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The application of immunotherapy for treating colorectal cancer (CRC) is currently a research hotspot, and neoadjuvant immunotherapy has shown initial success in treating CRC. The watch-and-wait (W&W) approach is often used after achieving a clinical complete response (cCR) following preoperative treatment of low rectal cancer. However, thus far, the W&W approach has not been reported for patients with colon cancer. Here, we report the case of a 64-year-old patient with heterogeneous multigenic CRC who achieved cCR after five sessions of neoadjuvant immunotherapy before surgery. A W&W approach was used to spare the patient from surgery. A 64-year-old male presented with intermittent abdominal pain. A colonoscopy examination detected an irregular cauliflower-like mass near the hepatic flexure of the ascending colon. The biopsy results indicated adenocarcinoma of the ascending colon. The patient was administered pembrolizumab (200 mg, ivgtt, q3w). After one cycle of treatment, the intestinal obstruction symptoms disappeared, and the treatment was continued for additional three sessions. After complete clinical remission of the tumor was confirmed, the W&W approach was adopted. Follow-up CT scans and colonoscopy examinations confirmed no local tumor regeneration or metastasis. Neoadjuvant immunotherapy is effective for patients with DNA mismatch repair gene deficiency and/or microsatellite instability high with a high rate of cCR or pathologic complete response. The W&W approach may also be suitable for patients with colon cancer. The safety and feasibility of watch and wait in patients with colon cancer need to be verified by more clinical data. [ABSTRACT FROM AUTHOR]

Mismatch repair proficient (MMRp) tumors of colorectal origin are one of the prevalent yet unpredictable clinical challenges. Despite earnest efforts, optimal treatment modalities have yet to emerge for this class. The poor prognosis and limited actionability of MMRp are ascribed to a low neoantigen burden and a desert-like microenvironment. This review focuses on the critical roadblocks orchestrated by an immune evasive mechanistic milieu in the context of MMRp. The low density of effector immune cells, their weak spatiotemporal underpinnings, and the high-handedness of the IL-17-TGF-b signaling are intertwined and present formidable challenges for the existing therapies. Microbiome niche decorated by Fusobacterium nucleatum alters the metabolic program to maintain an immunosuppressive state. We also highlight the evolving strategies to repolarize and reinvigorate this microenvironment. Reconstruction of anti-tumor chemokine signaling, rational drug combinations eliciting T cell activation, and reprograming the maladapted microbiome are exciting developments in this direction. Alternative vulnerability of other DNA damage repair pathways is gaining momentum. Integration of liquid biopsy and ex vivo functional platforms provide precision oncology insights. We illustrated the perspectives and changing landscape of MMRp-CRC. The emerging opportunities discussed in this review can turn the tide in favor of fighting the treatment dilemma for this elusive cancer. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Despite significant advances in medical treatment, chemotherapy as monotherapy can lead to substantial side effects and chemoresistance. This underscores the need for therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Polyphenols represent a diverse group of natural compounds that can target multiple signaling pathways in cancer cells to induce anti-cancer effects. Additionally, polyphenols have been shown to work synergistically with chemotherapeutics and other natural compounds in cancer cells. This review aims to provide a comprehensive insight into the synergistic mechanisms of selected polyphenols as chemosensitizers in CRC cells. Further research and clinical trials are warranted to fully harness the synergistic mechanisms of selected polyphenols combined with chemotherapy or natural compounds in improving cancer treatment outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: The majority of cases of colorectal cancer occur in those over the age of 65. Treatment of colorectal cancer in older adults warrants specific considerations due to the effects of aging on comorbidities, functional and cognitive status, and socioeconomic factors. Several recent advances have been made to improve oncological outcomes and reduce toxicities with colorectal cancer treatments in both localized and metastatic disease settings. This review highlights the importance of comprehensive geriatric assessment and provides recommendations to guide the management of older adults with colorectal cancer. It summarizes prospective data from recently reported clinical trials focused on older adults. Other recommendations must at times rely on extrapolations and post hoc analyses due to the underrepresentation of older adults in colorectal cancer trials. This review should also, therefore, serve as a call to action for the field to increase the representation of this substantial and often vulnerable group of patients in future colorectal cancer trials. Colorectal cancer (CRC) poses a significant global health challenge. Notably, the risk of CRC escalates with age, with the majority of cases occurring in those over the age of 65. Despite recent progress in tailoring treatments for early and advanced CRC, there is a lack of prospective data to guide the management of older patients, who are frequently underrepresented in clinical trials. This article reviews the contemporary landscape of managing older individuals with CRC, highlighting recent advancements and persisting challenges. The role of comprehensive geriatric assessment is explored. Opportunities for treatment escalation/de-escalation, with consideration of the older adult's fitness level. are reviewed in the neoadjuvant, surgical, adjuvant, and metastatic settings of colon and rectal cancers. Immunotherapy is shown to be an effective treatment option in older adults who have CRC with microsatellite instability. Promising new technologies such as circulating tumor DNA and recent phase III trials adding later-line systemic therapy options are discussed. Clinical recommendations based on the data available are summarized. We conclude that deliberate efforts to include older individuals in future colorectal cancer trials are essential to better guide the management of these patients in this rapidly evolving field. [ABSTRACT FROM AUTHOR]

Simple Summary: In 2020, more than 1.9 million cases of colorectal cancer (CRC) occurred, and almost 0.9 million patients died due to CRC throughout the world. There are differences in distribution and time variations in CRC between different countries. This diversity is mainly due to differences in risk factors among populations. CRC may be prevented by primary and secondary prevention methods. Primary prevention includes avoiding risk factors, e.g., alcohol consumption, and increasing protective factors, e.g., physical activity. The secondary prevention method, called CRC screening, consists of diagnosis and treatment of precancerous lesions of the colorectum. Although a large amount of evidence is available for different aspects of CRC, controversies remain regarding the most important factors and most effective control programs for CRC in different populations. In this review, we will present the most updated evidence regarding CRC's distribution, related factors, and preventive methods. Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer mortality worldwide. There are disparities in the epidemiology of CRC across different populations, most probably due to differences in exposure to lifestyle and environmental factors related to CRC. Prevention is the most effective method for controlling CRC. Primary prevention includes determining and avoiding modifiable risk factors (e.g., alcohol consumption, smoking, and dietary factors) as well as increasing protective factors (e.g., physical activity, aspirin). Further studies, especially randomized, controlled trials, are needed to clarify the association between CRC incidence and exposure to different risk factors or protective factors. Detection and removal of precancerous colorectal lesions is also an effective strategy for controlling CRC. Multiple factors, both at the individual and community levels (e.g., patient preferences, availability of screening modalities, costs, benefits, and adverse events), should be taken into account in designing and implementing CRC screening programs. Health policymakers should consider the best decision in identifying the starting age and selection of the most effective screening strategies for the target population. This review aims to present updated evidence on the epidemiology, risk factors, and prevention of CRC. [ABSTRACT FROM AUTHOR]

The intricate crosstalk of various cell death forms was recently implicated in cancers, laying a foundation for exploring the association between cell death and cancers. Recent evidence has demonstrated that biological networks outperform snapshot gene expression profiles at discovering promising biomarkers or heterogenous molecular subtypes across different cancer types. In order to investigate the behavioral patterns of cell death-related interaction perturbation in colorectal cancer (CRC), this study constructed the interaction-perturbation network with 11 cell death pathways and delineated four cell death network (CDN) derived heterogeneous subtypes (CDN1-4) with distinct molecular characteristics and clinical outcomes. Specifically, we identified a subtype (CDN4) endowed with high autophagy activity and the worst prognosis. Furthermore, AOC3 was identified as a potential autophagy-related biomarker, which demonstrated exceptional predictive performance for CDN4 and significant prognostic value. Overall, this study sheds light on the complex interplay of various cell death forms and reveals an autophagy-related gene AOC3 as a critical prognostic marker in CRC. In colorectal cancer, four cell death subtypes (CDN1-4) are identified, each with distinct traits and prognoses. [ABSTRACT FROM AUTHOR]

