Risk Of Colorectal Carcinoma Research Articles

Analysis of miR-143, miR-1, miR-210 and let-7e Expression in Colorectal Cancer in Relation to Histopathological Features.

Background: MicroRNAs (miRNAs) are small RNA molecules involved in the control of the expression of many genes and are responsible for, among other things, cell death, differentiation and the control of their division. Changes in miRNA expression profiles have been observed in colorectal cancer. This discovery significantly enriches our knowledge of the pathogenesis of colorectal cancer and offers new goals in diagnostics and therapy. Aim: The aim of this study was to analyze the expression of four miRNA sequences—miR-143, miR-1, miR-210 and let-7e—and to investigate their significance in the risk of developing colorectal cancer. Materials and methods: miRNA sequences were investigated in formalin-fixed, paraffin-embedded (FFPE) tissue in colorectal cancer patients (n = 150) and in cancer-free controls (n = 150). The real-time PCR method was used. Results: This study revealed a lower expression of miR-143 in colorectal cancer patients than in the controls. miR-143 was positively correlated with the degree of tumor differentiation (grading). Three out of four analyzed miRNA (miR-1, miR-210 and let-7e) were found to be statistically insignificant in terms of colorectal carcinoma risk. Conclusions: miR-143 may be associated with the development of colorectal cancer.

Kolorektální karcinom u pacientů s diabetes mellitus - epidemiologie, patofyziologie a implikace pro praxi

Diabetes mellitus (type 2 diabetes in particular) and colorectal carcinoma are relatively frequent diseases in our population. At the same time, these units share some common risk factors, for example obesity, lack of physical activity and hyperinsulinemia. Available data show patients with diabetes have increased risk of colorectal adenoma and carcinoma, increased risk of colorectal carcinoma at a lower age, as well as increased risk of relapse and increased mortality with colorectal cancer. The aim of this article is to point out the relationship between diabetes and colorectal carcinoma, with emphasis on the information important for clinical practice, particularly the screening of colorectal carcinoma and lifestyle recommendations for patients with diabetes. Therefore, we offer an overview of the important available publications which consider this topic.

EGFR-Based Targeted Therapy for Colorectal Cancer—Promises and Challenges

Colorectal carcinoma (CRC) is the most lethal and common form of cancer in the world. It was responsible for almost 881,000 cancer deaths in 2018. Approximately 25% of cases are diagnosed at advanced stages with metastasis—this poses challenges for effective surgical control and future tumor-related mortality. There are numerous diagnostic methods that can be used to reduce the risk of colorectal carcinoma. Among these, targeted nanotherapy aims to eliminate the tumor and any metastasis. Active targeting can increase the effectiveness and quantity of drugs delivered to the target site. Antibodies that target overexpressed receptors on cell surfaces and indicators are coupled with drug-loaded carriers. The major target receptors of chemotherapeutic drugs delivery include VEGFR, EGFR, FGFR, HER2, and TGF. On account of its major and diverse roles in cancer, it is important to target EGFR in particular for better tumor selection, as EGFR is overexpressed in 25 to 82% of colorectal carcinoma cases. The EGFR monoclonal immunoglobulins cetuximab/panitumumab can thus be used to treat colorectal cancer. This review examines carriers that contain cetuximab-conjugated therapeutic drugs as well as their efficacy in anticancer activities.

Clinicopathological characteristics of colorectal serrated polyposis syndrome (SPS): results of a multicenter study by the SPS Study Group in Japan

