Pattern Of Colorectal Cancer Research Articles

Potential oncogenic role of human cytomegalovirus and histone deacetylase 3 expression in colorectal cancer

Aims: This study was conducted to investigate whether there is a link between HDAC3 expression and clinical characteristics in colorectal cancer (CRC) patients and to detect the oncopotenial role of HCMV in colorectal cancer (CRC). Material and methods: 30 samples of formalin fixed-Paraffin embedded archival tissues were collected from patient suffering of CRC , In addition to 10 samples of free cancer tissue for determine of expression of HDAC3 and CMV by using immunohistochemistry. Results: HDAC3 expression by Immunohisto-chemical (IHC) staining was found in 19 samples (63. 3%) of CRC. While There is no expression of CMV in all samples of CRC and control groups. Conclusion: This study proved HDAC3 expression pattern in CRC, and the findings support HDAC3 as a supplementary marker to known histopathological diagnostic components; it could potentially be used in prognosis and targeted therapy. We also found that there is no correlation of the CMV infection and CRC as a pro-tumorigenic factor.

Identification of Endoplasmic Reticulum Stress-Related Subtypes, Infiltration Analysis of Tumor Microenvironment, and Construction of a Prognostic Model in Colorectal Cancer.

Simple SummaryUnderstanding how endoplasmic reticulum stress influences colorectal cancer progression and the composition of the tumor microenvironment is important for developing novel strategies in the treatment of colorectal cancer. In this study, we identified two endoplasmic reticulum stress-related subtypes of colorectal cancer with distinct prognosis and infiltration patterns in the tumor microenvironment. Besides, we constructed a prognostic model for predicting patients’ survival, which involved an endoplasmic reticulum stress-related 14-gene signature. Furthermore, by utilizing spatial transcriptomics data from two untreated colorectal cancer patients, we explored endoplasmic reticulum stress-related gene signatures at a subcellular level and found that colorectal cancer cells and regulatory T cells showed an evidently increased expression of endoplasmic reticulum stress-related gene signature, and cancer-associated fibroblasts might be the leading characteristic that distinguishes the endoplasmic reticulum stress-related subtypes of colorectal cancer. We suggest that targeting endoplasmic reticulum stress in colorectal cancer might reshape the exhausted tumor microenvironment and mitigate tumor progression.Recently, endoplasmic reticulum (ER) stress has been shown to influence tumor progression and immune cell function in the tumor microenvironment (TME). However, the underlying role of ER stress-related gene patterns in colorectal cancer (CRC) development remains unclear. We analyzed the ER stress-related gene patterns in 884 patients with CRC from the Gene Expression Omnibus database and evaluated the cell-infiltrating patterns in the TME. Two ER stress-related patterns were identified in patients with CRC that had distinct cell-infiltrating patterns in the TME and clinical characteristics. A risk score and nomogram based on 14 screened prognosis-correlated genes was built and validated to predict patient survival. Patients with a higher risk score were shown to have an unfavorable prognosis, and the risk score was associated with cell infiltration and drug sensitivity. Furthermore, spatial transcriptomics data were utilized to explore ER stress-related gene patterns in CRC tissues, and it was shown that ER stress phenotype involves in the formation of the immunosuppressive TME. This study demonstrated that ER stress-related gene patterns play a role in influencing the TME and predicting prognosis. These analyses of ER stress in the TME of CRC might deepen our understanding of CRC progression and immune escape and provide novel insights into therapeutic strategies.

Distribution features of genomic amplifications in microsatellite stable Chinese colorectal cancer.