The clinical implications of extrachromosomal DNA (ecDNA) in cancer therapy remain largely elusive. Here, we present a comprehensive analysis of ecDNA amplification spectra and their association with clinical and molecular features in multiple cohorts comprising over 13,000 pan-cancer patients. Using our developed computational framework, GCAP, and validating it with multifaceted approaches, we reveal a consistent pan-cancer pattern of mutual exclusivity between ecDNA amplification and microsatellite instability (MSI). In addition, we establish the role of ecDNA amplification as a risk factor and refine genomic subtypes in a cohort from 1015 colorectal cancer patients. Importantly, our investigation incorporates data from four clinical trials focused on anti-PD-1 immunotherapy, demonstrating the pivotal role of ecDNA amplification as a biomarker for guiding checkpoint blockade immunotherapy in gastrointestinal cancer. This finding represents clinical evidence linking ecDNA amplification to the effectiveness of immunotherapeutic interventions. Overall, our study provides a proof-of-concept of identifying ecDNA amplification from cancer whole-exome sequencing (WES) data, highlighting the potential of ecDNA amplification as a valuable biomarker for facilitating personalized cancer treatment. 'Extrachromosomal DNA has been previously linked to tumour progression and heterogeneity, but its potential as a cancer biomarker has not been fully explored. Here, the authors develop a computational framework to refine genomic subtypes and predict response to immunotherapy in gastrointestinal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. Developing liquid biopsies that aid in the detection and monitoring of recurrent CRC may improve clinical management and patient outcomes. In this study, we investigated a serially sampled blood assay of methylated DNA markers (MDMs) in combination with carcinoembryonic antigen as a clinical tool to surveil and monitor recurrent cancer in a prospective cohort of patients who completed curative-intent therapy for CRC. We demonstrated that the MDMs detected recurrent CRC before the clinical or radiographic detection of recurrence. In a small number of patients, we further showed that the MDMs may correlate with the tumor burden. These data highlight the importance of incorporating epigenetic signatures into liquid biopsies and support further research to validate the correlations of circulating tumor DNA with the tumor burden. Background: Radiographic surveillance of colorectal cancer (CRC) after curative-intent therapy is costly and unreliable. Methylated DNA markers (MDMs) detected primary CRC and metastatic recurrence with high sensitivity and specificity in cross-sectional studies. This study evaluated using serial MDMs to detect recurrence and monitor the treatment response to anti-cancer therapies. Methods: A nested case-control study was drawn from a prospective cohort of patients with CRC who completed curative-intent therapy for CRC of all stages. Plasma MDMs were assayed vis target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, and analyzed in combination with serum carcinoembryonic antigen to yield an MDM score. Clinical information, including treatment and radiographic measurements of the tumor burden, were longitudinally collected. Results: Of the 35 patients, 18 had recurrence and 17 had no evidence of disease during the study period. The MDM score was positive in 16 out of 18 patients who recurred and only 2 of the 17 patients without recurrence. The MDM score detected recurrence in 12 patients preceding clinical or radiographic detection of recurrent CRC by a median of 106 days (range 90–232 days). Conclusions: Plasma MDMs can detect recurrent CRC prior to radiographic detection; this tumor-agnostic liquid biopsy approach may assist cancer surveillance and monitoring. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common malignant cancers worldwide and seriously threatens human health. The clustered regulatory interspaced short palindromic repeat/CRISPR-associate nuclease 9 (CRISPR/Cas9) system is an adaptive immune system of bacteria or archaea. Since its introduction, research into various aspects of treatment approaches for CRC has been accelerated, including investigation of the oncogenes, tumor suppressor genes (TSGs), drug resistance genes, target genes, mouse model construction, and especially in genome-wide library screening. Furthermore, the CRISPR/Cas9 system can be utilized for gene therapy for CRC, specifically involving in the molecular targeted drug delivery or targeted knockout in vivo. In this review, we elucidate the mechanism of the CRISPR/Cas9 system and its comprehensive applications in CRC. Additionally, we discussed the issue of off-target effects associated with CRISPR/Cas9, which serves to restrict its practical application. Future research on CRC should in-depth and systematically utilize the CRISPR/Cas9 system thereby achieving clinical practice. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is currently one of the most common tumor types diagnosed worldwide. In the early stages, the disease responds well to surgical and chemotherapeutic treatment, but in the later stages when therapeutic options are exhausted, comprehensive genomic profiling can guide further treatment decisions. We present the case of a 46-year-old man of Ashkenazi Jewish ancestry who was diagnosed with KRAS-mutated metastatic colorectal cancer. After surgery and progression on standard FOLFOX/FOLFIRI + bevacizumab therapy, as well as on Trifluridine/Tipiracil, comprehensive genomic profiling was performed with the hope of expanding therapeutic options. Following comprehensive tumor molecular profiling via NGS, a discussion of the case was discussed at the local molecular tumor board in order to determine further treatment strategy. An activating variant of KRAS and PIK3CA, FLT3 and SRC amplification and damaging TP53 and APC variants were discarded by MTB as potential targetable biomarkers. The BRCA2 p.S1415fs*4 founder frameshift variant was of interest and the patient was included in the clinical trial investigating the efficacy of a PARP inhibitor talazoparib. Unfortunately, the disease progression was detected within one month of talazoparib treatment and the patient died during the 8th cycle of FOLFIRI + bevacizumab therapy rechallenge. [ABSTRACT FROM AUTHOR]

Purpose: Next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients. Patients and Methods: We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS in 107 Saudi Arabian patients without a family history of CRC. Results: Approximately 98% of patients had genetic alterations. Frequent mutations were observed in BRCA2 (79%), CHEK1 (78%), ATM (76%), PMS2 (76%), ATR (74%), and MYCL (73%). The APC gene was not included in the panel. Statistical analysis using the Cox proportional hazards model revealed an unusual positive association between poorly differentiated tumors and survival rates (p = 0.025). Although no significant univariate associations between specific mutations or overall mutation rate and overall survival were found, our preliminary analysis of the molecular markers for CRC in a predominantly Arab population can provide insights into the molecular pathways that play a significant role in the underlying disease progression. Conclusions: These results may help optimize personalized therapy when drugs specific to a patient's mutation profile have already been developed. [ABSTRACT FROM AUTHOR]

Simple Summary: Approximately 20% of colorectal cancer (CRC) cases are diagnosed in individuals under 40, with a severe prognosis due to germline variant accumulation. Many of these variants have been classified as hereditary cancer causative, while others remain poorly researched. The identification of germline variants across different populations is critical for accurate prognosis, treatment, and follow-up. We aimed to identify and predict the functional implications of germline variants using whole-genome sequencing of a Tunisian pedigree with Lynch syndrome CRC risk. Two SNPs/indels were identified in genes with CRC association (MLH1 and PRH1-TAS2R14) and four in genes with non-CRC cancer association (PPP1R13B, LAMA5, FTO, and NLRP14). Three structural variants overlapped genes associated with non-CRC digestive cancer (RELN, IRS2, and FOXP1) and one overlapped RRAS2 with non-CRC cancer associations. This study provides further evidence of genetic predisposition according to the risk clustering of variants based on their functional implications and risk mechanisms within the same pedigree. Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three "variant risk clusters" shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different "variant risk clusters" can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree. [ABSTRACT FROM AUTHOR]

Instruction: Lynch syndrome (LS) is the most common inherited cancer predisposition disorder of colorectal cancer (CRC) which is associated with pathogenic variants in 4 mismatch repair (MMR) genes. Here, we reported a multi-generation Chinese family clinically diagnosed with LS. Methods: To identify the underlying pathogenic gene variants, 30 whole blood samples and 4 colorectal cancer tissue samples and their clinical data were obtained from this four-generation family. Microsatellite instability-high (MSI) testing, immunohistochemistry (IHC), and Whole-Exome Sequencing (WES) were performed to identify the MMR/MSI and the underlying gene variants. The minigene splicing assay and in vitro splicing assay were used to explore the function of this variant. Results: MSI-H and dMMR was revealed by the MSI testing and IHC, Whole-Exome Sequencing (WES) in 3 patients successfully identified a splicing variant (c.793-1G>A) in intron 4 of MSH2. Sanger sequencing validated the WES results, and all the "healthy" individuals carrying the variant have been identified in the family by PCR. Bioinformatics analysis and in vitro minigene assay showed that the pathogenic variant affected the splicing process of MSH2 gene to generate 2 kinds defective transcription products, and consequently reduced the expression of MSH2 protein. The mutation carriers were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years because they both have a higher risk of LS. Discussion: We found a pathogenic splicing variant (rs863225397, c.793-1G>A) of MSH2 gene, and furtherly confirmed that this mutation plays an important role in LS patients of this pedigree based on the vitro study. Our study indicates that one splicing mutation in the MSH2 gene (c.793-1G>A) causes LS and highlights the importance of LS gene testing. [ABSTRACT FROM AUTHOR]