Serrated polyposis syndrome (SPS), a type of colorectal polyposis characterized by multiple serrated polyps, is associated with a high risk of colorectal carcinoma (CRC). This study aimed to clarify the clinicopathological characteristics of SPS in Japan. We investigated the clinicopathological characteristics of patients with SPS from the "Multicenter Study on Clinicopathological Characteristics of SPS (UMIN 000032138)" by the Colorectal Serrated Polyposis Syndrome (SPS) Study Group. In this study, patients were diagnosed with SPS based on the 2019 World Health Organization (WHO) SPS diagnostic criteria. Ninety-four patients were diagnosed with SPS in 10 institutions between January 2001 and December 2017. The mean number (± standard deviation [SD]) of resected lesions per patient was 11.3 ± 13.8. The mean age at diagnosis of SPS was 63.3 ± 11.6years, and 58 patients (61.7%) were male. Eighty-seven (92.6%) and 16 (17.0%) patients satisfied WHO diagnostic criteria I and II, respectively. Nine patients (9.6%) satisfied both criteria I and II. Carcinoma (T1-T4) were observed in 21 patients (22.3%) and 24 lesions. Of the 21 patients with CRC, 19 (90.4%) satisfied diagnostic criterion I, 1 (4.8%) satisfied diagnostic criterion II, and 1 (4.8%) satisfied diagnostic criteria I and II. There was no notable difference in the prevalence of CRC among patients who met diagnostic criterion I, II, and both I and II. Patients with SPS have a high risk of CRC and should undergo regular surveillance colonoscopy. Raising awareness of this syndrome is crucial.

Mutational analysis of driver genes defines the colorectal adenoma: in situ carcinoma transition

A large proportion of colorectal carcinomas (CRC) evolve from colorectal adenomas. However, not all individuals with colonic adenomas have a risk of CRC substantially higher than those of the general population. The aim of the study was to determine the differences or similarities of mutation profile among low- and high-grade adenomas and in situ carcinoma with detailed follow up. We have investigated the mutation spectrum of well-known genes involved in CRC (such as APC, BRAF, EGFR, NRAS, KRAS, PIK3CA, POLE, POLD1, SMAD4, PTEN, and TP53) in a large, well-defined series of 96 adenomas and in situ carcinomas using a high-throughput genotyping technique. Besides, the microsatellite instability and APC and MLH1 promoter methylation were studied as well. We observed a high frequency of pathogenic variants in the studied genes. The APC, KRAS and TP53 mutation frequencies were slightly lower in adenoma samples than in in situ carcinoma samples. Further, when we stratified mutation frequency based on the grade, the frequency distribution was as follows: low-grade adenoma—high-grade adenomas—in situ carcinoma: APC gene 42.9–56.0–54.5%; KRAS gene 32.7–32.0–45.5%; TP53 gene 8.2–20.0–18.2%. The occurrence of KRAS mutation was associated with the presence of villous histology and methylation of the APC promoter was significantly associated with the presence of POLE genetic variations. However, no association was noticed with the presence of any singular mutation and occurrence of subsequent adenoma or CRC. Our data supports the multistep model of gradual accumulation of mutations, especially in the driver genes, such as APC, TP53 and KRAS.

Identifying GNG4 might play an important role in colorectal cancer TMB.

Colorectal carcinoma (CRC) is one of the most leading cause of cancer death all over the world. The tumor immune microenvironment is illustrated to be necessary for the progress of CRC. And the accumulating evidence indicated that tumor mutation burden (TMB) is effective in differentiating responding population of immune checkpoint inhibitor (ICI) therapies in various cancers. In this study, we aimed to evaluated the potential relationship between TMB and the recurrence risk of CRC. The transcriptomic and clinical data of CRC patients were collected from The Cancer Genome Atlas (TCGA) database (n= 382). Then the genomic analysis of tumor mutation burden and tumor purity were conducted by a computational method based on transcriptomic data. Firstly, we accessed the distribution of TMB and preferences at the gene and mutation level using somatic mutation data from TCGA data about CRC. We identified that high TMB predicted better prognosis of CRC patients. Secondly, the differentially expressed genes (DEGs) between the low TMB and high TMB group was clarified. Then the protein-protein interaction (PPI) analysis was performed, and the results confirmed ten hub genes among the DEGs. Utilizing the GEPIA web-tool, we discovered that GNG4 was up-regulated in tumor tissues, and GNG4 was related to the overall survival (OS) and tumor free survival (TFS) of CRC patients. Therefore, we considered GNG4 was essential for the tumor immune microenvironment of CRC. Furthermore, we also accessed the protein level of GNG4 in CRC and liver metastases from CRC. In this study, GNG4 was demonstrated to be the key element of the CRC TMB, which will be essential for the ICI therapy of CRC. Besides, GNG4 was up-regulated in CRC and liver metastases from CRC tissues. Thus, we thought that GNG4 might play an important role in colorectal cancer TMB and induce its metastasis in liver.