e15509 Background: Genomic amplification is key mutational events in microsatellite stable (MSS) colorectal cancer (CRC). A distinctive amplification region of CRC is Chr20q. It was revealed by several investigations the most recurrent amplified band in CRC and often co-exist with Chr8q. However, there is very little data to describe the characteristics of chromosome co-exist amplifications in CRC. We did an exploratory analysis in this issue in a large size of Chinese CRC. Methods: A total of 1977 CRC with detected genomic amplifications were included in this analysis. Calling of single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels), fusions were performed using a wide panel next-generation sequencing (NGS) testing. Amplifications were stratified as high-level, moderate-level and low-level according to the number of copies (cut-off: 20, 8 copies). Results: Nine chromosome arm were detected amplified in more than 10% cases in this cohort. Chr20q (65.9%), Chr13q (57.1%) and Chr8q (34.3%) were the most frequent. Chr17q and Chr12q had more high-level amplifications than other chromosome arms with ratio of 54.9% and 33.7%, respectively. In contrast, Chr20q and ChrX substantially had low-level amplifications. 36.2% (715/1977) cases had amplifications on more than two chromosome arms (median 2, range 2-7). In patients (92%) with 2-4 co-current amplified chromosome arms, the most frequent co-amplified patterns were Chr20q-Chr13q (20%) and Chr20q-Chr8q (15%). Most patients among this subgroup had more than three amplified genes in Chr20q while only one amplified gene in Chr8q. In patients (8%) with 5-7 co-current amplified chromosome arms, the most frequent amplified regions were Chr20q, Chr8q and Chr7q, and more than 60% cases harbored Chr20q-Chr8q. Interestingly, these patients mainly had multiple amplified genes in Chr8q and only one amplified gene in Chr20q, in the contrary to the patients with 2-4 co-current amplified chromosome arms. In addition, high-level focal amplifications in Chr17q and Chr12q participated equally to the amplifications with other chromosome arms. Conclusions: Our analysis results suggested the heterogeneity of Chr20q co-amplifications patterns in CRC. Amplifications in Chr20q and Chr8q may play distinct critical roles in the tumorigenesis of CRC. High-level amplifications were, on the other hand, independent of their driven process.

Characterization of m6A Methylation Modification Patterns in Colorectal Cancer Determines Prognosis and Tumor Microenvironment Infiltration.

Cumulative studies have suggested that dysregulation of m6A regulators and immunity is highly linked to the prognosis of patients with cancer. However, the potential contribution of m6A modification patterns to the tumor microenvironment (TME) and the therapeutic efficacy of immunotherapy for colorectal cancer (CRC) remain elusive. A comprehensive analysis of the m6A modification profiles of 458 patients with CRC was performed by clustering 21 genes encoding m6A methylation regulators and linking the m6A modification pattern with TME characteristics. Using principal component analysis (PCA), a risk model was constructed to quantify individual m6A modification patterns in patients with CRC. The results indicated that the expression profiles and genetic mutations of 21 genes encoding m6A methylation regulators in CRC were characterized by a high degree of heterogeneity. Three m6A clusters had significant differences in prognosis, m6A modification patterns, and TME characteristics. Furthermore, a risk model, termed m6Ascore, was developed by PCA to quality m6A methylation patterns at an individual level. The m6Ascore could stratify patients into high- and low-m6Ascore groups. Further analyses demonstrated that the m6Ascore had a good predictive performance for overall survival and clinical efficacy of immunotherapy in patients with CRC. Finally, the predictive value of the model was validated by external cohorts. In conclusion, the comprehensive characterization of m6A methylation modification patterns might contribute to our understanding of the TME in CRC and the development of personalized antitumor immunotherapy in the future.

Patterns of Colorectal Cancer in Texas Counties From 2000 to 2017.

Residents living in Texas counties along the United States-Mexico border make up a unique demographic. These counties consist of a large proportion of Hispanic-Latinx people who experience a high rate of health uninsurance and underinsurance, low household income averages, and, as a whole, exhibiting relatively poor health outcomes compared to the US general population. Limited information exists regarding the effects of these characteristics on the incidence of colorectal cancer (CRC). Using data from the Texas Department of State Health Service, we calculated that the overall age-adjusted incidence rate (AAIR) of CRC was lower and decreased at a slower rate over time in Texas border counties compared with nonborder counties in Texas. The AAIR of CRC was lower and decreased at a slower rate over time in Texas border counties compared with nonborder counties in Texas. Conversely to other groups analyzed, the AAIR of CRC in individuals age 50-64 years in border counties increased. These findings are likely a reflection of less utilization of cancer screening in border counties than in nonborder counties. The increase in AAIR of CRC among individuals age 50-64 years in border counties warrants further investigation.

High Diversity of Glycosphingolipid Glycans of Colorectal Cancer Cell Lines Reflects the Cellular Differentiation Phenotype.