Simple Summary: Lynch syndrome is an autosomal dominant hereditary disease that confers a high risk of developing various types of tumors, especially colorectal and endometrial cancer. In recent years, the molecular mechanisms underlying Lynch syndrome have generated considerable interest. Several studies have highlighted the epiphenomenon of microsatellite instability, caused by a deficit in the ability of cells to repair DNA damage, as a disease-specific feature. The discovery of microRNAs has served to clarify how these small oligonucleotide molecules may contribute to the progression of Lynch syndrome by modulating the expression of several players involved in DNA repair pathways. The purpose of this review is to analyze the management of patients with Lynch syndrome by emphasizing the importance of microRNAs as markers or therapeutics for the development of novel clinical approaches. Lynch syndrome (LS), also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is an autosomal dominant cancer syndrome which causes about 2–3% of cases of colorectal carcinoma. The development of LS is due to the genetic and epigenetic inactivation of genes involved in the DNA mismatch repair (MMR) system, causing an epiphenomenon known as microsatellite instability (MSI). Despite the fact that the genetics of the vast majority of MSI-positive (MSI+) cancers can be explained, the etiology of this specific subset is still poorly understood. As a possible new mechanism, it has been recently demonstrated that the overexpression of certain microRNAs (miRNAs, miRs), such as miR-155, miR-21, miR-137, can induce MSI or modulate the expression of the genes involved in LS pathogenesis. MiRNAs are small RNA molecules that regulate gene expression at the post-transcriptional level by playing a critical role in the modulation of key oncogenic pathways. Increasing evidence of the link between MSI and miRNAs in LS prompted a deeper investigation into the miRNome involved in these diseases. In this regard, in this study, we discuss the emerging role of miRNAs as crucial players in the onset and progression of LS as well as their potential use as disease biomarkers and therapeutic targets in the current view of precision medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Rates of early-onset colorectal cancer (eoCRC), defined as <50 years of age at diagnosis, have increased. Nearly one-quarter of cases of eoCRC may be associated with a germline pathogenic variant (PGV) resulting in a hereditary cancer syndrome. In the present study, we reviewed patients with a history of colorectal cancer who were referred to medical genetics at our institution to better understand the prevalence and spectrum of PGVs in both patients with eoCRC as well as with average-onset CRC (aoCRC). We found that approximately one in four patients with eoCRC had a PGV, which included 8.3% with Lynch syndrome. In patients with aoCRC, similar rates of detection of PGVs were seen. In both groups, approximately one-third of patients referred to medical genetics did not undergo genetic testing. This study reinforces the importance for patients with CRC to undergo genetic testing, especially those with eoCRC. Over the past 20 years, rates of early-onset colorectal cancer (eoCRC), defined as <50 years of age at diagnosis, have increased, with 16–25% associated with a pathogenic germline variant (PGV) resulting in a hereditary cancer syndrome. In the present study, we sought to further characterize PGVs observed in patients with eoCRC. We conducted a retrospective analysis of patients with a history of CRC referred for genetic counseling at Mayo Clinic Rochester between April 2019 and April 2022. Three hundred and three CRC patients were referred to medical genetics, including 124 with a history of eoCRC. Only 84 patients (68%) with eoCRC referred for genetic counseling completed genetic testing, with an average of 48 genes evaluated. PGVs were identified in 27.4% with eoCRC, including 8.3% with Lynch syndrome (LS). Other detected PGVs known to increase the risk of CRC included MUTYH (4.8%), CHEK2 (3.6%), APC, BMPR1A, and TP53 (1.3% each). Among those with aoCRC, 109 patients (61%) completed genetic testing, among which 88% had either a dMMR tumor, personal history of an additional LS malignancy, or family history of LS malignancy, with PGVs detected in 23% of patients. This study reinforces the importance for all patients with CRC, especially those with eoCRC, to undergo germline testing. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, the authors will discuss the highlights of early onset colon cancer (EOCRC), an increasing but still unclear phenomenon. Indeed, the risk factors are largely similar to classic colon cancer (CRC), but it is still unclear what causes an increased risk of CRC at an early age. In addition, the issue of screening, which allows early diagnosis of the disease, is also important; the younger segment of the population is not included in such programs except if they belong to the highest-risk groups. If the phenomenon of EOCRC becomes more prominent, screening programs will have to be reviewed but with consideration of the consequences for health economics. In this review, we will focus on the epidemiological, prognostic, clinico-pathological, molecular, and therapeutic features of EOCRC; in particular, we will try to highlight the characteristics of the metastatic stage and the differences with CRC in older segments of the population. Despite a recent overall decrease in colorectal cancer (CRC) incidence and mortality, there has been a significant rise in CRC diagnoses in young adults. Early onset colorectal cancer (EOCRC) is defined as CRC diagnosed before the age of 50. Possible predisposing conditions include not only genetic syndromes but also other risk factors, such as microbiome alteration, antibiotic exposure, obesity, diabetes mellitus, and inflammatory bowel disease. EOCRC tends to be diagnosed later than in the older counterpart because of a lack of awareness and the fact that screening for CRC usually starts at the age of 50. Furthermore, CRC in young adults seems to be related to unique molecular features and more aggressive clinical behavior. This paper aims to provide an in-depth review of this poorly understood subject, with a comprehensive review of the state of the art and considerations for future perspectives. [ABSTRACT FROM AUTHOR]

Simple Summary: Early-onset colorectal cancer is increasing in incidence in the United States, and it is expected to more than double in the next 10 years. There are many risk factors that lead to the development of early-onset colorectal cancer, including hereditary cancer syndromes, such as Lynch syndrome, obesity, diet, sedentary lifestyle, inflammatory bowel disease and altered microbiome. There is a significant lack of awareness of early-onset colorectal cancer, and the rise in the number of cases indicates that more coordinated efforts are needed to understand and treat early-onset colorectal cancer better, through promoting the benefits of screening, including genetic profiling, and increasing adherence to current screening guidelines. The aim of this review is to discuss the available literature regarding early-onset colorectal cancer to better define the risk factors, histopathology, genetic makeup and management. Over the past decade, the incidence of colorectal cancer has increased in individuals under the age of 50 years. Meanwhile, the incidence has gradually decreased in the older population. As described herein, we reviewed the available literature to summarize the current landscape of early-onset colorectal cancer, including risk factors, clinicopathological presentation, genetic makeup of patients, and management. Currently, early-onset colorectal cancer is treated similarly as late-onset colorectal cancer, yet the available literature shows that early-onset colorectal cancer is more aggressive and different, and this remains a significant unmet need. A detailed understanding of early-onset colorectal cancer is needed to identify risk factors for the increased incidence and tailor treatments accordingly. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment in colorectal cancer (CRC), its impact on the infiltration of immune cells and clinical outcomes in patients with mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC has not been thoroughly investigated. In this study, we examine the expression pattern of cGAS-STING in tumor cells and its effect on the infiltrations of CD8+ and CD4+ T cells, as well as clinical outcomes including survival and recurrence in patients with pMMR/MSS CRC. Our current findings may offer novel insights and therapeutic strategies for patients with pMMR/MSS CRC. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment, thereby contributing to a more favorable response to immune checkpoint inhibitors (ICI) in colorectal cancer (CRC). However, the impact of the expression of cGAS-STING in tumor cells on the infiltration of CD8+ T cells and clinical outcomes in mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC remains largely unknown. Our findings reveal that 56.8% of all pMMR CRC cases were cGAS-negative/STING-negative expressions (cGAS−/STING−) in tumor cells, whereas only 9.9% of all pMMR CRC showed cGAS-positive/STING-positive expression (cGAS+/STING+) in tumor cells. The frequency of cGAS+/STING+ cases was reduced in the advanced stages of pMMR/MSS CRC, and histone methylation might be involved in the down-regulation of STING expression in tumor cells. Since the expression level of cGAS-STING in tumor cells has been associated with the infiltration of CD8+ and/or CD4+ T cells and the frequency of recurrence in pMMR/MSS CRC, decreased expression of cGAS-STING in tumor cells might lead to poor immune cell infiltration and worse prognosis in most pMMR/MSS CRC patients. Our current findings provide a novel insight for the treatment of patients with pMMR/MSS CRC. [ABSTRACT FROM AUTHOR]

