Molecular Features Of Colorectal Cancer Research Articles

Right vs. Left colorectal cancer – Where do we draw the line?

PurposeNo consensus on the definition of right and left colorectal cancer (CRC) exists, nor studies offering histological or molecular basis for such categorisation. This study investigated the regional variations in the histological and molecular characteristics of CRCs, with the objective of determining an optimal division point between right and left CRCs. Materials and methodsAn observational study of consecutive patients who underwent CRC resection (1995–2022) at Concord Hospital, Sydney was performed. Clinicopathological data were extracted from a prospective database and seven permutations of right-left divisions considered. Logistic regression tested association between the right-left divisions and pathological characteristics. Receiver operating characteristic and area under the curve (AUC) analyses determined the discriminative ability of each division to predict 18 pathology characteristics. Results3753 patients underwent a CRC resection (2120 male; mean 69.5yrs [SD12.6]). There was regional variation in tumours with respect to tumour infiltrating lymphocytes (TILs), mismatch repair deficiency (dMMR), and mutant BRAF (mBRAF). Left-sided tumours were less likely to demonstrate TILs (P < 0.001), be dMMR (P < 0.001), and express mBRAF (P < 0.001). Division at the descending-sigmoid junction yielded highest discriminative abilities: TILs – AUC 0.66, dMMR – AUC 0.76, and mBRAF – AUC 0.73. ConclusionThis is the first study to provide a pathological basis on which right- and left-sided cancers may be defined, and found the optimal division point between the right and left colorectum to be at the descending-sigmoid junction. Further research is needed to determine whether this can facilitate individualised patient management.

Comprehensive Proteogenomic Profiling Reveals the Molecular Characteristics of Colorectal Cancer at Distinct Stages of Progression.

Colorectal cancer is the second most common malignant tumor worldwide. Analysis of the changes that occur during colorectal cancer progression could provide insights into the molecular mechanisms driving colorectal cancer development and identify improved treatment strategies. In this study, we performed an integrated multiomic analysis of 435 trace tumor samples from 148 patients with colorectal cancer, covering nontumor, intraepithelial neoplasia (IEN), infiltration, and advanced stage colorectal cancer phases. Proteogenomic analyses demonstrated that KRAS and BRAF mutations were mutually exclusive and elevated oxidative phosphorylation in the IEN phase. Chr17q loss and chr20q gain were also mutually exclusive, which occurred predominantly in the IEN and infiltration phases, respectively, and impacted the cell cycle. Mutations in TP53 were frequent in the advanced stage colorectal cancer phase and associated with the tumor microenvironment, including increased extracellular matrix rigidity and stromal infiltration. Analysis of the profiles of colorectal cancer based on consensus molecular subtype and colorectal cancer intrinsic subtype classifications revealed the progression paths of each subtype and indicated that microsatellite instability was associated with specific subtype classifications. Additional comparison of molecular characteristics of colorectal cancer based on location showed that ANKRD22 amplification by chr10q23.31 gain enhanced glycolysis in the right-sided colorectal cancer. The AOM/DSS-induced colorectal cancer carcinogenesis mouse model indicated that DDX5 deletion due to chr17q loss promoted colorectal cancer development, consistent with the findings from the patient samples. Collectively, this study provides an informative resource for understanding the driving events of different stages of colorectal cancer and identifying the potential therapeutic targets. Significance: Characterization of the proteogenomic landscape of colorectal cancer during progression provides a multiomic map detailing the alterations in each stage of carcinogenesis and suggesting potential diagnostic and therapeutic approaches for patients.

A Four-Gene Panel in Rectal Swab Samples as a Biomarker for Colorectal Cancer Screening.