The role of appendectomy and cholecystectomy in the pathogenesis of colorectal carcinomas

BackgroundSeveral alterations in the gastrointestinal tract which occur after appendectomy or cholecystectomy have been suggested to raise the risk of developing colorectal carcinoma. Given the frequency that these procedures are performed, we sought to determine whether a history of either cholecystectomy or appendectomy increased the risk of future colorectal carcinoma. MethodsWe determined the number of patients with a history of appendectomy and cholecystectomy who developed colorectal carcinoma between January 2018 and February 2021, as well as the latency time between the two diseases. Secondly, we carried out a data-collection spanning 15 years after the primary surgery (January 2005–December 2006). ResultsThe post-cholecystectomy state is significantly more frequently observed in patients treated for colorectal carcinomas (both male and female), especially among those who developed right-sided or left-sided colon cancer, as opposed to anorectal cancer (p = 0.53). However, the time elapsed between the two diseases is 20–25 years, which appears to be markedly long regarding such a multifactorial disease as the colorectal carcinoma. No similar extra risk was observed among patients having appendectomy. Secondly, we found no extra risk during the first 15 years after cholecystectomy. ConclusionAlthough a statistically higher risk of colon cancer is observed after the removal of the gallbladder, but the latency time is long. Thus, cholecystectomy may not be an independent risk factor for colorectal carcinogenesis. Altogether, the patient is not exposed to a higher risk of colorectal carcinogenesis after having cholecystectomy.

Symptoms, diagnostic and therapy of perianal disease in patients with inflammatory bowel diseases

Symptoms, diagnostic and therapy of perianal disease in patients with inflammatory bowel diseases Abstract. Inflammatory bowel diseases (IBD) frequently affect the perianal region. Due to the great functional importance of the anorectum, this frequently results in a significant burden of disease for the patient. For assessment of perianal IBD symptoms, the clinical history is of great importance. Often, anorectal symptoms are not reported spontaneously by patients, and a respectful direct conversation remains crucial. More than 30 % of patients with Crohn's disease (CD) will develop perianal fistulas. Perianal fistulas can be further characterized by endoscopic ultrasound, MRI, and investigation under anesthesia. These investigations provide complementary information. Fistula therapy is based on symptoms; the short-term goal is improvement of pain and secretion; the long-term goal of treatment remains fistula closure. However, preservation of the anal sphincter is of utmost importance and incontinence needs to be avoided. Antibiotics and/ or seton drainage are the mainstay for acute fistula treatment. The anti-tumor necrosis factor antibody infliximab can improve fistula symptoms, as demonstrated in a randomized controlled study. Surgical fistula closure is only possible in a clinically stable situation without rectal inflammation or other symptoms of active CD. Several surgical strategies exist including 1) fistulotomy, 2) disconnection of the fistula, 3) filling of the fistula tract and 4) fistula ablation. The optimal strategy needs to be decided on an individual basis. Intraoperative application of mesenchymal donor stem cells into the fistula tract and surrounding tissue is possibly the most effective fistula therapy. Due to the significant logistic effort, this therapy is only available in a few selected centers. Currently, stem cell therapy for CD fistulas is limited to patients with no more than two external fistula openings. The therapy of fissures and hemorrhoids in IBD patients is similar to patients without intestinal inflammation; however, due to a high rate of complications, surgery should be avoided whenever possible in CD patients. Incontinence is a frequent problem in IBD patients leading to highly relevant restrictions in daily life. Therapy is directed against intestinal inflammation but also comprises measures for normalization of stool consistency and intestinal motility. However, there are no IBD-specific concepts for the treatment of incontinence. Functional intestinal diseases are frequent in IBD patients and can contribute to urge and incontinence. Some IBD patients might benefit from anorectal physiotherapy. IBD patients have an increased risk for colorectal carcinoma, fistula carcinoma and possibly also anal carcinoma. Therefore, malignancy needs to be excluded at reasonable intervals.