Background & Aims: In this retrospective study, we aimed to elucidate how the initial recurrence site influences the post-recurrence survival (PRS) after the curative resection of colorectal cancer. Patients and methods: We collected samples from patients with stage I-III colorectal adenocarcinoma who were admitted to Yunnan Cancer Hospital from January 2008 to December 2019. Four hundred and six patients who developed recurrence after radical resection were included. The cases were classified according to the original site of recurrence as follows: liver metastases (n = 98), lung metastases (n = 127), peritoneum (n = 32), other individual organ (n = 69), two or more organs or sites (n = 49), and local recurrence (n = 31). Kaplan–Meier survival curves were used to compare the PRS of patients with different initial sites of recurrence. The influence of the initial recurrence site on PRS was analyzed using the Cox proportional hazards model. Results: The 3-year PRS of simple liver metastasis was 54.04% (95% CI, 45.46%-64.24%), and the 3-year PRS of simple lung metastasis was 50.05% (95% CI, 42.50%-58.95%). No significant difference was observed between simple liver metastasis or simple lung metastasis and local recurrence with a 3-year PRS of 66.99% (95% CI, 53.23%-84.32%). The 3-year PRS for peritoneal metastases was 25.43% (95% CI, 14.76%-43.82%), and the 3-year PRS for two or more organ sites was 34.84% (95% CI, 24.16%-50.24%). The peritoneal (hazard ratio [HR], 1.75; 95% CI, 1.10–2.79; P = 0.0189) and metastasis to two or more organs or sites (HR, 1.59; 95% CI, 1.05–2.43; P = 0.0304) were PRS-independent adverse prognostic factors. Conclusion: The prognosis of patients with peritoneum and multiple organs or sites recurred was poor. This study suggests early monitoring of peritoneal and multiple organ or site recurrence after surgery. This part of patients should receive comprehensive treatment as early as possible to improve their prognosis. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the deadliest forms of cancer worldwide. CRC development occurs mainly through the adenoma-carcinoma sequence, which can last decades, giving the opportunity for primary prevention and early detection. CRC prevention involves different approaches, ranging from fecal occult blood testing and colonoscopy screening to chemoprevention. In this review, we discuss the main findings gathered in the field of CRC chemoprevention, focusing on different target populations and on various precancerous lesions that can be used as efficacy evaluation endpoints for chemoprevention. The ideal chemopreventive agent should be well tolerated and easy to administer, with low side effects. Moreover, it should be readily available at a low cost. These properties are crucial because these compounds are meant to be used for a long time in populations with different CRC risk profiles. Several agents have been investigated so far, some of which are currently used in clinical practice. However, further investigation is needed to devise a comprehensive and effective chemoprevention strategy for CRC. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the most frequently occurring cancers today, with a large percentage of cases having a hereditary basis. Lynch syndrome is the most common cause of hereditary colorectal cancer. The genetic defect characteristics of this syndrome involve mutations in mismatch repair (MMR) genes, which result in microsatellite instability. Early detection of the mutation can help evaluate the cancer risk and, consequently, a proper course of clinical management for the person harboring the mutation. Herein, we describe the first report of a c.1458dup (p.Glu487*) new mutation in a 53-year-old colorectal cancer patient with diagnosed Lynch syndrome. Additionally, the existence of lipomas in this patient and his family could be related to this syndrome. Further investigation may provide a possible visual clue that can indicate a need for genetic screening. [ABSTRACT FROM AUTHOR]

Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification. Methods: To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (< 20%), intermediate (20–80%), or high PRS (> 80%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22%, compared to 40% and 74% for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26% for non-carriers and 98% for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the most common tumors, and genetic predisposition is one of the key risk factors in the development of this malignancy. Lynch syndrome and familial adenomatous polyposis are the best-known genetic diseases associated with hereditary colorectal cancer. However, some other genetic disorders confer an increased risk of colorectal cancer, such as Li–Fraumeni syndrome (TP53 gene), MUTYH-associated polyposis (MUTYH gene), Peutz–Jeghers syndrome (STK11 gene), Cowden syndrome (PTEN gene), and juvenile polyposis syndrome (BMPR1A and SMAD4 genes). Moreover, the recent advances in molecular techniques, in particular Next-Generation Sequencing, have led to the identification of many new genes involved in the predisposition to colorectal cancers, such as RPS20, POLE, POLD1, AXIN2, NTHL1, MSH3, RNF43 and GREM1. In this review, we summarized the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and into the associated genetic disorders. Furthermore, we discussed the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a highly prevalent disease in developed countries. Inherited Mendelian causes account for approximately 5% of CRC cases, with Lynch syndrome and familial adenomatous polyposis being the most prevalent forms. Scientific efforts are focused on the discovery of new candidate genes associated with CRC and new associations of phenotypes with well-established cancer-related genes. BRCA1-associated ring domain (BARD1) gene deleterious germline variants are associated with a moderate increase in the relative risk of breast cancer, but their association with other neoplasms, such as CRC, remains unclear. Case presentation: We present the case of a 49-year-old male diagnosed with rectal adenocarcinoma whose maternal family fulfilled Amsterdam clinical criteria for Lynch syndrome. Genetic test confirmed the presence in heterozygosis of a germline pathogenic deletion of exons 8–11 in BARD1 gene. The predictive genetic study of the family revealed the presence of this pathogenic variant in his deceased cancer affected relatives, confirming co-segregation of the deletion with the disease. Conclusions: To the best of our knowledge, this is the first published work in which this BARD1 deletion is detected in a family with familial colorectal cancer type X (FCCTX) syndrome, in which the clinical criteria for Lynch syndrome without alteration of the DNA mismatch repair (MMR) system are fulfilled. Whether this incidental germline finding is the cause of familial colorectal aggregation remains to be elucidated in scientific forums. Patients should be carefully assessed in specific cancer genetic counseling units to account for hypothetical casual findings in other genes, in principle unrelated to the initial clinical suspicion, but with potential impact on their health. [ABSTRACT FROM AUTHOR]

Colorectal cancer has proven to be difficult to treat as it is the second leading cause of cancer death for both men and women worldwide. Recent work has shown the importance of microRNA (miRNA) in the progression and metastasis of colorectal cancer. Here, we develop a metric based on miRNA-gene target interactions, previously validated to be associated with colorectal cancer. We use this metric with a regularized Cox model to produce a small set of top-performing genes related to colon cancer. We show that using the miRNA metric and a Cox model led to a meaningful improvement in colon cancer survival prediction and correct patient risk stratification. We show that our approach outperforms existing methods and that the top genes identified by our process are implicated in NOTCH3 signaling and general metabolism pathways, which are essential to colon cancer progression. [ABSTRACT FROM AUTHOR]

Deficient mismatch repair (dMMR)/microsatellite instability (MSI) colorectal cancer (CRC) has high immunogenicity and better prognosis compared with proficient MMR (pMMR)/microsatellite stable (MSS) CRC. Although the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered to contribute to the high number of CD8+ TILs, its role in dMMR/MSI CRC is largely unknown. In this study, to examine the role of the cGAS-STING pathway on the recruitment of CD8+ TILs in dMMR/MSI CRC, we used public datasets and clinical tissue samples in our cohorts to evaluate the expression of cGAS, STING, and CD8+ TILs in pMMR/MSS and dMMR/MSI CRCs. According to the analysis of public datasets, the expression of cGAS-STING, CD8 effector gene signature, and CXCL10-CCL5, chemoattractants for CD8+ TILs which regulated by the cGAS-STING pathway, was significantly upregulated in dMMR/MSI CRC, and the expression of cGAS-STING was significantly associated with the expression of CD8 effector gene signature. Immunohistochemistry staining of the clinical tissue samples (n = 283) revealed that cGAS-STING was highly expressed in tumor cells of dMMR CRC, and higher expression of cGAS-STING in tumor cells was significantly associated with the increased number of CD8+ TILs. Moreover, we demonstrated that the downregulation of MMR gene in human CRC cell lines enhanced the activation of the cGAS-STING pathway. Taken together, for the first time, we found that dMMR/MSI CRC has maintained a high level of cGAS-STING expression in tumor cells, which might contribute to abundant CD8+ TILs and immune-active TME. [ABSTRACT FROM AUTHOR]