The dysregulation of gene expression is one of the key molecular features of colorectal cancer (CRC) development. This study aimed to investigate whether such dysregulation is reflected in rectal swab specimens of CRC patients and to evaluate its potential as a non-invasive approach for screening. We compared the expression level of 14 CRC-associated genes in tumor and adjacent non-tumor tissue of CRC patients and examined the correlation of their levels in tissue with paired rectal swab specimens. The level of these 14 genes in rectal swab specimens was compared among patients with CRC or polyp and control subjects, and the diagnostic potential of each dysregulated gene and the gene panel were evaluated. The expression of CXCR2, SAA, COX1, PPARδ, PPARγ, Groγ, IL8, p21, c-myc, CD44 and CSF1 was significantly higher in CRC, and there was a significant correlation in the levels of most of them between the CRC and rectal swab specimens. In the training study, we showed that CD44, IL8, CXCR2 and c-myc levels were significantly higher in the rectal swab specimens of the CRC patients. Such result was confirmed in the validation study. A panel of these four genes was developed, and ROC analysis showed that this four-gene panel could identify CRC patients with an AUC value of 0.83 and identify overall polyp and precancerous adenoma patients with AUC values of 0.6522 and 0.7322, respectively. Finally, the predictive study showed that the four-gene panel demonstrated sensitivities of 63.6%, 76.9% and 88.9% in identifying overall polyp, precancerous adenoma and CRC patients, respectively, whereas the specificity for normal subjects was 72.2%. The expression of CRC-associated genes in rectal swab specimens reflects the dysregulation status in colorectal tissue, and the four-gene panel is a potential non-invasive biomarker for early precancerous adenoma and CRC screening.

Type 2 diabetes mellitus and post-colonoscopy colorectal cancer: clinical and molecular characteristics and survival

PurposeStudies suggest that patients with type two diabetes mellitus (T2D) may be at increased risk of post-colonoscopy colorectal cancer (PCCRC). We investigated clinical and molecular characteristics and survival of T2D patients with PCCRC to elucidate how T2D-related PCCRC may arise.MethodsWe identified T2D patients with colorectal cancer (CRC) from 1995 to 2015 and computed prevalence ratios (PRs) comparing clinical and molecular characteristics of CRC in T2D patients with PCCRC vs. in T2D patients with colonoscopy-detected CRC (dCRC). We also followed T2D patients from the diagnosis of PCCRC/dCRC until death, emigration, or study end and compared mortality using Cox-proportional hazards regression models adjusted for sex, age, year of CRC diagnosis, and CRC stage.ResultsCompared with dCRC, PCCRC was associated with a higher prevalence of proximal CRCs (54% vs. 40%; PR: 1.43, 95% confidence interval [CI] 1.27–1.62) in T2D patients. We found no difference between PCCRC vs. dCRC for CRC stage, histology, and mismatch repair status. The proportion of CRCs that could be categorized as PCCRC decreased over time. Within one year after CRC, 63% of PCCRC vs. 78% of dCRC patients were alive (hazard ratio [HR] 1.85 [95% CI 1.47–2.31]). Within five years after CRC, 44% of PCCRC vs. 54% of dCRC patients were still alive (HR 1.44 [95% CI 1.11–1.87]).ConclusionThe increased prevalence of proximally located PCCRCs and the poorer survival may suggest overlooked colorectal lesions as a predominant explanation for T2D-related PCCRC, although altered tumor progression cannot be ruled out.

Intratumoral presence of the genotoxic gut bacteria pks+E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer

BackgroundThis study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks+Escherichia coli (pks+E.coli+), pks+E.coli- (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum).MethodsWe screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR.ResultsPks+E.coli+ was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks+E.coli+ and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks+E.coli- (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01).ConclusionIntratumoral pks+E.coli+ but not pks+E.coli- are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause.

The comparison of risk factors for colorectal neoplasms at different anatomical sites

AimBoth the clinical manifestation and molecular characteristics of colorectal cancer (CRC) vary according to the anatomical site. We explored the risk factors for four groups of colorectal neoplasms (CRN) at different anatomical sites.MethodsWe extracted data from the database of Tianjin Colorectal Cancer Screening Program from 2010 to 2020. According to the CRN anatomical sites, patients were divided into four groups: the proximal colon group, the distal colon group, the rectum group, and the multiple colorectal sites. Binary logistic regression analysis was used to explore the differences in risk factors of CRN at different anatomical sites.ResultsThe numbers of patients with CRN in the proximal colon, distal colon, rectum, and multiple colorectal sites were 4023, 6920, 3657, and 7938, respectively. Male sex was associated with a higher risk from the proximal colon to the rectum. Advanced age and obesity were also significantly associated with overall colorectal CRN risk, but there were some differences between men and women. Smoking was associated with CRN risk only in the distal colon and rectum in both men and women. Frequent alcohol consumption and family history of CRC in first-degree relatives (FDRs) were associated with the risk of multisite colorectal CRN only in males.ConclusionsWe observed differences in advanced age, obesity, smoking, alcohol consumption, and family history of colorectal cancer at different anatomical sites of colorectal neoplasms. These factors vary by gender.

