatin contacts is challenged by recent findings of low correlation between contact propensity and gene expression. To better understand the role of long-range interactions between distal regulatory elements during the early transformation from healthy colon to colorectal cancer, here we performed high resolution chromatin conformation capture for 33 samples including non-neoplastic mucosa, adenomatous polyps and adenocarcinomas, mostly from Familial Adenomatous Polyposis (FAP) patients. We identified hundreds of thousands of chromatin micro-structures, such as architectural stripes and loops, which originated from active cis-regulatory elements. Surprisingly, these structures progressively decayed throughout cancer progression, particularly at promoters. Meta-analyses revealed that this decay was independent of alterations in DNA methylation and chromatin accessibility. Interestingly, the degree of interaction loss was poorly correlated with gene expression changes. Instead, genes whose expression were disproportionately lower and higher than their relative promoter interaction in mucosa shifted their expression in polyps and adenocarcinomas to yield a more direct relationship between strength of interaction and gene expression. Our work provides the first high resolution 3D conformation maps during early cancer formation and progression, and provides novel insights into transcriptional readouts associated with fine-scale chromatin conformation alterations.

Overweight and obese persons have not only elevated rates of colorectal cancer (CRC), but also higher competing mortality and healthcare spending. We examined the cost-effectiveness of intensified CRC screening in overweight and obese persons.We adapted our validated decision analytic model of CRC screening to compare screening starting at 45 or 40 years of age instead of at 50 years of age, or shortening screening intervals, in women and men with body mass index (BMI) ranging from normal to grade III obesity. Strategies included colonoscopy every 10 years (Colo10) or every 5 years (Colo5), or annual fecal immunochemical test.Without screening, sex-specific total CRC deaths were similar for persons with overweight or obesity I-III, reflecting the counterbalancing of higher CRC risk by lower life expectancy as BMI rises. For all BMI and sex groups, Colo10 starting at 45 years of age or FIT starting at 40 years of age were cost-effective at a threshold of $100,000 per quality-adjusted life year gained. Colo10 starting at 40 years of age was cost-effective only for men with obesity II-III, at $93,300 and $80,400 per quality-adjusted life year gained, respectively. Shifting Colo10 to earlier starting ages was always preferred over Colo5 starting at later ages. Results were robust in sensitivity analysis, including varying all-cause mortality, complication, and BMI-specific CRC risks.CRC screening starting at 45 years of age with colonoscopy, or at 40 years of age with FIT, appears cost-effective for women and men across the range of BMI. In men with obesity II-III, who have the highest CRC but also all-cause mortality risks, colonoscopy starting at 40 years of age appears cost-effective. It remains to be decided whether BMI should be used as a single predictor or incorporated into a multivariable tool to tailor CRC screening.

INTRODUCTION Risk stratification has been proposed as a strategy to improve participation in colorectal cancer (CRC) screening, but evidence is lacking. We performed a randomized controlled trial of risk stratification using the National Cancer Institute's Colorectal Cancer Risk Assessment Tool (CCRAT) on screening intent and completion. METHODS A total of 230 primary care patients eligible for first-time CRC screening were randomized to risk assessment via CCRAT or education control. Follow-up of screening intent and completion was performed by record review and phone at 6 and 12 months. We analyzed change in intent after intervention, time to screening, overall screening completion rates, and screening completion by CCRAT risk score tertile. RESULTS Of the patients, 61.7% of patients were aged

