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Gastroenterology Jan 2020Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic... (Review)
Review
Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic changes associated with the development of precancerous colorectal adenomas and their progression to tumors, as well as the effects of defective DNA repair, chromosome instability, microsatellite instability, and alterations in the serrated pathway and DNA methylation. We provide insights into the different molecular subgroups of colorectal tumors that develop via each of these different mechanisms and their associations with patient outcomes.
Topics: Adenoma; Carcinogenesis; Colorectal Neoplasms; DNA Methylation; Disease Progression; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Humans; Microsatellite Instability; Mutation
PubMed: 31622622
DOI: 10.1053/j.gastro.2019.08.059 -
Clinical Interventions in Aging 2016Most colon tumors develop via a multistep process involving a series of histological, morphological, and genetic changes that accumulate over time. This has allowed for... (Review)
Review
Most colon tumors develop via a multistep process involving a series of histological, morphological, and genetic changes that accumulate over time. This has allowed for screening and detection of early-stage precancerous polyps before they become cancerous in individuals at average risk for colorectal cancer (CRC), which may lead to substantial decreases in the incidence of CRC. Despite the known benefits of early screening, CRC remains the second leading cause of cancer-related deaths in the United States. Hence, it is important for health care providers to have an understanding of the risk factors for CRC and various stages of disease development in order to recommend appropriate screening strategies. This article provides an overview of the histological/molecular changes that characterize the development of CRC. It describes the available CRC screening methods and their advantages and limitations and highlights the stages of CRC development in which each screening method is most effective.
Topics: Colonography, Computed Tomographic; Colorectal Neoplasms; Early Detection of Cancer; Genetic Testing; Humans; Mass Screening; Polyps; Precancerous Conditions; Risk Factors; Sigmoidoscopy; United States
PubMed: 27486317
DOI: 10.2147/CIA.S109285 -
Cureus Apr 2023Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. National screening guidelines have been implemented to identify and remove... (Review)
Review
Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. National screening guidelines have been implemented to identify and remove precancerous polyps before they become cancer. Routine CRC screening is advised for people with average risk starting at age 45 because it is a common and preventable malignancy. Various screening modalities are currently in use, ranging from stool-based tests (fecal occult blood test (FOBT), fecal immunochemical test (FIT), and FIT-DNA test), radiologic tests (computed tomographic colonography (CTC), double contrast barium enema), and visual endoscopic examinations (flexible sigmoidoscopy (FS), colonoscopy, and colon capsule endoscopy (CCE)) with their varying sensitivity and specificity. Biomarkers also play a vital role in assessing the recurrence of CRC. This review offers a summary of the current screening options, including biomarkers available to detect CRC, highlighting the benefits and challenges encompassing each screening modality.
PubMed: 37193451
DOI: 10.7759/cureus.37509 -
Nature Genetics Jul 2022To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated...
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.
Topics: Adenoma; Cell Transformation, Neoplastic; Colorectal Neoplasms; DNA Methylation; Humans; Single-Cell Analysis
PubMed: 35726067
DOI: 10.1038/s41588-022-01088-x -
World Journal of Gastroenterology May 2020In recent years, the serrated neoplasia pathway where serrated polyps arise as a colorectal cancer has gained considerable attention as a new carcinogenic pathway.... (Review)
Review
In recent years, the serrated neoplasia pathway where serrated polyps arise as a colorectal cancer has gained considerable attention as a new carcinogenic pathway. Colorectal serrated polyps are histopathologically classified into hyperplastic polyps (HPs), sessile serrated lesions, and traditional serrated adenomas; in the serrated neoplasia pathway, the latter two are considered to be premalignant. In western countries, all colorectal polyps, including serrated polyps, apart from diminutive rectosigmoid HPs are removed. However, in Asian countries, the treatment strategy for colorectal serrated polyps has remained unestablished. Therefore, in this review, we described the clinicopathological features of colorectal serrated polyps and proposed to remove HPs and sessile serrated lesions ≥ 6 mm in size, and traditional serrated adenomas of any size.
Topics: Adenoma; Clinical Decision-Making; Colectomy; Colon; Colonic Polyps; Colorectal Neoplasms; Humans; Hyperplasia; Intestinal Mucosa; Narrow Band Imaging; Practice Guidelines as Topic; Precancerous Conditions; Proctectomy; Rectum; Treatment Outcome
PubMed: 32476792
DOI: 10.3748/wjg.v26.i19.2276 -
CA: a Cancer Journal For Clinicians Jul 2018In the United States, colorectal cancer (CRC) is the fourth most common cancer diagnosed among adults and the second leading cause of death from cancer. For this...