One of the first studies to investigate this important question prospectively followed LS carriers getting colonoscopies every 3 years compared with those getting no screening and found that the 3-year screening interval decreased CRC risk and improved overall survival, establishing routine colonoscopy screening as the standard of care ([6]). At present, however, colonoscopy screening remains critical to LS surveillance, CRC risk reduction, and improved outcomes for all LS carriers. Lynch syndrome (LS) is one of the most common hereditary colorectal cancer (CRC) predisposition syndromes and is present in 1 out of 279 individuals in the general population ([1]) and in approximately 3% of unselected cases of CRC ([2]). [Extracted from the article]

Simple Summary: Promoting proper preventive interventions to reduce morbidity and mortality is one of the most important challenges pertaining to inherited conditions. Lynch syndrome (LS) is an inherited disorder that predisposes to several kinds of tumor and is responsible for a relevant proportion of human colorectal and endometrial cancers. Recent knowledge has allowed for a better understanding of the genetic cause, pathogenesis, underlying immunological mechanisms, epidemiological distribution, and prevalence of this disease. This opens up unpredictable perspectives of translating such knowledge into validated programs for prevention and surveillance, in order to reduce the health impact of this disease through medical interventions before cancer development. In our review, we summarize the updated guidelines of the screening, surveillance, and risk-reducing strategies for LS patients. Moreover, we present novel opportunities in the treatment and prevention of LS patients through harnessing the immune system using immunocheckpoint inhibitors and vaccines. Lynch syndrome (LS) is the most common inherited disorder responsible for an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts, caused by a germline pathogenic variant affecting the DNA mismatch repair system. Surveillance and risk-reducing procedures are currently available and warranted for LS patients, depending on underlying germline mutation, and are focused on relevant targets for early cancer diagnosis or primary prevention. Although pharmacological approaches for preventing LS-associated cancer development were started many years ago, to date, aspirin remains the most studied drug intervention and the only one suggested by the main surveillance guidelines, despite the conflicting findings. Furthermore, we also note that remarkable advances in anticancer drug discovery have given a significant boost to the application of novel immunological strategies such as immunocheckpoint inhibitors and vaccines, not only for cancer treatment, but also in a preventive setting. In this review, we outline the clinical, biologic, genetic, and morphological features of LS as well as the recent three-pathways carcinogenesis model. Furthermore, we provide an update on the dedicated screening, surveillance, and risk-reducing strategies for LS patients and describe emerging opportunities of harnessing the immune system. [ABSTRACT FROM AUTHOR]

Understanding the properties of human leukocyte antigen (HLA) peptides (immunopeptides) is essential for precision cancer medicine, while the direct identification of immunopeptides from small biopsies of clinical tissues by mass spectrometry (MS) is still confronted with technical challenges. Here, to overcome these hindrances, high-field asymmetric waveform ion mobility spectrometry (FAIMS) is introduced to conduct differential ion mobility (DIM)-MS by seamless gas-phase fractionation optimal for scarce samples. By established DIM-MS for immunopeptidomics analysis, on average, 42.9 mg of normal and tumor colorectal tissues from identical patients (n = 17) were analyzed, and on average 4921 immunopeptides were identified. Among these 44,815 unique immunopeptides, two neoantigens, KRAS-G12V and CPPED1-R228Q, were identified. These neoantigens were confirmed by synthetic peptides through targeted MS in parallel reaction monitoring (PRM) mode. Comparison of the tissue-based personal immunopeptidome revealed tumor-specific processing of immunopeptides. Since the direct identification of neoantigens from tumor tissues suggested that more potential neoantigens have yet to be identified, we screened cell lines with known oncogenic KRAS mutations and identified 2 more neoantigens that carry KRAS-G12V. These results indicated that the established FAIMS-assisted DIM-MS is effective in the identification of immunopeptides and potential recurrent neoantigens directly from scarce samples such as clinical tissues. An optimized method for mass spectrometry based immunopeptidomics analysis using high-field asymmetric waveform ion mobility spectrometry is presented and identifies 44,815 HLA-bound peptides (HLAp) from colorectal cancer samples. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is a disease that usually shows no evident clinical symptoms in the early stages, often leading to late diagnosis. Over the past few years, a new approach based on liquid biopsy has gained far-reaching applications in less-invasive CRC diagnosis and management, allowing for the use of extracellular nucleic acids as promising biomarkers to detect CRC at an early stage and monitor disease recurrence. That is why an up-to-date review and discussion of in-depth liquid biopsy-derived DNA and RNA biomarkers is essential. We hereby offer an overview of known predisposing genetic factors for developing sporadic and hereditary CRC, and an extensive repertoire of available extracellular DNA/RNA molecules with their potential clinical applications and shortcomings. Our review may be of value to experts dealing with CRC at the molecular level as well as to clinical professionals aiming for a better understanding of state-of-the-art techniques in CRC diagnosis and management. Colorectal cancer (CRC) is the 3rd most common malignant neoplasm worldwide, with more than two million new cases diagnosed yearly. Despite increasing efforts in screening, many cases are still diagnosed at a late stage, when mortality is high. This paper briefly reviews known genetic causes of CRC (distinguishing between sporadic and familial forms) and discusses potential and confirmed nucleic acid biomarkers obtainable from liquid biopsies, classified by their molecular features, focusing on clinical relevance. We comment on advantageous aspects such as better patient compliance due to blood sampling being minimally invasive, the possibility to monitor mutation characteristics of sporadic and hereditary CRC in a disease showing genetic heterogeneity, and using up- or down-regulated circulating RNA markers to reveal metastasis or disease recurrence. Current difficulties and thoughts on some possible future directions are also discussed. We explore current evidence in the field pointing towards the introduction of personalized CRC management. [ABSTRACT FROM AUTHOR]

Objective: Lynch syndrome (LS) pre-screening methods remain under-investigated in colorectal cancers (CRCs) in Asia. Here, we aimed to systematically investigate LS pre-screening and comprehensively characterize LS CRCs. Methods: Microsatellite instability (MSI) and germline variants of DNA mismatch repair (MMR) genes were examined in 406 deficient MMR (dMMR) and 250 proficient MMR CRCs. The genetic differences between LS and sporadic CRCs were studied with whole exome sequencing analysis. Results: The incidence of dMMR in Chinese patients with CRCs was 13.8%. Consistency analysis between MMR immunohistochemistry (IHC) and MSI testing showed the kappa value was 0.758. With next-generation sequencing (NGS), germline variants were detected in 154 CRCs. Finally, 88 patients with CRC were identified as having LS by Sanger sequencing. Among them, we discovered 21 previously unreported pathogenic germline variants of MMR genes. Chinese patients with LS, compared with sporadic CRCs, tended to be early-onset, right-sided, early-stage and mucinous. Overall, the performance of MMR IHC and MSI testing for LS pre-screening was comparable: the area under the ROC curve for dMMR, MSI-H, and MSI-H/L was 0.725, 0.750, and 0.745, respectively. dMMR_MSI-H LS and sporadic CRCs showed substantial differences in somatic genetic characteristics, including different variant frequencies of APC, CREBBP, and KRAS, as well as different enriched pathways of VEGF, Notch, TGFβR, mTOR, ErbB, and Rac protein signal transduction. Conclusions: MMR IHC and MSI testing were effective methods for LS pre-screening. The revealed clinical and somatic genetic characteristics in LS CRCs may have the potential to improve the performance of LS pre-screening in combination with dMMR/MSI. [ABSTRACT FROM AUTHOR]

To date, anticancer immunotherapy has presented some clinical benefits to most of advanced mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC) patients. In addition to MSI status, we aimed to reveal the potential predictive value of adenomatous polyposis coli (APC) gene mutations in CRC patients. A total of 238 Chinese CRC patients was retrospectively identified and analyzed for clinical features and gene alternations in APC-mutant type (MT) and APC-wild-type (WT) groups. Clinical responses were then evaluated from the public TCGA database and MSKCC immunotherapy database. Although programmed cell death ligand 1 (PD-L1) level, MSI status, loss of heterogeneity at the human leukocyte antigen (HLA LOH), and tumor neoantigen burden (TNB) level were not statistically different between the APC-MT group and APC-WT group, tumor mutation burden (TMB) level was significantly higher in APC-MT patients (P < 0.05). Furthermore, comutation analysis for APC mutations revealed co-occurring genomic alterations of PCDHB7 and exclusive mutations of CTNNB1, BRAF, AFF3, and SNX25 (P < 0.05). Besides, overall survival from MSKCC-CRC cohort was longer in the APC-WT group than in the APC-MT group (HR 2.26 (95% CI 1.05–4.88), P < 0.05). Furthermore, most of patients in the APC-WT group were detected as high-grade immune subtypes (C2–C4) comparing with those in the APC-MT group. In addition, the percentages of NK T cells, Treg cells, and fibroblasts cells were higher in APC-WT patients than in APC-MT patients (P < 0.05). In summary, APC mutations might be associated with poor outcomes for immunotherapy in CRC patients regardless of MSI status. This study suggested APC gene mutations might be a potential predictor for immunotherapy in CRC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C