The molecular characteristics of colorectal cancer: Impact of Ibuprofen and hyperthermia.

Despite various treatment options available for colorectal cancer, the survival rates for patients remain low. This study investigated the effects of hyperthermia and Ibuprofen on human colorectal adenocarcinoma cells (HT-29) viability, proliferation, and gene expression related to tumor suppression, Wnt signaling pathways, proliferation, and apoptosis The cells were exposed to hyperthermia at 42 or 43°C for 3 hours or Ibuprofen at different concentrations (700-1500 μM), and the effects were analyzed through MTT assay, trypan blue staining, and quantitative Real-time PCR. The study used quantitative Real-time PCR (qRT-PCR) to evaluate the effect of hyperthermia and Ibuprofen on the expression of various genes associated with tumor suppression, proliferation, Wnt signaling pathway, and apoptosis. The results revealed that hyperthermia caused a minor reduction in the viability and proliferation of HT-29 cells, but the decrease was not statistically significant (P<0.05). On the other hand, Ibuprofen caused a concentration-dependent decrease in the viability and proliferation of HT-29 cells. Both hyperthermia and Ibuprofen reduced the expression of WNT1, CTNNB1, BCL2, and PCNA genes, and increased the expression of KLF4, P53, and BAX genes. However, the changes in gene expression were not statistically significant in cells treated with hyperthermia. The findings suggest that Ibuprofen is more effective in reducing cancer cell proliferation by promoting apoptosis and inhibiting the Wnt signaling pathway than hyperthermia, which had some impact but was not statistically significant. The study highlights the potential of Ibuprofen as a targeted therapy for colorectal cancer.

Clinical, Pathological, and Molecular Characteristics in Colorectal Cancer

Colorectal cancer (CRC) is the third most diagnosed cancer worldwide, and the second leading cause of death in patients with cancer [...].

Somatic mutations in colorectal cancer: regional experience

Introduction. Colorectal cancer is one of the most common malignant neoplasms in economically developed countries, ranking 3rd and 2nd in the structure of morbidity and mortality, respectively. Current knowledge about the molecular features of colorectal cancer is necessary to implement the principle of personalized therapy.&#x0D; Aim. To study regional features of tumor genomic landscape in colorectal cancer.&#x0D; Materials and methods. The retrospective study from 2019 to 2022 included 153 patients with stage IIV colorectal cancer aged 32 to 80 years, with a median of 63.8 years. DNA samples extracted from paraffin blocks of tumor tissue were analyzed using a real-time polymerase chain reaction. The study patients included 43.8% of males and 56.2% of females.&#x0D; Results. Somatic mutations were detected in 48.4% of patients. The maximum number of mutations was detected in the KRAS gene 60 (81%). The mutation rate was significantly higher in females versus males. KRAS mutations predominate in the colon compared to the rectum, accounting for 66.7 and 33.3%, respectively. In tumors of the right colon, these mutations were detected in 18.3% of cases, and in the left colon, 48.4%. NRAS mutations were found in 9.5% of cases, mainly in tumors of the left colon. BRAF mutations were diagnosed in 6 patients, 5 of them were women, and the tumors were localized in the right colon. The highest rate of KRAS mutations was observed in codons 12 and 13, accounting for 86.7% of cases. The G12V mutation occurred in the majority of patients (25%), followed by G12D (20%) and G12A (16.6%).&#x0D; Conclusion. Somatic mutations in RAS and BRAF genes in colorectal cancer were detected in 48.4% of patients in the Tambov region. Among them, there is a predominance of KRAS mutations 81% in females. KRAS oncogenic mutations are predictors of treatment response and prognosis.

Screening and Prognostic Value of Methylated Septin9 and its Association With Clinicopathological and Molecular Characteristics in Colorectal Cancer.