In the United States, colorectal cancer (CRC) is the fourth most common cancer diagnosed among adults and the second leading cause of death from cancer. For this guideline update, the American Cancer Society (ACS) used an existing systematic evidence review of the CRC screening literature and microsimulation modeling analyses, including a new evaluation of the age to begin screening by race and sex and additional modeling that incorporates changes in US CRC incidence. Screening with any one of multiple options is associated with a significant reduction in CRC incidence through the detection and removal of adenomatous polyps and other precancerous lesions and with a reduction in mortality through incidence reduction and early detection of CRC. Results from modeling analyses identified efficient and model-recommendable strategies that started screening at age 45 years. The ACS Guideline Development Group applied the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria in developing and rating the recommendations. The ACS recommends that adults aged 45 years and older with an average risk of CRC undergo regular screening with either a high-sensitivity stool-based test or a structural (visual) examination, depending on patient preference and test availability. As a part of the screening process, all positive results on noncolonoscopy screening tests should be followed up with timely colonoscopy. The recommendation to begin screening at age 45 years is a qualified recommendation. The recommendation for regular screening in adults aged 50 years and older is a strong recommendation. The ACS recommends (qualified recommendations) that: 1) average-risk adults in good health with a life expectancy of more than 10 years continue CRC screening through the age of 75 years; 2) clinicians individualize CRC screening decisions for individuals aged 76 through 85 years based on patient preferences, life expectancy, health status, and prior screening history; and 3) clinicians discourage individuals older than 85 years from continuing CRC screening. The options for CRC screening are: fecal immunochemical test annually; high-sensitivity, guaiac-based fecal occult blood test annually; multitarget stool DNA test every 3 years; colonoscopy every 10 years; computed tomography colonography every 5 years; and flexible sigmoidoscopy every 5 years. CA Cancer J Clin 2018;68:250-281. © 2018 American Cancer Society.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; American Cancer Society; Colorectal Neoplasms; Early Detection of Cancer; Humans; Mass Screening; Middle Aged; Risk; United States
PubMed: 29846947
DOI: 10.3322/caac.21457 -
Circulation Aug 2018Heart failure (HF) survival has improved, and nowadays, many patients with HF die of noncardiac causes, including cancer. Our aim was to investigate whether a causal...
BACKGROUND
Heart failure (HF) survival has improved, and nowadays, many patients with HF die of noncardiac causes, including cancer. Our aim was to investigate whether a causal relationship exists between HF and the development of cancer.
METHODS
HF was induced by inflicting large anterior myocardial infarction in APC mice, which are prone to developing precancerous intestinal tumors, and tumor growth was measured. In addition, to rule out hemodynamic impairment, a heterotopic heart transplantation model was used in which an infarcted or sham-operated heart was transplanted into a recipient mouse while the native heart was left in situ. After 6 weeks, tumor number, volume, and proliferation were quantified. Candidate secreted proteins were selected because they were previously associated both with (colon) tumor growth and with myocardial production in post-myocardial infarction proteomic studies. Myocardial gene expression levels of these selected candidates were analyzed, as well as their proliferative effects on HT-29 (colon cancer) cells. We validated these candidates by measuring them in plasma of healthy subjects and patients with HF. Finally, we associated the relation between cardiac specific and inflammatory biomarkers and new-onset cancer in a large, prospective general population cohort.
RESULTS
The presence of failing hearts, both native and heterotopically transplanted, resulted in significantly increased intestinal tumor load of 2.4-fold in APC mice (all P<0.0001). The severity of left ventricular dysfunction and fibrotic scar strongly correlated with tumor growth ( P=0.002 and P=0.016, respectively). We identified several proteins (including serpinA3 and A1, fibronectin, ceruloplasmin, and paraoxonase 1) that were elevated in human patients with chronic HF (n=101) compared with healthy subjects (n=180; P<0.001). Functionally, serpinA3 resulted in marked proliferation effects in human colon cancer (HT-29) cells, associated with Akt-S6 phosphorylation. Finally, elevated cardiac and inflammation biomarkers in apparently healthy humans (n=8319) were predictive of new-onset cancer (n=1124) independently of risk factors for cancer (age, smoking status, and body mass index).