Lynch syndrome (LS) is an autosomal dominant inherited cancer predisposition disorder, which may manifest as colorectal cancer (CRC), endometrial cancer (EC) or other malignancies of the gastrointestinal and genitourinary tract as well as the skin and brain. Its genetic cause is a defect in one of the four key DNA mismatch repair (MMR) loci. Testing of patients at risk is currently based on the absence of MMR protein staining and detection of mutations in cancer tissue and the germline, microsatellite instability (MSI) and the hypermethylated state of the MLH1 promoter. If LS is shown to have caused CRC, lifetime follow-up with regular screening (most importantly, colonoscopy) is required. In recent years, DNA and RNA markers extracted from liquid biopsies have found some use in the clinical diagnosis of LS. They have the potential to greatly enhance the efficiency of the follow-up process by making it minimally invasive, reproducible, and time effective. Here, we review markers reported in the literature and their current clinical applications, and we comment on possible future directions. [ABSTRACT FROM AUTHOR]

Detecting microsatellite instability (MSI) in colorectal cancers (CRCs) is essential because it is the determinant of treatment strategies, including immunotherapy and chemotherapy. Yet, no attempt has been made to exploit transcriptomic profile and tumor microenvironment (TME) of it to unveil MSI status in CRC. Hence, we developed a novel TME-aware, single-transcriptome predictor of MSI for CRC, called MAP (Microsatellite instability Absolute single sample Predictor). MAP was developed utilizing recursive feature elimination-random forest with 466 CRC samples from The Cancer Genome Atlas, and its performance was validated in independent cohorts, including 1118 samples. MAP showed robustness and predictive power in predicting MSI status in CRC. Additional advantages for MAP were demonstrated through comparative analysis with existing MSI classifier and other cancer types. Our novel approach will provide access to untouched vast amounts of publicly available transcriptomic data and widen the door for MSI CRC research and be useful for gaining insights to help with translational medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability. Up to 15–20% of colorectal cancers carry alterations in DDR. However, the role of DDR alterations as a prognostic factor and as a therapeutic target must be elucidated. To date, disappointing results have been obtained in different clinical trials mainly due to poor molecular selection of patients. Several challenges must be overcome before these compounds may have an impact on colorectal cancer. For instance, although some preclinical evidence showed the vulnerability of a subset of CRCs to PARP inhibitors, no specific clinical or molecular biomarkers have been validated to select patients. Moreover, different DDR alterations may not equally confer platinum sensitivity in CRC patients. Further efforts are needed in both preclinical and clinical settings to exploit DDR alterations as therapeutic targets and to eventually discover PARP or other DDR inhibitors (e.g., Wee1) with clinical benefit on colorectal cancer patients. Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15–20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and has the second highest mortality rate globally. Thanks to the advent of next-generation sequencing technologies, several novel candidate genes have been proposed for CRC susceptibility. Germline biallelic mutations in one or more of the 22 currently recognized Fanconi anemia (FA) genes have been associated with Fanconi anemia disease, while germline monoallelic mutations, somatic mutations, or the promoter hypermethylation of some FANC genes increases the risk of cancer development, including CRC. The FA pathway is a substantial part of the DNA damage response system that participates in the repair of DNA inter-strand crosslinks through homologous recombination (HR) and protects genome stability via replication fork stabilization, respectively. Recent studies revealed associations between FA gene/protein tumor expression levels (i.e., FANC genes) and CRC progression and drug resistance. Moreover, the FA pathway represents a potential target in the CRC treatment. In fact, FANC gene characteristics may contribute to chemosensitize tumor cells to DNA crosslinking agents such as oxaliplatin and cisplatin besides exploiting the synthetic lethal approach for selective targeting of tumor cells. Hence, this review summarizes the current knowledge on the function of the FA pathway in DNA repair and genomic integrity with a focus on the FANC genes as potential predisposition factors to CRC. We then introduce recent literature that highlights the importance of FANC genes in CRC as promising prognostic and predictive biomarkers for disease management and treatment. Finally, we represent a brief overview of the current knowledge around the FANC genes as synthetic lethal therapeutic targets for precision cancer medicine. [ABSTRACT FROM AUTHOR]

Background: Stemness refers to the capacities of self-renewal and repopulation, which contributes to the progression, relapse, and drug resistance of colorectal cancer (CRC). Mounting evidence has established the links between cancer stemness and intratumoral heterogeneity across cancer. Currently, the intertumoral heterogeneity of cancer stemness remains elusive in CRC. Methods: This study enrolled four CRC datasets, two immunotherapy datasets, and a clinical in-house cohort. Non-negative matrix factorization (NMF) was performed to decipher the heterogeneity of cancer stemness. Multiple machine learning algorithms were applied to develop a nine-gene stemness cluster predictor. The clinical outcomes, multi-omics landscape, potential mechanisms, and immune features of the stemness clusters were further explored. Results: Based on 26 published stemness signatures derived by alternative approaches, we decipher two heterogeneous clusters, low stemness cluster 1 (C1) and high stemness cluster 2 (C2). C2 possessed a higher proportion of advanced tumors and displayed worse overall survival and relapse-free survival compared with C1. The MSI-H and CMS1 tumors tended to enrich in C1, and the mesenchymal subtype CMS4 was the prevalent subtype of C2. Subsequently, we developed a nine-gene stemness cluster predictor, which robustly validated and reproduced our stemness clusters in three independent datasets and an in-house cohort. C1 also displayed a generally superior mutational burden, and C2 possessed a higher burden of copy number deletion. Further investigations suggested that C1 enriched numerous proliferation-related biological processes and abundant immune infiltration, while C2 was significantly associated with mesenchyme development and differentiation. Given results derived from three algorithms and two immunotherapeutic cohorts, we observed C1 could benefit more from immunotherapy. For patients with C2, we constructed a ridge regression model and further identified nine latent therapeutic agents, which might improve their clinical outcomes. Conclusions: This study proposed two stemness clusters with stratified prognosis, multi-omics landscape, potential mechanisms, and treatment options. Current work not only provided new insights into the heterogeneity of cancer stemness, but also shed light on optimizing decision-making in immunotherapy and chemotherapy. [ABSTRACT FROM AUTHOR]