Screening of CRC continues to show poor compliance of endoscopy examination. The detection of mSEPT9 in peripheral blood is among the safe and simple early screening methods for CRC. The issue of how to elucidate whether detection of mSEPT9 in peripheral blood can effectively improve compliance of endoscopy and increase the early diagnosis rate of CRC and the relationship between levels of mSEPT9 in the peripheral blood and clinical stage, pathological classification, and expression of characteristic molecules in CRC remains unsolved. A total of 7759 individuals participated in the study that was performed using a questionnaire for screening of high-risk CRC. The endoscopic detection compliance of individuals with high-risk CRC who underwent the fecal occult blood test (FOBT) or mSEPT9 test was compared based on the results of the questionnaire. Additionally, correlation of mSEPT9 levels in the peripheral blood with clinicopathological features, mutation status of TP53, mismatch repair deficiency (dMMR), and KRAS/NRAS/BRAF/PIK3CA genotype was analyzed, and association of biomarkers with cancer-specific survival (CSS) and time to recurrence (TTR) was compared. We also detected levels of mSEPT9 in the peripheral blood of patients with CRC 7 days after surgery and compared the prognostic value of mSEPT9 with CEA. Results of our study showed that the mSEPT9 test could improve compliance of endoscopy and indicated a higher percentage of patients with positive mSEPT9 willing to undergo endoscopy detection than in those with positive FOBT. The specificity and sensitivity of mSEPT9 were better than that of FOBT for the detection of CRC. mSEPT9 was associated with the TNM stage, dMMR, and mutations in TP53, BRAF, and PIK3CA. A Ct value of mSEPT9 ≤ 37.5 was significantly related to poor CSS. mSEPT9 could affect association of dMMR and BRAF and PIK3CA mutations with CSS in a specific stage of CRC. The positive rate of mSEPT9 after surgery was found to correlate with poor TTR, and sensitivity was higher than CEA. The combination of mSEPT9 with CEA had a better prognostic value than that of mSEPT9 alone. The level of mSEPT9 was related to dMMR, mutations in TP53, BRAF, and PIK3CA, and was an effective biomarker for the prognosis of patients with CRC.

The association between ERK inhibitor sensitivity and molecular characteristics in colorectal cancer

The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerful in vitro model system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.

Mutational Characterization of Colorectal Cancer from Korean Patients with Targeted Sequencing.

Purpose: Effective treatment of colorectal cancer could benefit from understanding molecular characteristics including mutation profiles of important genes. This study aimed to explore the molecular characteristics of colorectal cancer based on next generation sequencing.Methods: The mutational characteristics by targeted next generation sequencing in 172 colorectal tumor samples from Korean patients were evaluated to explore their associations with clinical features. Targeted sequencing of 375 genes was performed with an average target-depth of 800X.Results: TP53 and APC showed higher mutation frequencies from the left-sided tumors, while CTNNB1 were more frequent from the right-sided tumors. The tumor suppressor NOTCH1 and the DNA strand break repair gene PALB2 were more frequently mutated in early onset tumors. KRAS and PTEN mutations were more frequent from patients with advanced cancers by cancer antigen markers. TP53 and BRAF mutations were more frequent from patients of T3 and T4 stages, where their variant allele fractions were generally higher in T4 tumors, implying that advanced tumors have higher fraction of cancer cells with TP53 and BRAF mutations. Mutational profiles of these patients were also assessed with other clinical features. Comparison of mutational characteristics with the Caucasian subjects from independent data showed that the identified mutational characteristics are largely Korean-specific except for a few key colorectal cancer genes.Conclusion: Next generation sequencing-based targeted sequencing can provide valuable information on molecular characterization of colorectal cancer patients, and its clinically relevant information can provide benefits to better understand colorectal cancer.

The impact of ARID1A mutation on molecular characteristics in colorectal cancer.

ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC. We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability [MSI], tumour mutational burden [TMB], programmed death ligand 1 [PD-L1] and estimated infiltrating immune cells), clinicopathological featuresand related pathways were analysed using next-generation sequencing, RNA sequencingand immunohistochemistry. ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell-inflamed microenvironment (PD-L1 expressionand high estimated infiltrating cytotoxic T lymphocytes [CTLs]) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expressionand high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples. Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status.