MDR1 C3435T POLYMORPHISM: A PRELIMINARY STUDY ON ITS RELATIONSHIP WITH THE RISK OF COLORECTAL CANCER

Objective: Colorectal carcinoma (CRC) is the third most frequent cancer in the world and a heterogenious disease which aroze from one or a combination of different genetic mechanisms. The multiple drug resistance-1 (MDR1) gene which encodes P-glycoprotein (P-gp) plays a part in the bioavailability of drugs and cell toxicity. In the current study, we aimed to investigate the possible relation between the MDR1 gene C3435T polymorphism and CRC risk in the Turkish population. Material and Methods: Forty three patients (26 men, 17 women) with CRC and 48 healthy controls (34 men, 14 women) were included in the study. The MDR1 C3435T genotypes were determined by the Restriction Fragment Length Polymorphism (RFLP) method. Results: Statistical significance was obtained in terms of genotype distributions of MDR1 C3435T genotypes between study groups. The frequencies of MDR1 C3435T CC, TT and CT genotypes in the CRC patient group were found as 16.3%, 32.6% and 51.2%, respectively. The frequency of the homozygous TT genotype was found as 32.6% in CRC patients while it was identified as 14.6% in controls (p=0.04; OR=2.82, 95% CI: 1.01-7.87). When the patients were compared with the healthy population, TT genotype carriers of MDR1 C3435T polymorphism were found at 2.8-fold (p<0.05 ) increased risk for the development of CRC. Conclusion: Our results show that the MDR1 C3435T polymorphism might be one of the genetic risk factors for CRC development in the Turkish population.

Abstracts and Case Studies for the College of American Pathologists 2021 (CAP21) Annual Meeting

Abstracts and Case Studies for the College of American Pathologists 2021 (CAP21) Annual Meeting

The Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies

Primary sclerosing cholangitis (PSC) is an immune-related cholangiopathy characterized by biliary inflammation, cholestasis, and multifocal bile duct strictures. It is associated with high rates of progression to end-stage liver disease as well as a significant risk of cholangiocarcinoma (CCA), gallbladder cancer, and colorectal carcinoma. Currently, no effective medical treatment with an impact on the overall survival is available, and liver transplantation is the only curative treatment option. Emerging evidence indicates that gut microbiota is associated with disease pathogenesis. Several studies analyzing fecal and mucosal samples demonstrate a distinct gut microbiome in individuals with PSC compared to healthy controls and individuals with inflammatory bowel disease (IBD) without PSC. Experimental mouse and observational human data suggest that a diverse set of microbial functions may be relevant, including microbial metabolites and bacterial processing of pharmacological agents, bile acids, or dietary compounds, altogether driving the intrahepatic inflammation. Despite critical progress in this field over the past years, further functional characterization of the role of the microbiota in PSC and related malignancies is needed. In this review, we discuss the available data on the role of the gut microbiome and elucidate important insights into underlying pathogenic mechanisms and possible microbe-altering interventions.

Immunohistochemical and Molecular Studies of p53 and KRAS Protein and Their Relations to Colorectal Carcinoma