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

Familial adenomatous polyposis (FAP) patients develop hundreds of premalignant polyps that progress to colorectal cancer due to a germline mutation in the APC tumor suppressor. Polyps from FAP patients uniquely facilitate interrogation of the continuum of malignant transformation from histologically normal mucosa to benign and dysplastic polyps and eventual adenocarcinomas. As part of the Human Tumor Atlas Network (HTAN), we performed multi-omic profiling, including whole genome sequencing, on 135 samples from six FAP patients across the pre-malignant continuum spanning all physical regions of the large intestine, and serving as the most comprehensive FAP dataset available. Through a comparative analysis with a published FAP cohort (58 multi-region samples across 5 patients) and sporadic colorectal cancer cohort (n=57), each including benign and malignant samples, we evaluate the timing of driver acquisitions at each stage of malignant progression. Despite being separated by vast regions of histologically normal mucosa, independently evolving polyps show extensive mutation sharing, suggesting FAP polyps are polyclonal in origin. Finally, we leverage a simplified mechanistic model of embryonic colonic development demonstrating that the path to malignant transformation in FAP is consistent with polyclonal origins attributable to early mixing, perhaps as early as in-utero. Taken together, the HTAN FAP Atlas provides a novel window into the earliest stages of cancer formation and may illuminate barriers to malignant transformation and opportunities for earlier intervention. Citation Format: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Emma Monte, Si Wu, Casey Hanson, Nasim Bararpour, Stephanie Neves, Lihua Jiang, Kévin Contrepois, Hayan Lee, Tuhin K. Guha, Zheng Hu, Rozelle Laquindanum, Meredith A. Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Jeannie Chan, Mathew Ellenberger, Winston R. Becker, Bahareh Bahmani, Basil Michael, Jeanne Shen, Samuel Lancaster, Uri Ladabaum, Anshul Kundaje, Teri A. Longacre, William J. Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. The polyclonal path to malignant transformation in familial adenomatous polyposis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3497.

Purpose: Multiplex gene panel testing (MGPT) is used to identify individuals with an inherited susceptibility to cancer. However, little is known about the uptake of screening and surveillance among patients after MGPT and genetic counseling. The purpose of this study was to measure the uptake of guideline-concordant breast cancer screening after genetic testing and counseling. Patients and Methods: 2,000 patients who met NCCN testing guidelines or had ≥2.5% probability of a pathogenic/likely pathogenic variant (PV) were recruited at three cancer genetics clinics (University of Southern California (USC) Norris Comprehensive Cancer Center, Los Angeles County + USC Medical Center, Stanford Cancer Institute) from July 2014 through November 2016. All patients had 25- or 28-gene MGPT and results were disclosed by a genetic counselor, who provided screening recommendations to patients based on their risk. Post-test surveys were administered at three months, six months, one year, two years, and three years. Results: 1,614/2,000 (80.7%) patients were female and 1,147/1,614 (71.7%) completed at least one survey regarding MRI screening for breast cancer over the three years of longitudinal follow-up. Of these, 94/1,147 (8.2%) patients tested positive for at least one PV in a breast cancer risk gene; 58/94 (61.7%) tested positive for PVs in a high-risk breast cancer gene (BRCA1/2 (n=53), CDH1, PALB2, TP53 (n=5)), and 34/94 (36.2%) of patients tested positive for a PV in a gene characterized as moderate-risk at the time of disclosure (CHEK2, ATM, NBN). MRIs were recommended to 43/58 (74.1%) patients with a high-risk breast cancer gene PV, 20/34 (58.8%) patients with a moderate-risk gene PV, and 171/1,053 (16.2%) patients without a breast cancer risk gene PV. Multivariate logistic regression models revealed that patients with a high-risk gene PV were more likely to undergo MRI screening within 3 months of receiving genetic test results (OR=6.54 95% CI [3.09 - 14.43], p< 0.001), within one year (OR=1.34 95% CI [1.18 - 1.52], p< 0.001), two years (OR=1.43 95% CI [1.24 – 1.65], p< 0.001), and three years (OR=1.44 95% CI [1.25 – 1.66], p< 0.001) when compared to patients without a PV. Patients with a moderate-risk PV were also more likely to have undergone MRI within 3 months of receiving genetic test results (OR=2.89 95% CI [1.05 - 7.81], p=0.036), within one year (OR=1.33 95% CI [1.10 - 1.62], p=0.004), two years (OR=1.31 95% CI [1.09 - 1.59], p=0.004), and three years (OR=1.44 95% CI [1.18 - 1.76], p< 0.001), compared to those without a PV (Table 1). Conclusions: After three years of longitudinal follow up of 2000 patients in this multicenter prospective cohort study, patients with a PV in a breast cancer susceptibility gene were more likely to undergo guideline concordant breast MRI compared to patients without a PV. Carriers of high-risk breast cancer gene PVs were over six times as likely to have undergone MRI compared to patients without PVs within the first three months after genetic results disclosure and counseling. These results demonstrate the effectiveness of MGPT and genetic counseling in guiding patients with PVs in breast cancer susceptibility genes to the appropriate adoption of guideline-concordant screening. Odds ratios of MRI screening in patients carrying PV in breast cancer risk genes. Odds in relation to patients who do not carry a PV High risk gene PV: BRCA1/2, CDH1, PALB2, TP53; Moderate Risk PV: CHEK2, ATM, NBN. Percent of patients having undergone an MRI at the specified time points High risk gene PV: BRCA1/2, CDH1, PALB2, TP53; Moderate Risk PV: CHEK2, ATM, NBN. Citation Format: Leah A. Naghi, Charite N. Ricker, Duveen Sturgeon, Julie Culver, Kerry Kingham, Rachel Hodan, Nicolette M. Chun, John Kidd, Joseph Bonner, Christine Hong, Meredith Mills, Sidney S. Lindsey, Kevin McDonnell, Uri Ladabaum, James M. Ford, Stephen Grube, Allison W. Kurian, Gregory E. Idos. Uptake of Breast Cancer MRI Screening in Patients After Multiplex Gene Panel Testing [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-07.