Clinicopathological and molecular features of colorectal cancer with synchronous adenoma

Objective To investigate the clinicopathological and molecular features of colorectal cancer (CRC) with synchronous adenoma and to describe features of synchronous adenomas in CRC patients. Methods Single-centre retrospective cohort of 180 patients were included. The clinicopathological and endoscopic data were collected. The expression mismatch repair (MMR) proteins were detected by immunohistochemistry. The determination of microsatellite instability (MSI) was performed by multiple fluorescence PCR, and the mutations of genes were detected by real-time PCR. Results Among all cases, 49 were diagnosed as CRC with synchronous adenoma, and 131 were diagnosed as solitary CRC. Some of the differences between the groups are: higher incidence was found in male (71.4 vs. 52.6%, p = .023) and in patients with habit drinking (34.7 vs. 14.5%, p = .030) and with other neoplastic diseases (42.7 vs. 26%, p = .028). Less tumors in the synchronous group were diagnosed as stage III and IV than in the solitary group (28.6 vs. 45%, p = .045). One and four mutant subtypes of KRAS gene mutations were detected insynchronous group and solitary group respectively.The prevalence of BRAF mutations in solitary group was higher than that in the synchronous group (7.4 vs. 0%, p = .045). A total of 123 adenomas were found in synchronous group and they tend to be smaller than 10 mm (74%). Conclusion Gender, a habit of drinking and other neoplastic diseases are risk factors for the development of a synchronous adenoma. With a low rate of BRAF mutations, the responses to monoclonal antibody and prognosis of patients with synchronous adenomas may be better than that of solitary CRC.

Evaluation of Concordance Between Deficient Mismatch Repair and Microsatellite Instability Testing and Their Association with Clinicopathological Features in Colorectal Cancer.

BackgroundMicrosatellite instability (MSI) is one of the most important molecular characteristics of colorectal cancer (CRC), which mainly results from defective DNA mismatch repair (MMR). This study was performed to investigate the concordance between deficient MMR and MSI testing, and to evaluate the association of these two results with clinicopathological characteristics in Chinese CRC patients.MethodsA total of 738 CRC patients were included. Tumor tissues and paired peripheral blood specimens were obtained. Screening for MMR was investigated using immunohistochemical (IHC) technique, and multiple polymerase chain reaction-capillary electrophoresis (PCR-CE) method was performed to detect the MSI status. All clinicopathological data, immunohistochemistry and microsatellite instability analyses were then statistically analyzed.ResultsOf the 738 (17.75%) CRC patients, 131 expressed as deficient mismatch repair (dMMR) status, and postmeiotic segregation increased 2 (PMS2) deficiency was the most frequent deficiency among these four MMR proteins. MSI-high (MSI-H) status occurred in 74 of the 738 (10.03%) CRC patients, 55 of whom showed instability at all six mononucleotides repeat markers. dMMR was significantly associated with MSI-H and moderate concordance was observed between IHC and PCR-CE in evaluating deficient MMR/MSI through Kappa test. Statistically, dMMR was significantly associated with younger age, right-sided colon and poor differentiation. MSI-H was associated with younger age, right-sided colon, poor differentiation, mucinous type and tumor, node, metastasis (TNM) stage II.ConclusionA moderate concordance between deficient MMR and MSI testing indicates that both IHC and PCR-CE methods should be routinely tested to provide reliable data for clinical treatment decisions.