The study inc1uded 50 tissue blocks embedded in paraffin wax (16 females and 34 males), obtained from a patients group with (CRC) colorectal cancer , as well as 35 Tissue blocks that were embedded in paraffin wax from norma1 co1on (ulcerative co1itis) as controls. A relatively few oncogenes and most prominently tumor-suppressing genes, Kirastien rat sarcoma virus (KRAS), and P53 genes have been mutated into a significant part of CRCs, and a broad collection of mutated genes has been defined in CRC subsets. Current findings showed very significant differences between patients and control subjects in the p53 positive rate (P<0.001). TP53 Pro/Pro genotype positivity was higher in the contro1 group I than in the patient group I and this was a significant difference (Pi<0.001) with an odd ratio of less than one. The genotype Pro/Pro was considered to be protective against colorectal carcinoma preventively fractured 0.767. The positive rate of p53 Arg/Arg genotype in patients was more frequent and statistically significant (P <0.01), because the odd ratio was more than one. The genotype Arg/Arg would be considered a colorectal carcinoma risk factor. We conclude that p53 over expression is used as an indicator of p53 mutation (as identified by immuno-historic chemistry) and KRAS protein expression was negatively impaired for all the patients in the current study.

ID: 3521920 CLINICOPATHOLOGICAL CHARACTERISTICS OF SERRATED POLYPOSIS SYNDROME: RESULTS OF A MULTICENTER STUDY BY THE COLORECTAL SERRATED POLYPOSIS SYNDROME (SPS) STUDY GROUP IN JAPAN

Serrated polyposis syndrome (SPS) is one of the colorectal polyposis, characterized by the occurrence of multiple serrated lesions.SPS is known to have a higher risk of colorectal carcinoma (CRC). The aim of this study was to clarify the clinicopathological characteristics of SPS in Japan.

Malignancies in spondyloarthritis with and without concomitant psoriasis, and the effect of disease modifying anti-rheumatic drugs.

To determine the risk of 6 types of malignancies in spondyloarthritis (SpA) with and without psoriasis (PsO) and on disease-modifying anti-rheumatic drugs (DMARDs), compared to non-specific back pain (NSBP). Medical records were retrieved. Patients with SpA with and without PsO were identified and compared to those with NSBP. Clinical data; follow-up duration; comorbidities; dates and types of cancer diagnosed; types and duration of DMARD therapy were collected. Propensity score adjustment was used to compare the risks of malignancies between SpA, SpA with and without PsO, and NSBP. Cox regression analysis was used to determine the risk of malignancy in DMARD therapy. A total of 3020 patients with SpA and 2527 patients with NSBP were studied. The mean follow-up duration in patients with SpA and NSBP was 9.6 years and 13.5 years respectively. Incidence and risk of malignancies were compatible between SpA and NSBP. The incidences of various carcinomas (per 1000 patient-years) in SpA were: 1.37 for colorectal carcinoma; 0.30 for carcinoma of pancreas; 0.30 for carcinoma of stomach; and 0.91 for lymphomas. Risk of colorectal carcinoma (HR 2.46; p=0.03) and lymphomas (HR 2.86; p=0.04) was increased in SpA with concomitant PsO. DMARD therapy was not associated with increased risks of malignancies after adjustment for confounding factors. Risk of malignancy was increased in SpA with PsO but not in other subtypes of SpA or DMARD therapy.

Study of the relation between the colorectal neoplasm and visceral fat accumulation in postmenopausal women

ObjectiveThis study aimed to show the relation ship between colorectal carcinoma (CRC) and visceral adiposity in Egyptian postmenopausal women.BackgroundObesity is known to be an important risk factor for CRC, especially in women. The risk of CRC is greater with the visceral fat accumulation not total body fat content.Patients and methodsThis case–control study included 90 postmenopausal female patients: 45 women with CRC, 20 women with colorectal polyps, and 25 healthy women. Data were collected and statistically analyzed. CRC was diagnosed by colonoscopy and histopathology. Metabolic parameters were assessed according to the BMI and the waist to hip ratio.ResultsVisceral fat was significantly higher in patients with CRC and colorectal polyps compared with the control group. The prevalence of CRC increased with increasing visceral fat content. The study showed that 37 (82.2%) patients with CRC were obese [19 (42.2%) of these patients were overweight and 18 (40%) were obese class I and class II]. Also, 19 (95%) patients with colorectal polyps were obese [11 (55%) of these patients were overweight and eight (40%) patients were obese class I and class II].ConclusionVisceral fat area is highly associated with CRC.