The landmark Centers for Medicare & Medicaid Services (CMS) decision memo on blood-based biomarkers to screen for colorectal cancer (CRC) sets thresholds of 74% or higher for sensitivity and 90% or higher for specificity for CRC. This approach does not consider detection of advanced precancerous lesions as true positives. We contrasted the impact of counting advanced precancerous lesions as true vs false positives and projected CRC outcomes under contrasting tests in a validated model. A test with the threshold performance set by CMS decreased CRC incidence by 30% and CRC mortality by 48% in individuals aged 45 years. If this test also detected advanced precancerous lesions with 30% sensitivity, CRC incidence decreased by 45% and mortality by 58%, but the CRC specificity of the test of only 88% would not satisfy the CMS threshold. CMS should reconsider its definition of threshold specificity for CRC screening biomarkers. Future coverage determinations on biomarkers to screen for cancer should consider detection of relevant precursor lesions and projected outcomes.

Introduction: Gastric cancer is inherited as an autosomal dominant condition in hereditary diffuse gastric cancer (HDGC). The gene associated with HDGC is an E-cadherin gene CDH1. At the time of initiation of this study, it was estimated that 70% of patients who inherited the CDH1 gene mutation would develop gastric cancer. We hypothesized that the rate of signet ring cell cancer in asymptomatic patients with CDH1 mutations may be higher than anticipated and that the surgery could be conducted with acceptable short-term and long-term complications suggesting that the quality of life with the surgery is acceptable. Methods: We prospectively studied the role of total gastrectomy in symptomatic and asymptomatic patients with CDH1 mutations. A total of 43 patients with mutations of the CDH1 gene were studied prospectively, including 8 with symptoms and 35 without symptoms. Total gastrectomy was recommended to each. Quality of life was assessed in patients who underwent prophylactic gastrectomy. Proportions are compared with Fisher’s exact test. Results: In total, 13 (30%) asymptomatic patients declined surgery. Total gastrectomy was performed in 8 symptomatic patients and 22 asymptomatic patients of whom only 3 asymptomatic patients (14%) had endoscopically proven signet ring cell cancer preoperatively, while 21 of 22 (95%) had it on final pathology (p = 0.05). Each asymptomatic patient was T1, N0, while seven out of eight symptomatic patients had T3-T4 tumors and six had positive lymph nodes. None had operative complications or operative death. The median follow-up was 7 years. Five (63%) symptomatic patients died, while only one (95%) prophylactic patient died of a non-gastric cancer- or surgery-related issue (p = 0.05). A total of 15 prophylactic patients had long-term follow-up. Each had significant weight loss (mean 23%) but all had a normal body mass index. In total, 40% had bile reflux gastritis controlled with sucralfate. Each returned to work and, if given the choice, said that they would undergo the surgery again. Conclusions: Total gastrectomy is indicated for patients who have an inherented CDH1 mutation. Endoscopic screening is not reliable for diagnosing signet ring cell stomach cancer. If patients wait for symptoms, they will have a more advanced disease and significantly reduced survival. Operative complications of prophylactic gastrectomy are minimal, and long-term quality of life is acceptable.