Background: We report the first case of a patient affected by peritoneal metastases from colon cancer, arising in the context of Lynch syndrome with pathological complete response. The patient was treated with immunotherapy and cytoreductive surgery. This paper discusses the implications of these novel therapies for the management of PM.Case Presentation: A 50-year-old man affected by Lynch syndrome was referred to our institution for metachronous peritoneal recurrence of ascending colon adenocarcinoma. As a second-line treatment, he received Nivolumab therapy with stable disease. Patient underwent cytoreductive surgery with residual disease and a pathological complete response. Flow cytometry described a particular immune sub-population response. There was no evidence of disease progression after nine months.Conclusion: This is the first report of a Lynch patient affected by peritoneal metastases of colorectal cancer, treated with cytoreductive surgery (CRS) and resulting in a pathological complete response after immune checkpoint inhibitors treatment (ICIs). This case report may suggest that patients with peculiar immunological features could benefit from a tailored approach, since "classical" CRS paradigms may not effectively predict the clinical outcome. Further large-scale studies are needed to determine the correct operative management of such patients (tailored or "standard" CRS), defining the correct surgical timing and eventual discontinuation of ICI therapy after surgery. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Metabolic reprogramming represents an important cancer hallmark in CRC. Reprogramming core metabolic pathways in cancer cells, such as glycolysis, glutaminolysis, oxidative phosphorylation, and lipid metabolism, is essential to increase energy production and biosynthesis of precursors required to support tumor initiation and progression. Accumulating evidence demonstrates that activation of oncogenes and loss of tumor suppressor genes regulate metabolic reprogramming through the downstream signaling pathways. Protein kinases, such as AKT and c-MYC, are the integral components that facilitate the crosstalk between signaling pathways and metabolic pathways in CRC. This review provides an insight into the crosstalk between signaling pathways and metabolic reprogramming in CRC. Targeting CRC metabolism could open a new avenue for developing CRC therapy by discovering metabolic inhibitors and repurposing protein kinase inhibitors/monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Background: In China, the prevalence and mortality of colorectal cancer (CRC) have always been high, and more than 95% of CRC cases have evolved from colorectal polyps (CPs), especially adenoma. Early detection and treatment of CPs through colonoscopy is essential to reduce the incidence of CRC. Helicobacter pylori (Hp) is regarded as a risk factor for gastritis and gastric cancer and may also be a risk factor for CPs and CRC. However, few studies based on vast clinical cases exist in China to clarify whether Hp is a risk factor for CPs and CRC, and whether Hp-positive patients need to undergo colonoscopy checks earlier. This article attempts to make up for that deficiency. Method: This cross-sectional study was conducted based on 13,037 patients without a treatment history of Hp who underwent their first gastroscopy and colonoscopy simultaneously at The First Affiliated Hospital of Zhejiang Chinese Medical University from January 2018 to December 2019. Pearson χ2 test and logistic regression were used to determine whether Hp is a risk factor for CPs and CRC. Multifactor analysis of variance was used to define the impact of Hp on CPs prevalence with different ages, sexes. Results: For Chinese individuals, Hp is a risk factor for CPs and CRC. The odds ratio (OR) value are 1.228 (95% CI, 1.130 to 1.336) and 1.862 (95% CI 1.240-2.796), respectively. Hp-positive patients have a higher probability of multiple or large intestinal polyps. However, Hp infection does not increase the incidence of adenomas, nor does it affect the pathological type of adenomas. The OR of Hp on the risk of CPs was 1.432 (95%CI 1.275-1.608) for males but increased to 1.937 (95%CI 1.334-2.815) for those aged 35 to 40. For females, the results were similar. Conclusions: For the Chinese, Hp is a risk factor for CPs and CRC (OR>1); the infection of Hp increased CPs risk in Chinese of all ages, especially aged 35-40, suggesting that Hp-positive patients should undergo colonoscopy frequently. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second-most commonly diagnosed cancer worldwide. Early diagnosis improves prognosis and long-term outcomes. Several studies have found tumor-associated autoantibodies in CRC patients. We aimed to provide an overview on CRC-associated autoantibodies and their reported diagnostic, prognostic, and predictive performance when used singly or in combination. We systematically reviewed studies on CRC-related autoantibodies published till March 2018 and critically analyzed the role of these autoantibodies in CRC. In general, autoantibodies were of low sensitivity when tested individually and the diagnostic characteristics improved when tested in combination. Autoantibodies against CCD83, carcinoembryonic antigen, MAPKAPK3, RPH 3AL, SEC61b, and SPAG9 showed high sensitivity and specificity when tested alone. When tested in combination, autoantibodies against three antigens (PIM1, MAPKAPK3, and ACVR2B) showed high sensitivity and specificity. So far, most CRC-associated autoantibodies have been evaluated in single or in a small number of studies. In contrast, anti-p53 antibodies have been studied in a larger number of CRC studies, but, so far, none of them have high diagnostic characteristics. CRC-associated autoantibodies are detectable from the early stages of malignancy, pointing to their possible use in the early detection of CRC. Some studies suggest that CRC-associated autoantibodies may be a guide to prognosis in CRC. [ABSTRACT FROM AUTHOR]

Familial non-medullary thyroid cancer (FNMTC) is a form of endocrine malignancy exhibiting an autosomal dominant mode of inheritance with largely unknown germline molecular mechanism. Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is another hereditary autosomal dominant cancer syndrome which, if proven to be caused by germline mutations in mismatch repair genes (MMR)— MLHL , MSH2 , MSH6 , PMS2 , and EPCAM —is called Lynch syndrome (LS). LS results in hereditary predisposition to a number of cancers, especially colorectal and endometrial cancers. Tumors in LS are characterized by microsatellite instability (MSI) and/or loss of MMR protein expression in immunohistochemistry (IHC). MSI is a rare event in thyroid cancer (TC), although it is known to occur in up to 2.5% of sporadic follicular TC cases. There are limited data on the role of germline MMR variants FNMTC. The goal of this study was to analyze the potential clinical and molecular association between HNPCC and FNMTC. We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds encompassing 383 participants (104 affected, 279 unaffected), aged 43.5 [7-99] years with FNMTC, and performed high-throughput whole-exome sequencing (WES) of peripheral blood DNA samples of selected 168 participants (54 affected by FNMTC and 114 unaffected). Total affected by thyroid cancer members per family ranged between 2 and 9 patients. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1.0 [0.2-5.0] cm, multifocal growth in 44%, and gross extrathyroidal extension in 11.3%. Central neck lymph node metastases were found in 40.3% of patients at presentation, 12.9% presented with lateral neck lymph node metastases, and none had distant metastases. Family history screening revealed one Caucasian family meeting the clinical criteria for FNMTC and HNPCC, with five members affected by FNMTC and at least eight individuals reportedly unaffected by HNPCC-associated tumors. In addition, two family members were affected by melanoma. Genome Analysis Tool Kit (GATK) pipeline was used in variant analysis. Among 168 sequenced participants, a heterozygous missense variant in the MSH2 gene (rs373226409; c.2120G>A; p.Cys707Tyr) was detected exclusively in FNMTC- HNPCC- kindred. In this family, the sequencing was performed in one member affected by FNMTC, HPNCC-associated tumors and melanoma, one member affected solely by HNPCC-associated tumor, and one member with FNMTC only, as well as seven unaffected family members. The variant was present in all three affected adults, and in two unaffected children of the affected member, under the age of 18 years, and was absent in non-affected adults. This variant is predicted to be damaging/pathogenic in 17/20 in-silico models. However, immunostaining performed on the thyroid tumor tissue of two affected by FNMTC family members revealed intact nuclear expression of MSH2 , and microsatellite stable status in both tumors that were tested. Although the MSH2 p.Cys707Tyr variant is rare with a minor allele frequency (MAF) of 0.00006 in Caucasians; it is more common in the South Asian population at 0.003 MAF. Therefore, the MSH2 variant observed in this family is unlikely to be an etiologic factor of thyroid cancer and a common genetic association between FNMTC and HNPCC has not yet been identified. This is the first report known to us on the co-occurrence of FNMTC and HNPCC. The co-occurrence of FNMTC and HNPCC-associated tumors is a rare event and although presented in a single family in our large FNMTC cohort, a common genetic background between the two comorbidities could not be established. [ABSTRACT FROM AUTHOR]

Background: The effects of adjuvant chemotherapy in patients with stage II colorectal cancer (CRC) has been in controversy for a long time. Our study aimed to find an effective inflammatory marker to predict the effects of chemotherapy.Methods: Seven hundred eight stage II CRC patients in our institution were included. The subpopulation treatment effect pattern plot (STEPP) analysis was used to determine the optimal inflammatory marker and cut-off value. Propensity score matching (PSM) was performed to balance discrepancy between the chemotherapy and non-chemotherapy group. Survival analyses based on overall survival (OS) and cancer-specific survival (CSS) were performed with Kaplan-Meier methods with log-rank test and Cox proportional hazards regression. The restricted mean survival time (RMST) was used to measure treatment effect.Results: The platelet to lymphocyte ratio (PLR) was chosen as the optimal marker with a cut-off value of 130 according to STEPP. In OS analysis, PLR was significantly associated with the effects of chemotherapy (interaction p = 0.027). In the low-PLR subgroup, the chemotherapy patients did not have a longer OS than the non-chemotherapy patients (HR: 0.983, 95% CI: 0.528-1.829). In the high-PLR subgroup, the chemotherapy patients had a significantly longer OS than the non-chemotherapy patients (HR: 0.371, 95% CI: 0.212-0.649). After PSM, PLR was still associated with the effects of chemotherapy. In CSS analysis, PLR was not significantly associated with the effects of chemotherapy (interaction p = 0.116). In the low-PLR subgroup, the chemotherapy patients did not have a longer CSS than the non-chemotherapy patients (HR: 1.016, 95% CI: 0.494-2.087). In the high-PLR subgroup, the chemotherapy patients had a longer CSS than the non-chemotherapy patients (HR: 0.371, 95% CI: 0.212-0.649). After PSM, PLR was not associated with the effects of chemotherapy.Conclusions: PLR is an effective marker to predict the effects of chemotherapy in patients with stage II CRC. [ABSTRACT FROM AUTHOR]