CONCLUSIONS
We demonstrate that the presence of HF is associated with enhanced tumor growth and that this is independent of hemodynamic impairment and could be caused by cardiac excreted factors. A diagnosis of HF may therefore be considered a risk factor for incident cancer.
Topics: Adenomatous Polyps; Adult; Aged; Animals; Anterior Wall Myocardial Infarction; Case-Control Studies; Cell Proliferation; Disease Models, Animal; Female; Genes, APC; HT29 Cells; Heart Failure; Humans; Inflammation Mediators; Intercellular Signaling Peptides and Proteins; Intestinal Neoplasms; Intestinal Polyps; Male; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Prognosis; Risk Assessment; Risk Factors; Signal Transduction; Time Factors; Tumor Burden; Ventricular Remodeling
PubMed: 29459363
DOI: 10.1161/CIRCULATIONAHA.117.030816 -
Science (New York, N.Y.) Feb 2018Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with...
Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of and Genes for colibactin () and toxin (), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with (expressing colibactin), and enterotoxigenic showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.
Topics: Adenomatous Polyposis Coli; Animals; Bacterial Toxins; Bacteroides fragilis; Biofilms; Carcinogenesis; Colon; Colonic Neoplasms; DNA Damage; Escherichia coli; Gastrointestinal Microbiome; Humans; Interleukin-17; Intestinal Mucosa; Metalloendopeptidases; Mice; Peptides; Polyketides; Precancerous Conditions
PubMed: 29420293
DOI: 10.1126/science.aah3648 -
The Lancet. Digital Health Jun 2022Artificial intelligence (AI) tools increase detection of precancerous polyps during colonoscopy and might contribute to long-term colorectal cancer prevention. The aim...
BACKGROUND
Artificial intelligence (AI) tools increase detection of precancerous polyps during colonoscopy and might contribute to long-term colorectal cancer prevention. The aim of the study was to investigate the incremental effect of the implementation of AI detection tools in screening colonoscopy on colorectal cancer incidence and mortality, and the cost-effectiveness of such tools.
METHODS
We conducted Markov model microsimulation of using colonoscopy with and without AI for colorectal cancer screening for individuals at average risk (no personal or family history of colorectal cancer, adenomas, inflammatory bowel disease, or hereditary colorectal cancer syndrome). We ran the microsimulation in a hypothetical cohort of 100 000 individuals in the USA aged 50-100 years. The primary analysis investigated screening colonoscopy with versus without AI every 10 years starting at age 50 years and finishing at age 80 years, with follow-up until age 100 years, assuming 60% screening population uptake. In secondary analyses, we modelled once-in-life screening colonoscopy at age 65 years in adults aged 50-79 years at average risk for colorectal cancer. Post-polypectomy surveillance followed the simplified current guideline. Costs of AI tools and cost for downstream treatment of screening detected disease were estimated with 3% annual discount rates. The main outcome measures included the incremental effect of AI-assisted colonoscopy versus standard (no-AI) colonoscopy on colorectal cancer incidence and mortality, and cost-effectiveness of screening projected for the average risk screening US population.
FINDINGS
In the primary analyses, compared with no screening, the relative reduction of colorectal cancer incidence with screening colonoscopy without AI tools was 44·2% and with screening colonoscopy with AI tools was 48·9% (4·8% incremental gain). Compared with no screening, the relative reduction in colorectal cancer mortality with screening colonoscopy with no AI was 48·7% and with screening colonoscopy with AI was 52·3% (3·6% incremental gain). AI detection tools decreased the discounted costs per screened individual from $3400 to $3343 (a saving of $57 per individual). Results were similar in the secondary analyses modelling once-in-life colonoscopy. At the US population level, the implementation of AI detection during screening colonoscopy resulted in yearly additional prevention of 7194 colorectal cancer cases and 2089 related deaths, and a yearly saving of US$290 million.
INTERPRETATION
Our findings suggest that implementation of AI detection tools in screening colonoscopy is a cost-saving strategy to further prevent colorectal cancer incidence and mortality.
FUNDING
European Commission and Japan Society of Promotion of Science.
Topics: Aged; Aged, 80 and over; Artificial Intelligence; Colonoscopy; Colorectal Neoplasms; Cost-Benefit Analysis; Humans; Mass Screening; Middle Aged
PubMed: 35430151
DOI: 10.1016/S2589-7500(22)00042-5