199 Clinical and Molecular Characteristics of Early-Onset Colorectal Cancer Across Various Ethnicities

INTRODUCTION: Colorectal cancer (CRC) is the third most common cancer in the United States. Guidelines from the American Cancer Society recommend CRC screening at 45 years of age in average-risk patient populations. Previous studies have shown an increase in incidence of CRC in African Americans (AAs) less than 50 years of age. We aimed to examine the disease characteristics of patients with early-onset CRC (EOCRC) across different races. METHODS: A retrospective cross-sectional study was performed using our electronic pathology database. All patients diagnosed with CRC between January 2012 and September 2018 were included. Data regarding patient demographics, co-morbid conditions and patient presentation was noted. In addition to information regarding the location, staging and molecular features of CRC. RESULTS: A total of 627 patients with CRC were identified. Out of these, 117 (18.6%) were younger than 50 years of age (EOCRC). Table 1 compares the baseline characteristics of patients across different races. The mean age of onset of CRC was significantly lower in Hispanics compared to Caucasians [56.6 years vs 61.6 years, P value = 0.0002] and AAs [56.6 years vs 60.2 years, P value = 0.01]. The clinical and molecular features of CRC across different racial groups are summarized in Table 2. The proportion of patients with early-onset CRC was higher in Hispanics as compared to Caucasians (27.9% vs 16.0%, P value = 0.004) and AAs (27.9% vs 16.9%, P = 0.03). On a multivariate analysis after adjusting for confounders, the proportion of Hispanics with early-onset CRC was significantly higher as compared to Caucasians [OR: 2.2, (95% CI 1.3–3.7), P value = 0.003]. Hispanics were less likely to harbor BRAF mutation as compared to Caucasians (5.1% vs 13.1%, P-value: 0.05), while Hispanics were more likely to have mutations in MSH-6 (100% vs 91.3%, P-value: 0.01) and MSH-2 (100% vs 94.2%, P-value = 0.05) as compared to AAs. CONCLUSION: Our study shows that proportion of patients with early-onset CRC is higher in Hispanics as compared to Caucasians and AAs. In addition, there are unique molecular features specific to CRC across various racial groups. Our findings raise concerns that there might be knowledge gaps regarding early-onset CRC amongst minority populations. Further large multi-center studies are needed to better understand the unique clinical and molecular characteristics in early-onset CRC in minority populations.

312 Patients With Very Early Onset Colorectal Cancer Have Increased Microsatellite Instability

INTRODUCTION: The incidence of colorectal cancer (CRC) in young patients has been increasing. This has led to increase interest in the molecular patterns and epigenetics of CRC in this age group. Microsatellite instability has been noted to be a positive prognostic factor in CRC. We aimed to evaluate the disease and molecular characteristics of patients with early-onset CRC (40-49 years of age) and compare them with those of very early-onset CRC (&lt;40 years of age). METHODS: A retrospective cross-sectional study was performed using our electronic pathology database. All patients diagnosed with CRC between January 2012 and September 2018 were included. Data regarding patient demographics, comorbid conditions and patient presentation was noted. We also noted information regarding the location, staging and molecular features of CRC. RESULTS: A total of 627 patients with CRC were identified. Out of these, 117 (18.6%) were younger than 50 years of age (early-onset CRC). From patients &lt; 50 years of age, 74 (63.2%) had early-onset CRC (40-49 years of age) and 36.8% of patients had very early-onset (&lt;40 years of age). The mean age was 45.4 in those between 40-49 years of age and 33.5 in those &lt; 40 years of age. The most common complaint in early-onset CRC was rectal bleeding (44.6%), while abdominal pain was the most common (39.5%) complaint in the very-early onset CRC group. There were no differences in stage of CRC among both groups. Microsatellite instability (MSI) was more common in patients with very early-onset CRC (40.7 vs 13.6%, P-value = 0.009) as compared to those with early onset CRC. Other clinical and molecular features of patients with very-early onset CRC are summarized in Table 1. CONCLUSION: There are unique clinical characteristics and molecular features in patients with very-early onset CRC. Our study shows that patients very early-onset CRC have increased MSI. Although our study limitations include a small sample size and an experience from a single center, our findings suggest that further understanding of molecular features in patients with very early-onset CRC is needed to improve diagnosis and management of CRC in this age group.

Role of the Microbiome in the Formation and Development of Colorectal Cancer.

The clinical, histopathological, and molecular characteristics of colorectal cancer vary considerably. Factors associated with the heterogeneity of this disease and with understanding the effects of heterogeneity on disease progression and response to therapy are critical for the better stratification of patients and the development of new therapeutic methods. Although studies have focused mainly on tumor molecular profiling, current molecular predictive and prognostic factors are relevant to specific groups of colorectal cancer patients and are mostly used to predict the applicability of targeted biological agents rather than to predict their benefits. Molecular profiling fails to capture aspects important for tumor growth and aggressiveness, including the tumor microenvironment. The gut microbiome, consisting of specific communities of all commensal, symbiotic, and pathogenic microorganisms, has been shown to have a significant impact on the development of many diseases, including Crohns disease, type II diabetes, and obesity. Recent studies have indicated that long-term dysbiosis of the intestinal microflora can influence the development and progression of colorectal cancer, as well as tumor aggressiveness and response to treatment. This review article summarizes current knowledge of the gut microbiome in colorectal cancer, including the various mechanisms by which the gut microbiome affects the intestinal wall, thereby contributing to the development and progression of colorectal cancer. This work was supported by Ministry of Health of the Czech Republic (project AZV 16-31966A), project of Ministry of Education, Youth and Sports of the Czech Republic - NPU I - LO1413 a Ministry of Health of the Czech Republic - RVO (MMCI, 00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 15. 4. 2019 Accepted: 17. 6. 2019.