Background: Algorithms that use administrative health and electronic medical record (EMR) data to determine cancer recurrence have the potential to replace chart reviews. This study evaluated algorithms to determine breast and colorectal cancer recurrence in a Canadian province with a universal health care system.Methods: Individuals diagnosed with stage I-III breast or colorectal cancer diagnosed from 2004 to 2012 in Manitoba, Canada were included. Pre-specified and conditional inference tree algorithms using administrative health and structured EMR data were developed. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) correct classification, and scaled Brier scores were measured.Results: The weighted pre-specified variable algorithm for the breast cancer validation cohort (N = 1181, 167 recurrences) demonstrated 81.1% sensitivity, 93.2% specificity, 61.4% PPV, 97.4% NPV, 91.8% correct classification, and scaled Brier score of 0.21. The weighted conditional inference tree algorithm demonstrated 68.5% sensitivity, 97.0% specificity, 75.4% PPV, 95.8% NPV, 93.6% correct classification, and scaled Brier score of 0.39. The weighted pre-specified variable algorithm for the colorectal validation cohort (N = 693, 136 recurrences) demonstrated 77.7% sensitivity, 92.8% specificity, 70.7% PPV, 94.9% NPV, 90.1% correct classification, and scaled Brier score of 0.33. The conditional inference tree algorithm demonstrated 62.6% sensitivity, 97.8% specificity, 86.4% PPV, 92.2% NPV, 91.4% correct classification, and scaled Brier score of 0.42.Conclusions: Algorithms developed in this study using administrative health and structured EMR data to determine breast and colorectal cancer recurrence had moderate sensitivity and PPV, high specificity, NPV, and correct classification, but low accuracy. The accuracy is similar to other algorithms developed to classify recurrence only (i.e., distinguished from second primary) and inferior to algorithms that do not make this distinction. The accuracy of algorithms for determining cancer recurrence only must improve before replacing chart reviews. [ABSTRACT FROM AUTHOR]

Transcriptomic deregulation by epigenetic mechanisms plays a crucial role in the heterogeneous progression of colorectal cancer (CRC). Herein, we first demonstrated that the frequencies of the aberrancies of DNA methylation-correlated (METcor) and microRNA (miRNA)-correlated (MIRcor) genes were significantly co-regulated. Next, through integrative clustering of the expression profiles of METcor and MIRcor genes, four molecular subtypes were identified in CRC patients from The Cancer Genome Atlas and then validated in four independent datasets. More importantly, the four subtypes were well characterized and showed distinct clinical and molecular features: (i) S-I: high metabolic activity, sensitive to 5-fluorouracil-based chemotherapy and good prognosis; (ii) S-II: moderate metabolic activity, marked proliferation, frequent KRAS mutation and intermediate prognosis; (iii) S-III: moderate metabolic activity, marked proliferation, promoter DNA hypermethylation, high mutation burden, frequent BRAF and EGFR mutations, moderate levels of epithelial-mesenchymal transition (EMT) and transforming growth factor β (TGFβ) signals, immune-inflamed phenotype, sensitive to cetuximab and death protein-1 inhibitor treatment and relatively poor prognosis and (iv) S-IV: miRNA overexpression, stem/serrated/mesenchymal-like properties, hypoxia, high levels of EMT and TGFβ signals, immune-excluded phenotype and poor prognosis. Overall, this study established a molecular classification based on epigenetically regulated gene expression profiles, thereby providing a better understanding of the epigenetic mechanisms underlying CRC heterogeneity. [ABSTRACT FROM AUTHOR]

Background: Metabolic reprograming have been associated with cancer occurrence and progression within the tumor immune microenvironment. However, the prognostic potential of metabolism-related genes in colorectal cancer (CRC) has not been comprehensively studied. Here, we investigated metabolic transcript-related CRC subtypes and relevant immune landscapes, and developed a metabolic risk score (MRS) for survival prediction.Methods: Metabolism-related genes were collected from the Molecular Signatures Database and metabolic subtypes were identified using an unsupervised clustering algorithm based on the expression profiles of survival-related metabolic genes in GSE39582. The ssGSEA and ESTIMATE methods were applied to estimate the immune infiltration among subtypes. The MRS model was developed using LASSO Cox regression in the GSE39582 dataset and independently validated in the TCGA CRC and GSE17537 datasets.Results: We identified two metabolism-related subtypes (cluster-A and cluster-B) of CRC based on the expression profiles of 539 survival-related metabolic genes with distinct immune profiles and notably different prognoses. The cluster-B subtype had a shorter OS and RFS than the cluster-A subtype. Eighteen metabolism-related genes that were mostly involved in lipid metabolism pathways were used to build the MRS in GSE39582. Patients with higher MRS had worse prognosis than those with lower MRS (HR 3.45, P < 0.001). The prognostic role of MRS was validated in the TCGA CRC (HR 2.12, P = 0.00017) and GSE17537 datasets (HR 2.67, P = 0.039). Time-dependent receiver operating characteristic curve and stratified analyses revealed the robust predictive ability of the MRS in each dataset. Multivariate Cox regression analysis indicted that the MRS could predict OS independent of TNM stage and age.Conclusions: Our study provides novel insight into metabolic heterogeneity and its relationship with immune landscape in CRC. The MRS was identified as a robust prognostic marker and may facilitate individualized therapy for CRC patients. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is the most malignant complication in patients with Crohn's disease (CD). We report 6 cases of CD-related CRC treated surgically at our hospital. Case presentation: From 2010 to 2016, six CD patients were diagnosed with CRC. All patients were diagnosed with CD at < 25 years old, and the interval from onset of CD to diagnosis of CRC was > 10 years (range, 15–42 years) in all patients. The histological type of cancer was mucinous carcinoma in two cases, well-differentiated tubular adenocarcinoma in two cases, and moderately differentiated tubular adenocarcinoma in two cases. CRC was detected by screening colonoscopy in three cases (50%), and from clinical symptoms in the remaining three cases (50%). Two cases underwent colonoscopy within 2 months after symptom onset, detecting CRC in the relatively early stage. However, one case was diagnosed with advanced-stage CRC by endoscopy 1 year after symptom onset, and experienced poor prognosis. Conclusions: Regular surveillance colonoscopy is needed to detect early-stage CRC in CD patients. Clear surveillance methods need to be established based on evidence. [ABSTRACT FROM AUTHOR]

Background: This multicenter study aimed to reveal the genetic spectrum of colorectal cancer (CRC) with deficient mismatch repair (dMMR) and build a screening model for Lynch syndrome (LS). Methods: Through the immunohistochemical (IHC) screening of mismatch repair protein results in postoperative CRC patients, 311 dMMR cases, whose germline and somatic variants were detected using the ColonCore panel, were collected. Univariate and multivariate logistic regression analysis was performed on the clinical characteristics of these dMMR individuals, and a clinical nomogram, incorporating statistically significant factors identified using multivariate logistic regression analysis, was constructed to predict the probability of LS. The model was validated externally by an independent cohort. Results: In total, 311 CRC patients with IHC dMMR included 95 identified MMR germline variant (LS) cases and 216 cases without pathogenic or likely pathogenic variants in MMR genes (non-Lynch-associated dMMR). Of the 95 individuals, approximately 51.6%, 28.4%, 14.7%, and 5.3% cases carried germline MLH1, MSH2, MSH6, and PMS2 pathogenic or likely pathogenic variants, respectively. A novel nomogram was then built to predict the probability of LS for CRC patients with dMMR intuitively. The receiver operating characteristic (ROC) curve informed that this nomogram-based screening model could identify LS with a higher specificity and sensitivity with an area under curve (AUC) of 0.87 than current screening criteria based on family history. In the external validation cohort, the AUC of the ROC curve reached 0.804, inferring the screening model's universal applicability. We recommend that dMMR-CRC patients with a probability of LS greater than 0.435 should receive a further germline sequencing. Conclusion: This novel screening model based on the clinical characteristic differences between LS and non-Lynch-associated dMMR may assist clinicians to preliminarily screen LS and refer susceptible patients to experienced specialists. [ABSTRACT FROM AUTHOR]

Background: Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC).Methods: An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP).Results: The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma.Conclusions: This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors. [ABSTRACT FROM AUTHOR]