Colorectal cancer (CRC)–associated changes of protein glycosylation have been widely studied. In contrast, the expression of glycosphingolipid (GSL) patterns in CRC has, hitherto, remained largely unexplored. Even though GSLs are major carriers of cell surface carbohydrates, they are understudied due to their complexity and analytical challenges. In this study, we provide an in-depth analysis of GSL glycans of 22 CRC cell lines using porous graphitized carbon nano–liquid chromatography coupled with electrospray ionization–mass spectrometry. Our data revealed that the GSL expression varies among different cell line classifications, with undifferentiated cell lines showing high expression of blood group A, B, and H antigens while for colon-like cell lines the most prominent GSL glycans contained (sialyl)-LewisA/X and LewisB/Y antigens. Moreover, the GSL expression correlated with relevant glycosyltransferases that are involved in their biosynthesis as well as with transcription factors (TFs) implicated in colon differentiation. Additionally, correlations between certain glycosyltransferases and TFs at mRNA expression level were found, such as FUT3, which correlated with CDX1, ETS2, HNF1A, HNF4A, MECOM, and MYB. These TFs are upregulated in colon-like cell lines pointing to their potential role in regulating fucosylation during colon differentiation. In conclusion, our study reveals novel layers of potential GSL glycans regulation relevant for future research in colon differentiation and CRC.

Patterns of colorectal cancer (CRC) screening rates among the average risk U.S. population.

65 Background: There is consensus that the proportion of the average-risk US population up-to-date with CRC screening (58-65%) is insufficient. However, estimates of average risk CRC screening rates are inconsistent and impacted by inclusion of higher-risk individuals, and differing study designs. Accurate measurement of population screening rates is key to addressing gaps in care and assessing the impact of newer CRC screening tests. Methods: The study included individuals aged 50-75 years in a large de-identified claims database, with continuous enrollment during year of analysis, and a variable length baseline enrollment of 1-10 years. Average-risk designation excluded higher risk diagnoses (CRC familial syndromes, colorectal polyp or history of colorectal polyp, history of/current CRC, family history of gastrointestinal cancer, and inflammatory bowel disease). Up-to-date status was assessed within guideline-based time periods: colonoscopy (10 years); FIT or FOBT (annually); mt-sDNA (3 years); flexible sigmoidoscopy/CT colonography (5 years). Analyses assessed the proportion estimated as up-to-date and examined the sensitivity to: a) patient population (average-risk only vs. including higher-risk); b) study design (yearly cross-sectional vs. cohort of 50-year-old patients; c) methods (percent in patients with 10 years of enrollment vs. Kaplan Meier (KM) of censored variable pre-screening period). Results: The cross-sectional analysis average-risk population included 5.3 million individuals. Estimates of the proportion of those up-to-date with screening guidelines for average-risk patients varied by study design, population, and estimation method. KM estimates among the average-risk population (50-75) showed 49-50% were up-to-date in each calendar year. Including higher-risk patients in the KM analysis resulted in 70% up-to-date among the mixed average+higher-risk population. Using a cohort study design (average-risk patients aged 60 with 10 years of baseline data), 65% were up-to-date by age 60. Conclusions: In the base case analysis only half of average risk individuals were up-to-date with CRC screening, a rate lower than typically cited. Sensitivity analyses resulted in substantially different estimates and demonstrate the importance of clearly communicating the methodology used to define the study population. Higher rates quoted in the lay press and medical publications may be based on mixed populations of average+higher-risk individuals or on study designs that do not represent the full population at risk.

Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis.

Aberrant regulation of ubiquitination often leads to metabolic reprogramming in tumor cells. However, the underlying mechanisms are not fully understood. Here we demonstrate that OTUB2, an OTU deubiquitinase, is upregulated in colorectal cancer (CRC) and exacerbates the progression of CRC through modulating the aerobic glycolysis. Mechanistically, OTUB2 directly interacts with pyruvate kinase M2 (PKM2) and inhibits its ubiquitination by blocking the interaction between PKM2 and its ubiquitin E3 ligase Parkin, thereby enhancing PKM2 activity and promoting glycolysis. In response to glucose starvation stress, the effect of OTUB2 on PKM2 is enhanced, which confers metabolic advantage to CRC cells. Moreover, OTUB2 depletion reduces glucose consumption, lactate production, and cellular ATP production. OTUB2-knockout CRC cells exhibit attenuated proliferation and migration, as well as an elevated level of apoptosis and increased sensitivity to chemotherapy drugs. Furthermore, in vivo assays show that knockout of OTUB2 inhibits tumor growth in mice. Taken together, these findings reveal the critical role of OTUB2 in the regulation of glycolysis and illustrate the molecular mechanism underlying its role as a negative regulator of PKM2 ubiquitination in CRC, establishing a bridge between OTUB2-regulated PKM2 ubiquitination and altered metabolic patterns in CRC and suggesting that OTUB2 is a promising target for CRC treatment.