Differentiating Colorectal Carcinoma From Diverticulitis With Computerised Tomography: Does Every Patient Need Follow-Up Colonoscopy After an Episode of Acute Diverticulitis?

PurposeTo correlate computerised tomography (CT) and endoscopic follow-up (FU) in differentiating presentations of acute diverticulitis (AD) and colorectal carcinoma (CRC).MethodsPatient’s discharge summaries between April 2018 and September 2019, stating AD under-diagnosis were retrieved. Admission details, CT reports, endoscopic findings and histopathology results were retrospectively collected from prospectively maintained data.ResultsIn our study period of 17 months, we identified 150 patients with an admission diagnosis of AD. In total, 134 patients had a CT confirmed diagnosis of AD; 61% had uncomplicated acute diverticulitis (UAD) and 39% complicated acute diverticulitis (CAD). The mean age of the patients was 64 years, and 59% were female. Of the 134, 15 patients were excluded, and 119 with AD were discharged with a plan to have FU endoscopy. Overall, 75% of the patients managed to undergo complete endoscopic investigation, 4% had incomplete endoscopy, and 21% failed to attend endoscopy. Follow-up (FU) endoscopic investigation found polyps in 20 patients; seven were reported as tubular adenomas with low-grade dysplasia and 10 as non-concerning hyperplastic or sessile polyps. One was inflammatory, and two were malignant. CT scans for two patients with malignant polyps were reported as CAD with suspicion of sigmoid cancer in one and right-sided perforated diverticulitis in the other. Both patients were female aged over 60 years.ConclusionsThis study demonstrates that a selective approach is more appropriate for endoscopic FU after an episode of AD. Risk stratification is required to allocate FU endoscopic investigation for patients at high risk for CRC.

The Health Benefits of Dietary Fibre.

Background: Dietary fibre consists of non-digestible forms of carbohydrate, usually as polysaccharides that originate from plant-based foods. Over recent decades, our diet within Westernised societies has changed radically from that of our hominid ancestors, with implications for our co-evolved gut microbiota. This includes increased ingestion of ultra-processed foods that are typically impoverished of dietary fibre, and associated reduction in the intake of fibre-replete plant-based foods. Over recent decades, there has been a transformation in our understanding of the health benefits of dietary fibre. Objective: To explore the current medical literature on the health benefits of dietary fibre, with a focus on overall metabolic health. Data Sources: We performed a narrative review, based on relevant articles written in English from a PubMed search, using the terms ‘dietary fibre and metabolic health’. Results: In the Western world, our diets are impoverished of fibre. Dietary fibre intake associates with overall metabolic health (through key pathways that include insulin sensitivity) and a variety of other pathologies that include cardiovascular disease, colonic health, gut motility and risk for colorectal carcinoma. Dietary fibre intake also correlates with mortality. The gut microflora functions as an important mediator of the beneficial effects of dietary fibre, including the regulation of appetite, metabolic processes and chronic inflammatory pathways. Conclusions: Multiple factors contribute to our fibre-impoverished modern diet. Given the plethora of scientific evidence that corroborate the multiple and varied health benefits of dietary fibre, and the risks associated with a diet that lacks fibre, the optimization of fibre within our diets represents an important public health strategy to improve both metabolic and overall health. If implemented successfully, this strategy would likely result in substantial future health benefits for the population.

Increased risk of preneoplastic colonic lesions and colorectal carcinoma in acromegaly: multicenter case-control study.