All major U.S. guidelines now endorse average-risk colorectal cancer (CRC) screening at 45-49 years of age. Concerns exist that endoscopic capacity may be strained, that low-risk persons may self-select for screening, and that calculations of the adenoma detection rate may be diluted. We analyzed age-specific screening colonoscopy volumes and lesion detection rates before vs after the endorsement of CRC screening at 45-49 years of age.We compared colonoscopy volumes and lesion detection rates in our healthcare system during period 1 (October 2017 to December 2018), before the first change in guidelines, vs period 2 (January 2019 to August 2021), the era of new guidelines.The proportion of first-time screening colonoscopies performed in 45- to 49-year-olds increased from 3.5% to 11.6% (relative risk, 3.36; 95% CI, 2.45-4.61). The period 2 detection rates for adenoma, advanced adenoma, sessile serrated lesion, advanced sessile serrated lesion, adenomas per colonoscopy, and lesions per colonoscopy were very similar for 45- to 49-year-olds (34.3%, 6.3%, 8.6%, 2.9%, 0.58, and 0.69, respectively) and 50- to 54-year-olds (38.2%, 5.8%, 9.4%, 3.0%, 0.63, and 0.76, respectively) at first-time screening, and for 60- to 64-year-olds at rescreening (33.4%, 6.1%, 7.2%, 2.3%, 0.61, and 0.70, respectively). All detection rates, adenomas per colonoscopy, and lesions per colonoscopy increased from period 1 to period 2 (eg, overall adenoma detection rate 35.1% vs 42.6%; P.0001), without any decreases among 45- to 49-year-olds.In our healthcare system, a lower CRC screening initiation age has modestly affected colonoscopy volume by age without compromising screening yield. Lesion detection rates, including for advanced adenomas, in average-risk 45- to 49-year-olds approximate those in 50- to 54-year-olds at first-time screening and 60- to 64-year-olds at rescreening. National monitoring is needed to assess fully the impact of lowering the CRC screening initiation age.

The incidence of colorectal cancer (CRC) is increasing worldwide. CRC has high mortality when detected at advanced stages, yet it is also highly preventable. Given the difficulties in implementing major lifestyle changes or widespread primary prevention strategies to decrease CRC risk, screening is the most powerful public health tool to reduce mortality. Screening methods are effective but have limitations. Furthermore, many screen-eligible people remain unscreened. We discuss established and emerging screening methods, and potential strategies to address current limitations in CRC screening. A quantum step in CRC prevention might come with the development of new screening strategies, but great gains can be made by deploying the available CRC screening modalities in ways that optimize outcomes while making judicious use of resources.