Area-Level Determinants in Colorectal Cancer Spatial Clustering Studies: A Systematic Review.

The increasing pattern of colorectal cancer (CRC) in specific geographic region, compounded by interaction of multifactorial determinants, showed the tendency to cluster. The review aimed to identify and synthesize available evidence on clustering patterns of CRC incidence, specifically related to the associated determinants. Articles were systematically searched from four databases, Scopus, Web of Science, PubMed, and EBSCOHost. The approach for identification of the final articles follows PRISMA guidelines. Selected full-text articles were published between 2016 and 2021 of English language and spatial studies focusing on CRC cluster identification. Articles of systematic reviews, conference proceedings, book chapters, and reports were excluded. Of the final 12 articles, data on the spatial statistics used and associated factors were extracted. Identified factors linked with CRC cluster were further classified into ecology (health care accessibility, urbanicity, dirty streets, tree coverage), biology (age, sex, ethnicity, overweight and obesity, daily consumption of milk and fruit), and social determinants (median income level, smoking status, health cost, employment status, housing violations, and domestic violence). Future spatial studies that incorporate physical environment related to CRC cluster and the potential interaction between the ecology, biology and social determinants are warranted to provide more insights to the complex mechanism of CRC cluster pattern.

A STUDY OF HISTOPATHOLOGICAL DISTRIBUTION IN COLORECTAL CANCER

Despite of advances in surgical techniques and adjuvant chemotherapeutic regimens, colorectal cancer remains one of the major leading causes of deaths worldwide. Histopathology is an important factor in the treatment and prognosis of cancer. The purpose of this study was to describe the different histopathological pattern in colorectal cancer. 81 cases of colorectal carcinoma received in pathology department over a period of four years were included in the study. The surgical specimen and colonoscopic biopsies' gross features were noted and samples were stained with Haematoxylin and Eosin. Detailed microscopic examination of tumor with lymph node status was done followed by histological typing. Grading of the tumor, age and sex distribution of cases were also noted. The commonest histopathological nding was adenocarcinoma 75.32% followed by mucinous adenocarcinoma 9.88% and signet ring cell carcinoma 8.64%. Among 61 cases of adenocarcinoma most commonly moderately differentiated adenocarcinoma 60.66% was noted.

Interferon-induced protein 16 expression in colorectal cancer and its correlation with proliferation and immune signature markers.

Interferon-induced protein 16 (IFI16) is important for innate immune recognition of foreign/damaged DNA. Abnormal IFI16 expression is closely related to the occurrence of multiple malignant tumours, but its expression pattern in colorectal cancer (CRC) remains unclear. The present study aimed to investigated IFI16 expression and association with cell proliferation in CRC tissues and adjacent normal tissues. A multiplex immunofluorescence panel of antibodies against IFI16, Ki-67 and phosphorylated (p)-ERK1/2 was applied to assess a tissue microarray (TMA). The TMA included 77 CRC samples and 74 normal adjacent tissue samples which were collected from The First People's Hospital of Yunnan Province (Kunming, China) (3 paracancerous tissues were lost because of repeated cutting). Immunohistochemistry was used to detect CD8+ tumour-infiltrating lymphocyte (TIL) abundance and programmed death-ligand 1 (PD-L1) expression in cancer tissues. The present study demonstrated that IFI16 localized to the nucleus of CRC cells. Although IFI16 was weakly expressed in normal mucosal epithelial cells, absent to strong expression was detectable in different patients with CRC. Typically, IFI16 was not co-localized with Ki-67 within CRC cells. The multiplex immunofluorescence data demonstrated that the proportion of IFI16−/Ki-67+ cells from CRC tissues was 57.13%; however, that of IFI16+/Ki-67+ cells was 1.50%. The IFI16−/Ki-67+ phenotype was significantly positively associated with the tumor-node-metastasis stage and was marginally significantly correlated with lymph node metastasis. p-ERK1/2 protein was primarily localized to the cytoplasm and cell membrane of CRC cells and sometimes to the nucleus. Although, IFI16 demonstrated a strong correlation with p-ERK1/2, IFI16 did not co-localize with p-ERK1/2 and the proportion of IFI16 and p-ERK1/2 double-negative CRC cells was 84.95%. IFI16 expression displayed no significant association with CD8+ TILs or PD-L1. However, a strong positive correlation between CD8+ TILs and PD-L1 was observed. High CD8+ TIL infiltration in CRC tissue was associated with lower lymph node metastasis and tumor-node-metastasis stage. In summary, the results of the present study provided a novel insight for the role of IFI16 in CRC occurrence via the regulation of cancer cell proliferation.