Abstract 4324: Prognostic potential of DNA methylation levels of EPDR1 and CHST10 in colorectal cancer

Abstract Chromosomal instability (CIN), microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP) are well-characterized molecular features of colorectal cancer (CRC). Aberrant DNA methylation may associate with MSI-high and CIMP-high phenotype in CRC. Studies on aberrant DNA methylation are likely to help in the identification of biomarkers clinically relevant to the process of tumorigenesis. In this study, we explored DNA methylation profile changes in CRC with MSI through genome-wide DNA methylation profiling analysis. Of 34 altered genes, three hypermethylated (pidermal growth factor, EGF; carbohydrate sulfotransferase 10, CHST10; ependymin related 1, EPDR1) candidates were further validated in 75 CRC patients. All validated genes, except EGF, were significantly correlated with MSI status. In addition, methylation of EPDR1 or CHST10 was significantly correlated with better prognosis and mutations in BRAF and TGFβR2. Beside, we found a positive correlation between the methylation of EPDR1 and CHST10. Methylation of EPDR1 was also significantly correlated with node negativity and a lower tumor stage. Negative correlations between mRNA expression and DNA methylation level of both EPDR1 and CHST10 were reported in The Cancer Genome Atlas (TCGA) dataset, revealing that DNA methylation has a crucial function in modulating expressions of EPDR1 and CHST10 in CRC cells. These results suggest that DNA methylation levels of EPDR1 and CHST10 may serve as potential prognostic markers for CRC. Citation Format: Chun-Ho Chu, Shih-Ching Chang, Hsiu-Hua Wang, Shung-Haur Yang, Te-Chang Lee, Kuo-Chu Lai. Prognostic potential of DNA methylation levels of EPDR1 and CHST10 in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4324.

Meat consumption and BRAF mutation status in colorectal cancer.

e15135 Background: Consumption of red and processed meat has been associated with increased risk of developing colorectal cancers, but less is known about the association of meat consumption with tumor molecular features. In this study, we tested the association of total meat consumption with molecular features of colorectal cancer and overall survival in a local cohort of patients. Methods: Data on meat consumption were collected using self-directed environmental surveys from patients with stage IV/locally advanced, treatment refractory colorectal cancer who were enrolled on the Assessment of Targeted Therapies Against Colorectal Cancer clinical protocol. Data on tumor molecular features were collected through medical record review. Patients were categorized into low, medium or high meat consumption groups based on servings per day tertile. Associations between tumor molecular features and meat intake were evaluated by Chi-square and logistic regression. Potential effects of meat consumption on overall survival were assessed using Cox Proportional Hazards models. Analyses were conducted with IBM SPSS v25. Results: Patients consumed an average of 0.74, 1.57 and 3.32 servings of meat per day in the low, medium and high categories, respectively. Out of 593 patients with evaluable data, 27 were found to have a BRAF V600E mutation. Total meat consumption differed significantly by BRAF V600E mutation status (p value 0.02) and by sex (p value &lt; .01), but did not differ by tumor location, microsatellite instability, or RAS mutation status. Using logistic regression, we found that compared to patients with the highest level of meat consumption, those in the medium consumption group may be less likely to have a BRAF V600E mutation (OR 0.24; p value 0.08). Although meat consumption may be associated with BRAF mutation status, it was not predictive of overall survival in our analyses. Conclusions: Among patients in our study, meat consumption may be associated with tumor BRAF V600E mutation status but is not directly associated with survival. Additional work is needed to test this association in cohorts including more BRAF mutant cases. If confirmed, this finding may add further insight into the etiology and biology of these tumors.