BACKGROUND & AIMS: Sessile serrated polyps (SSPs) could account for a substantial proportion of colorectal cancers. We aimed to increase clarity on SSP prevalence and clinical features. METHODS: We performed a systematic review of Medline, Web of Science, Embase, and Cochrane databases for original studies published in English since 2000. We included studies of different populations (United States general or similar), interventions (colonoscopy, autopsy), comparisons (world regions, alternative polyp definitions, adenoma), outcomes (prevalence, clinical features), and study designs (cross-sectional). Random-effects regression was used for meta-analysis where possible. RESULTS: We identified 74 relevant colonoscopy studies. SSP prevalence varied by world region, from 2.6% in Asia (95% CI, 0–5.9%) to 10.5% in Australia (95% CI, 2.8%–18.2%). Prevalence values did not differ significantly between the United States and Europe (P=.51); the pooled prevalence was 4.6% (95% CI, 3.4%–5.8%), and SSPs accounted for 9.4% of polyps with malignant potential (95% CI, 6.6%–12.3%). Mean prevalence was higher when assessed through high-performance exams (9.1%; 95% CI, 4.0%–14.2%, P=.04) and with alternative definition of clinically relevant serrated polyps (12.3%; 95% CI, 9.3%–15.4%; P

Rates of incomplete colonoscopy in non-expert settings range up to 13%. Expert colonoscopists can complete ~ 95% colonoscopies when other endoscopists fail; however, a small number remain incomplete even in expert hands, typically due to bowel fixity. Pentax Retroview™ (EC-3490TLi) is a new slim colonoscope with a short turning radius (STR) and greater tip deflection (210°), which allows easy maneuverability across sharply angulated/fixed colonic bends. We evaluated the utility of this colonoscope for completing colonoscopies that fail even in the hands of expert colonoscopists. Retrospective chart review was performed, and main outcomes measured included cecal intubation rate, lesions detected, dosage of sedation used, and complications. Using the STR colonoscope, complete colonoscopy to the cecum was possible in 34/37 patients (91.9%). No loss of lumen/blind advancement was necessary in any of the procedures. No adverse events occurred. Among the completed colonoscopies, 6/34 (17.6%) patients had adenomas, all proximal to the site of prior failure, including one advanced adenoma. All failures (n = 3, 8.1%) had a history of cancer surgeries, with peritoneal carcinomatosis/extensively fixed/frozen bowel (two patients) and an additional diverticular stricture with colo-vesical fistula (one patient). STR colonoscope facilitates completion of a high proportion (91.9%) of colonoscopies that previously failed in expert hands. Its STR allows easy maneuverability across segments of sharp angulation with bowel fixity without need for blind advancement. The use of this colonoscope led to the detection of adenomas in 17.6% of patients, all proximal to the site of prior failed colonoscopy.

In 2018, the American Gastroenterological Association's Center for GI Innovation and Technology convened a consensus conference, entitled "Colorectal Cancer Screening and Surveillance: Role of Emerging Technology and Innovation to Improve Outcomes." The conference participants, which included more than 60 experts in colorectal cancer, considered recent improvements in colorectal cancer screening rates and polyp detection, persistent barriers to colonoscopy uptake, and opportunities for performance improvement and innovation. This white paper originates from that conference. It aims to summarize current patient- and physician-centered gaps and challenges in colonoscopy, diagnostic and therapeutic challenges affecting colonoscopy uptake, and the potential use of emerging technologies and quality metrics to improve patient outcomes.

Author(s): Lee, Briton; Keyes, Erin; Rachocki, Carly; Grimes, Barbara; Chen, Ellen; Vittinghoff, Eric; Ladabaum, Uri; Somsouk, Ma | Abstract: Background a aimsReports of mailed fecal immunochemical test (FIT) outreach effectiveness over time are minimal. We aimed to better evaluate a mailed FIT program with longitudinal metrics.MethodsA total of 10,771 patients aged 50 to 75 years not up-to-date with colorectal cancer screening were randomized to intervention or usual care. The intervention arm received an advanced notification call and informational postcard prior to a mailed FIT. Usual care was at the discretion of the primary care provider. Patients were followed for up to 2.5 years. The primary outcome was the difference in cumulative proportion of completed FIT screening between arms. Screening was further examined with the proportion of time up-to-date, consistency of adherence, and frequency of abnormal FIT.ResultsThe cumulative proportion of FIT completion was higher in the outreach intervention (73.2% vs 55.1%; P l .001). The proportion of time covered by screening was higher in the intervention group (46.8% vs 27.3%; Δ19.6%; 95% confidence interval, 18.2%-20.9%). Patients assigned to FIT outreach were more likely to consistently complete FITs (2 completed of 2 offered) (50.1% vs 21.8%; P l .001). However, for patients who did not complete the FIT during the first cycle, only 17.1% completed a FIT during the second outreach cycle. The number and overall proportion of abnormal FIT was significantly higher in the outreach intervention (6.9% Outreach vs 4.1% Usual Care; P l .01).ConclusionsOrganized mailed FIT outreach significantly increased colorectal cancer screening over multiple years in this safety-net health system. Although mailing was overall effective, the effect was modest in patients who did not complete FIT in first cycle of intervention. (ClincialTrials.gov, NCT02613260).