A newly developed PCR-based method revealed distinct Fusobacterium nucleatum subspecies infection patterns in colorectal cancer.

SummaryFusobacterium nucleatum, which has four subspecies (nucleatum, animalis, vincentii and polymorphum), plays an important role in promoting colorectal cancer (CRC). However, as there is no efficient method of differentiating these subspecies in the context of a rich gut microbiota, the compositions in CRC remain largely unknown. In this study, a PCR‐based differentiation method enabling profiling of F. nucleatum infection in CRC at the subspecies level was developed. Based on the analysis of 53 F. nucleatum genomes, we identified genetic markers specific to each subspecies and designed primers for the conserved sequences of those markers. The PCR performance of the primers was tested with F. nucleatum and non‐nucleatum Fusobacterium strains, and complete consistence with taxonomy was achieved. Additionally, no non‐specific amplification occurred when using human DNA. The method was then applied to faecal (n = 58) and fresh‐frozen tumour tissue (n = 100) samples from CRC patients, and wide heterogeneity in F. nucleatum subspecies compositions in the gut microbiota among CRC patients was observed. Single‐subspecies colonization was common, whereas coexistence of four subspecies was rare. Subspecies animalis was most prevalent, while nucleatum was not frequently detected. The results of this study contribute to our understanding of the pathogenicity of F. nucleatum at the subspecies level and the method developed has potential for clinical and epidemiological use.

Interleukin 10 level in the peritoneal cavity is a prognostic marker for peritoneal recurrence of T4 colorectal cancer

Peritoneal recurrence (PR) is a major relapse pattern of colorectal cancer (CRC). We investigated whether peritoneal immune cytokines can predict PR. Cytokine concentrations of peritoneal fluid from CRC patients were measured. Patients were grouped according to peritoneal cancer burden (PCB): no tumor cells (≤ pT3), microscopic tumor cells (pT4), or gross tumors (M1c). Cytokine concentrations were compared among the three groups and the associations of those in pT4 patients with and without postoperative PR were assessed. Of the ten cytokines assayed, IL6, IL10, and TGFB1 increased with progression of PCB. Among these, IL10 was a marker of PR in pT4 (N = 61) patients based on ROC curve (p = 0.004). The IL10 cut-off value (14 pg/mL) divided patients into groups with a low (7%, 2 of 29 patients) or high (45%, 16 of 32 patients) 5-year PR (p < 0.001). Multivariable analysis identified high IL10 levels as the independent risk factor for PR. Separation of patients into training and test sets to evaluate the performance of IL10 cut-off model validated this cytokine as a risk factor for PR. Peritoneal IL10 is a prognostic marker of PR in pT4 CRC. Further research is necessary to identify immune response of intraperitoneal CRC growth.

TIGIT promotes CD8+T cells exhaustion and predicts poor prognosis of colorectal cancer.