Current international guidelines recommend colonoscopy in patients with acromegaly at the time of diagnosis, even though the risk of developing colorectal neoplasm is still controversial. The main objective of this Argentine multicenter study was to analyze through screening colonoscopy the presence of advanced neoplastic lesions considered as precancerous, in patients with acromegaly compared to a control group. This is a case-control retrospective study. Full length colonoscopy of 70 acromegalic patients and 128 control subjects were studied. Polyps were classified into non pre-cancerous lesions and advance neoplastic lesions which included advanced adenomas (preneoplastic) and colorectal carcinomas. Thirty three out of 70 acromegalic patients and 32 out of 128 subjects controls presented polyps in the colonoscopy [47.1% vs 25%, p = 0.002, OR 2.68]. Non precancerous polyps were found in 11 (15.7%) and 23 (17.9%) (p = 0.690), while advanced neoplastic lesions were found in 22 (31.4%) and 9 (7.0%) (p = 0,0001 - OR: 6.06) patients and controls respectively. Advanced adenomas and colorectal carcinomas were found in 18 (27.3%) and 9 (7.0%) (p = 0,0006-OR: 4,57), and 4 (5.7%) and 0 (0.0%) p = 0.0063) of patients and controls respectively. The presence of insulin resistance was the only statistically significant associated factor among acromegalic patients with and without colonic polyps. Our findings show an increased risk of preneoplastic colonic lesions and colorectal carcinoma in patients with chronic and sustained GH excess compared to a control group. This supports the recommendation to perform screening colonoscopy at diagnosis of acromegaly.

Universal tumor screening for lynch syndrome: perspectives of patients regarding willingness and informed consent.

Aim: Lynch Syndrome is associated with a significant risk of colorectal carcinoma (CRC) and other cancers. Universal tumor screening is a strategy to identify high-risk individuals by testing all CRC tumors for molecular features suggestive of Lynch Syndrome. Patient interest in screening and preferences for consent have been underexplored. Methods: A postal survey was administered to CRC patients in a Canadian province. Results: Most patients (81.4%) were willing to have tumors tested if universal tumor screening were available and were willing to discuss test results with family members and healthcare professionals. The majority (62.6%) preferred informed consent be obtained prior to screening. Conclusion: Patients were supportive of universal screening. They expected consent to be obtained, contrary to current practice across Canada and elsewhere.

Abstract 1134: Developing an early expression-based signature to assess interval colorectal carcinoma risk

Abstract Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer mortality in the developed world including Singapore. Despite an aging populace which is now more compliant to having a baseline colonoscopy at age 50 or earlier, interval cancer (cancer that develops in between colonoscopies) is an unmet critical problem. The identification of early driver genes that can serve as biomarkers for CRC risk will aid in clinical management decision to counter cancer-associated mortality and morbidity. We profiled the genome-wide expression of matched mucosa (M), mucosa next to tumor (MT) and tumor (T) samples of a series of 23 patients using Affymetrix Gene Array. M samples are at least 20 cm away from the tumor and MT samples are adjoining the T samples but maintained the normal colonic crypt architecture of M. We discovered that thirty-nine dysregulated genes in MT samples compared to M samples persists until tumor formation. These early driver genes comprise not only tumor suppressors or oncogenes but included metabolic and transporter genes indicating that transformation towards malignancy requires the disruption of many pathways. Majority of these genes were down-regulated; the top three most drastically down-regulated genes include AQP8 (a water transporter), CA7 (a metabolic gene) and PHLPP2 (a tumor suppressor). Further analysis indicates that the three genes were already down-regulated in the normal appearing mucosa of a ‘healthy' individual compared to age-, gender-, ethnicity-matched (AGE-) controls seven years before recto-sigmoid cancer was diagnosed. This suggests that the dysregulation can occur several years before tumor formation and hence could possibly be used as early or pre-cancer biomarker. We have validated the down-regulation of the 3 genes in an independent series of 135 CRC samples from the same center using real-time RT-PCR assays. Correlation of the expression with clinicopathological features of the patients (gender, tumor site, age-group) and molecular subtypes (CMS 1-4) of the tumors will be ascertained to assess whether the signature is applicable to all CRC subtypes. Furthermore, the expression in matched blood samples will also be determined to explore feasibility of using these samples for assessing interval colorectal carcinoma risk. Citation Format: Peh Yean Cheah, Lai Fun Thean, Kuen Kuen Lam, Soo Chin Liew, Michelle Wong, Nicholas Koh, Michelle Lo, Emile Tan, Choong Leong Tang. Developing an early expression-based signature to assess interval colorectal carcinoma risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1134.