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected patients, leading to colorectal cancer (CRC), and is an ideal model to study early transition to CRC. We performed deep multi-omic profiling of 135 normal mucosal, benign and dysplastic polyps and adenocarcinoma samples from 6 FAP patients who consented to broad data sharing. Whole genome sequencing indicates that spatially separated polyps from the same donor harbor numerous mutations in common, but evolve independently, consistent with a model of polyclonal origin and spreading. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during early hyperplasia, dysplasia and cancer formation. These involve processes such as cell proliferation, immune response, alterations in metabolism (including amino acids, lipids), hormones, and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin/NSAIDs, a common preventative treatment of FAP patients. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in cancer formation and potential mechanisms of pharmaceutical prophylaxis.

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of pre-cancer-associated fibroblasts. In the cancerous state, we observe T cell exhaustion, RUNX1-regulated cancer-associated fibroblasts and increasing accessibility associated with HNF4A motifs in epithelia. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated 451,886 single-cell chromatin accessibility profiles and 208,557 single-cell transcriptomes from 48 polyps, 27 normal tissues, and 6 CRCs collected from patients with and without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from normal to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T-cells, and a subtype of FOX-regulated pre-cancer associated fibroblasts. In the cancerous state, we observe T-cell exhaustion, RUNX1-regulated cancer associated fibroblasts, and increasing accessibility associated with HNF4A motifs in epithelia. Methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.

Background The adenoma detection rate at screening (ADR) predicts interval colorectal cancer. Monitoring other lesion detection rates and colonoscopy indications has been proposed. We developed a comprehensive, automated colonoscopy audit program based on standardized clinical documentation, explored detection rates across indications, and developed the Adenoma Detection Rate – Extended to all Screening / Surveillance (ADR-ESS) score. Methods In a prospective cohort study, we calculated overall and advanced adenoma and sessile serrated lesion (SSL) detection rates among 15,253 colonoscopies by 35 endoscopists from 4 endoscopy units across all colonoscopy indications. We explored correlations between detection rates, and the precision and stability of ADR-ESS versus ADR. Results The overall “screening, first” ADR was 36.3% (95% confidence interval [CI], 34.5%–38.1%). The adenoma detection rate was lower for “screening, not first” (relative rate [RR], 0.80; 95% CI, 0.74–0.87) and “family history” (RR, 0.84; 95% CI, 0.74–0.96), and higher for “surveillance” (RR, 1.22; 95% CI, 1.15–1.31) and “follow-up, FIT” (RR, 1.21; 95% CI, 1.07–1.37). For “screening, first,” the detection rates for advanced adenoma, SSL, and advanced SSL were 6.7% (95% CI, 5.7%–7.7%), 7.2% (95% CI, 6.2%–8.2%), and 2.6% (95% CI, 2.0%–3.2%), respectively. Adenoma and SSL detection were correlated (r = 0.44; P = .008). ADR-ESS had substantially narrower confidence intervals and less period-to-period variability than ADR, and was not improved by weighting for indication volume and correction for detection by indication. Conclusions Comprehensive, automated colonoscopy audit based on standardized clinical documentation is feasible. Adenoma detection is a fair but imperfect proxy for SSL detection. ADR-ESS increases the precision of adenoma detection assessments and emphasizes quality across colonoscopy indications.