TIGIT is a lymphocyte surface receptor, which is mainly expressed on the surface of CD8+T cells. The role of TIGIT in colorectal cancer and its expression pattern in colorectal cancer infiltrating lymphocytes are still controversial. This study aimed at identifying the function of TIGIT in colorectal cancer. Patients with colorectal cancer showed significantly higher TIGIT+CD8+T cell infiltration in tumor tissues, metastases compared with paired PBMC and normal tissues through flow cytometry. TIGIT+CD8+T cells showed an exhausted phenotype and expressed low levels of killer cytokines IFN-γ, IL-2, TNF-α. In addition, more inhibitory receptors such as PD-1, LAG-3, and TIM-3 were expressed on the surface of TIGIT+CD8+T cells. TGF-β1 could promote the expression of TIGIT and inhibit CD8+T cell function in vitro. Moreover, the accumulation of TIGIT+T cells in tumors was associated with advanced disease, predicted early recurrence, and reduced survival rates in colorectal cancer patients. Our results indicate that TIGIT can be a biological marker for the prognosis of colorectal cancer, and TIGIT can be used as a potential target for treatment.

Type 2 Diabetes Associated with Abnormal p53 Immunohistochemical Patterns in Colorectal Cancer

Abnormal p53 immunohistochemical pattern (p53-AP) including overexpression, complete absence and heterogeneity is surrogate of TP53 mutation. Using 742 cases of colorectal cancer (CRC), we show p53-AP is more common among type 2 diabetes (T2DM) patients than non-T2DM. Univariately, T2DM was significantly associated with p53-AP in overall patients, patients with microsatellite instability (MSI) stable/MSI-low phenotype or distal colorectal location. Furthermore, p53-AP was positively associated with lymph node metastasis and high TNM stage. Metformin treatment was negatively associated with p53-AP in T2DM patients. The results suggested T2DM might influence carcinogenesis, progression and prognosis via inducing TP53 mutation and abnormal p53 expression in CRC.

Clinicopathological features of mismatch repair protein expression patterns in colorectal cancer

Microsatellite instability (MSI) is reflective of a deficient mismatch repair (dMMR) system, which is mostly associated with the methylation of mismatch repair (MMR) genes and BRAF mutations in sporadic colorectal cancers (CRCs). We performed a retrospective study to analyze the clinicopathological features of dMMR CRCs and their association with the BRAF V600E mutation. The incidence of dMMR CRCs in our cohort was 7.4 % (118/1603). Immunohistochemistry (IHC) revealed four common dMMR IHC patterns in 116 dMMR CRCs from 110 patients. dMMR type 1 (MLH1-/PMS2-) CRCs were the most frequent pattern, usually showing typical proximal location and MSI histology. The BRAF V600E mutation was almost exclusively observed in dMMR type 1 (32 of 72) and dMMR type 2 (PMS- only, 7 of 18) CRCs (p = 0.001). Patients with dMMR type 3 (MSH2-/MSH6-) CRCs were usually diagnosed at younger ages (p < 0.001) and had the strongest family history of Lynch syndrome-associated tumors (p = 0.002). dMMR type 3 CRCs frequently presented at advanced stages (p = 0.005) with perineural invasion (p = 0.021). We also found a significant positive association of dMMR type 1 and type 3 with advanced stages of CRC, whereas dMMR types 2 and 4 (MSH6- only) were usually diagnosed at early stages of CRC (p < 0.001). In conclusion, BRAF V600E mutations almost exclusively occurred in dMMR type 1 and 2 CRCs. Patterns of MMR protein expression display distinct associations with tumor staging and age at diagnosis.

Prognostic value of metastatic pattern in colorectal cancer: a multicenter retrospective analysis in a real-life cohort

Background Metastatic patterns have been linked with prognosis in colorectal cancer. We aim to determine the distribution of metastases, their dynamics during disease and their prognostic impact for specific clinical treatment scenarios (resection of metastasis and/or systemic treatment, best supportive care). Material and methods 978 patients diagnosed with metastatic colorectal adenocarcinoma treated at three oncological centers from 2006 to 2018 were included. Overall survival was assessed depending on tumor load, distribution of metastases and treatment of the patients. Results Most patients had single site metastasis (n = 684; 69.9%): 398 patients had liver (n = 398; 40.7%) and 103 patients had lung only metastasis (10.6%). The number of organs involved in metastases at diagnosis was highly prognostic (HR 0.77; CI 0.65, 0.90), whereas the additional gain of metastases during progression of the disease was not. The majority of patients (62.9–74.2%) with initial lung, liver or both metastases retained their initial metastatic status. In the overall population, lung only metastases were associated with the most favorable outcome (HR 0.64; CI 0.50, 0.81). This was also observed in patients receiving best supportive care (HR 0.45; CI 0.27, 0.75). Resection of lung only metastases resulted in longer median survival (102.2 months). A relevant survival difference in patients treated by systemic therapy alone was not observed. Lung only metastasis was associated with rectal cancer (p < .001) and RAS-mutation (p = .01); both, lung and liver metastasis were associated with time from diagnosis to first metastasis (p < .001). Conclusion The number of organs involved in metastasis at diagnosis but not the total cumulative number of involved organs is of prognostic relevance in colorectal adenocarcinoma. This prognostic relevant initial metastasis distribution remains unchanged in the majority of patients during the disease. However, the prognostic impact of the metastatic pattern is potentially altered by treatment modality.

Abstract 3872: Spatial and multi-omics characterization of the tumor microenvironment in colorectal cancer

Abstract Background: Colorectal cancer is a heterogeneous disease, harboring tremendous differences in genetic mutations, gene expression pathways, and the tumor microenvironment. While there has been recent progress in understanding immune infiltration patterns in colorectal cancer, the majority of patients are thus far largely refractory to immunotherapy, and the underlying mechanism remains poorly understood. Here, we present a large-scale multi-omics analyses on 161 colorectal cancer tumors. More specifically, we aim to characterize the spatial and phenotypic profiles as well as the relationships between the different cell populations in the tumor microenvironment using multiplex immunohistochemistry. Methods: Tissue microarrays were constructed, comprising the tumor core, close-to-edge, tumor edge, and adjacent normal tissues for each tumor. H&amp;E and multiplex immunohistochemistry were performed by staining 7 markers (cytokeratin [CK], CD3, CD8, FOXP3, CD68, PD-L1 and DAPI). This allows for simultaneous detection of different cell populations, including CK+ epithelial cells, CD68+ macrophages, CD3+ T cells, CD8+ T cells, and FOXP3 regulatory T cells. Further complementing the study were whole genome sequencing to describe genetic mutations and tumor mutation burden, along with whole transcriptome sequencing to investigate differential gene expression and pathway enrichment. MSI status was determined from whole genome sequencing data, and molecular subtypes were called from RNA-sequencing data. Results: Based upon spatial patterns of immune cell infiltration, we qualitatively and quantitatively describe several immune infiltration subtypes which were further correlated with tumor mutation burden and neoantigen burden, activation of major oncogenic pathways and inflammatory signatures. The density of immune cells varies across the different tumor sites, from the adjacent normal tissue into the tumor core. We have also uncovered interactions between the different cell populations within the tumor microenvironment. Overall, the integration of data from multiple platforms represents a comprehensive interrogation into the complex tumor microenvironment in colorectal cancer. Conclusion: There exists a substantial variability in the transcriptomic landscape and the immune infiltration patterns across different patients. This demonstrates the complex interplay between the different cell populations in the tumor microenvironment, representing the fine balance between immune activation and suppression. Citation Format: Christine L. Eng, Joe P. Yeong, Andy Nguyen, Amanda Y. Guo, Brenda Tay, Mei Mei Chang, Sherlly Lim, Clarinda W. Chua, Harini Srinivasan, Lindsay H. Kua, Fiona Y. Lee, Dominique C. Macalinao, ThinZar Aung, Anders J. Skanderup, Tony K. Lim, Iain B. Tan, Si-Lin Koo. Spatial and multi-omics characterization of the tumor microenvironment in colorectal cancer [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 3872.

Diabetes mellitus and colorectal carcinoma outcomes: a meta-analysis.

The impact of diabetes mellitus (DM) on colorectal cancer (CRC) outcomes remains unknown. We studied this by conducting a meta-analysis to evaluate (1) CRC outcomes with and without DM and (2) treatment patterns. We searched PubMed, EMBASE, Google Scholar, and CINAHL for full-text English studies from 1970 to 12/31/2017. We searched keywords, subject headings, and MESH terms to locate studies of CRC outcomes/treatment and DM. Studies were evaluated by two oncologists. Of 14,332, 48 met inclusion criteria. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method, we extracted study location, design, DM definition, covariates, comparison groups, outcomes, and relative risks and/or hazard ratios. We utilized a random-effects model to pool adjusted risk estimates. Primary outcomes were all-cause mortality (ACM), disease-free survival (DFS), relapse-free survival (RFS), and cancer-specific survival (CSS). The secondary outcome was treatment patterns. Forty-eight studies were included, 42 in the meta-analysis, and 6 in the descriptive analysis, totaling > 240,000 patients. ACM was 21% worse (OR 1.21, 95% CI 1.15-1.28) and DFS was 75% worse (OR 1.75, 95% CI: 1.33-2.31) in patients with DM. No differences were detected in CSS (OR 1.10, 95% CI 0.98-1.23) or RFS (OR 1.12, 95% CI 0.91-1.38). Descriptive analysis of treatment patterns in CRC and DM suggested potentially less adjuvant therapy use in cases with DM and CRC. Our meta-analysis suggests that patients with CRC and DM have worse ACM and DFS than patients without DM, suggesting that non-cancer causes of death in may account for worse outcomes.

Abstract C005: Racial disparity, stage at diagnosis, and treatment patterns of colorectal cancer: Analysis of data from a hospital-based cancer registry, Virginia 2008-2016

Abstract Background: Using hospital-based cancer registry data, we examined the predictors of late-stage CRC diagnosis and identified factors contributing to CRC treatment patterns in Virginia. Methods: We conducted a retrospective cohort study using the Sentara Cancer Registry for patients diagnosed with CRC from 2008 to 2016. Patients' demographics and clinical characteristics were summarized and compared between Caucasian and African American in a bivariate analysis using the Chi-square test for categorical variables, and the Student's t test for continuous variables. A hierarchical logistic regression model adjusting for age, sex, race, marital status, primary payer, cancer site, initial year of diagnosis, and the Charlson Comorbidity Index (CCI) was used to model the odds of late-stage CRC disease, and to determine factors associated with treatment patterns, i.e., surgery, chemotherapy, and radiation. Adjusted odds ratios with their 95% confidence intervals were reported. Results: The data consisted of 4,505 cases of CRC reported to Sentara hospitals during 2008 to 2016. Among these patients, 2,371 (54.34%) were diagnosed late and 1,992 (45.66%) were early-stage diagnosis. About three quarters of the patients were Caucasian (74.93%). On average, patients were 65.95 years old (SD=13.22), and the majority were males (52.01%), married (55.8%), and had primarily Medicare (57.02%), followed by private insurance (31.88%). During the study period, the overall rate of CRC diagnosis decreased from 12.32% in 2008 to 10.36% in 2016. About 47.26% of the patients had a Charlson Comorbidity Index (CCI) score ≤ 2. The bivariate analysis of racial disparity revealed that African American with CRC are younger than their counterpart Caucasian (p &amp;lt; 0.0001), and they are generally more likely to be late-stage diagnosis (59.41% vs. 52.65%; P &amp;lt; 0.0001). Time to treatment initiation is statistically higher among Black than White (p = 0.0307). The fully adjusted multilevel logistic regression model showed a nonexistent racial disparity in late stage diagnosis between White and Black. The odds of late-stage CRC diagnosis were higher among younger patients (&amp;lt;50), those with a CCI score greater than 5, and among the uninsured and self-pay (All P&amp;lt;0.05). For treatment patterns, younger patients (&amp;lt;50) had higher odds of having surgery, performing chemotherapy and radiation. The odds of surgery are less likely among Black and more likely among those with a private insurance, and a CCI score between 3 and 5 (All P&amp;lt;0.05). Finally, the likelihood of performing radiation is statistically significantly less among patients with a CCI score between 3 and 5 and above 5, [OR=0.563 (95%CI: 0.398 - 0.795]. Race, sex, and marital status were not significant predictors of late stage CRC, chemotherapy, and radiation. Conclusion: The impact of patient demographics and clinical factors on late stage and treatment patterns is striking in Virginia. These findings suggest the need for policy to try to delineate those factors associated with those disparities. Citation Format: Hadiza Galadima, Georges Adunlin, Marybeth Hughes, and Jennifer May. Racial disparity, stage at diagnosis, and treatment patterns of colorectal cancer: Analysis of data from a hospital-based cancer registry, Virginia 2008-2016 [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C005.