CDX2 Loss Research Articles

Cdx2 Regulates Intestinal EphrinB1 through the Notch Pathway.

The majority of colorectal cancers harbor loss-of-function mutations in APC, a negative regulator of canonical Wnt signaling, leading to intestinal polyps that are predisposed to malignant progression. Comparable murine APC alleles also evoke intestinal polyps, which are typically confined to the small intestine and proximal colon, but do not progress to carcinoma in the absence of additional mutations. The Cdx transcription factors Cdx1 and Cdx2 are essential for homeostasis of the intestinal epithelium, and loss of Cdx2 has been associated with more aggressive subtypes of colorectal cancer in the human population. Consistent with this, concomitant loss of Cdx1 and Cdx2 in a murine APC mutant background leads to an increase in polyps throughout the intestinal tract. These polyps also exhibit a villous phenotype associated with the loss of EphrinB1. However, the basis for these outcomes is poorly understood. To further explore this, we modeled Cdx2 loss in SW480 colorectal cancer cells. We found that Cdx2 impacted Notch signaling in SW480 cells, and that EphrinB1 is a Notch target gene. As EphrinB1 loss also leads to a villus tumor phenotype, these findings evoke a mechanism by which Cdx2 impacts colorectal cancer via Notch-dependent EphrinB1 signaling.

S1656 Not Your Standard Adenocarcinoma, a Case of Medullary Carcinoma of the Colon

INTRODUCTION: Adenocarcinoma of the colon is the most common type of colon cancer. Medullary carcinoma (MC) of the colon is a rare histological subtype of adenocarcinoma. MC has been described to have specific histopathological features but can still be difficult to distinguish from poorly differentiated adenocarcinoma. We aim in this case report to shed light on this rare subtype of colon cancer and describe its histopathological features. CASE DESCRIPTION/METHODS: 76-year-old male presented to our hospital reporting 3 months of back pain, fatigue, and 10lb weight loss. Past medical history significant for atrial fibrillation and history of renal cell carcinoma. CT abdomen/pelvis showed a necrotic mass within the ascending colon suggestive of colon cancer. Metastatic lymph nodes were also suspected on the scan. Subsequent colonoscopy showed a large mass at the hepatic flexure. Multiple biopsies were taken from mass. Histopathologic sections showed sheets of malignant epithelial cells extending from the submucosa into the lamina propria. Immunohistochemical staining demonstrated that the malignant cells were positive for pan-cytokeratin, but negative for CK20, CDX2, S-100, CD45, synaptophysin, chromogranin, and PSA. These initial findings were consistent with invasive poorly differentiated carcinoma. Further immunohistochemical testing was done and showed mismatch repair deficiency with loss of MLH1 and PMS2 consistent with medullary carcinoma of the colon, which typically shows aberrant loss of CK20 and CDX2 (typical markers of colorectal adenocarcinoma). Due to patients advanced disease (stage IV), decision made to start palliative chemotherapy with Xeloda + Oxaliplatin + Avastin. Patient passed away approximately three months after initial diagnosis. DISCUSSION: MC of the colon is extremely rare with limited clinical and epidemiologic data. Based on population-based analysis, medullary carcinoma makes up 5-8 cases for every 10,000 colon cancers diagnosed. Most patients are diagnosed earlier in the disease course and metastatic disease is seen in 10% of patients at time of diagnosis. Immunohistochemical analysis is essential to differentiate from poorly-differentiated and undifferentiated colon adenocarcinomas. Classic findings include loss of staining for MLH-1 and CDX-2. In the current published data, overall prognosis of MC is favorable when compared to poorly differentiated or undifferentiated adenocarcinomas. However, data is limited regarding available treatment strategies and response.Figure 1

Colorectal Adenocarcinomas Harboring ALK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 12 Cases and Review of the Literature.

This study determined the frequency and the clinicopathologic and genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.

Detection of postoperative plasma circulating tumour DNA and lack of CDX2 expression as markers of recurrence in patients with localised colon cancer

BackgroundColon cancer (CC) is a heterogeneous disease. Novel prognostic factors beyond pathological staging are required to accurately identify patients at higher risk of relapse. Integrating these new biological factors, such as plasma circulating tumour DNA (ctDNA), CDX2 staining, inflammation-associated cytokines and transcriptomic consensus molecular subtypes (CMS) classification, into a multimodal approach may improve our accuracy in determining risk of recurrence.MethodsOne hundred and fifty patients consecutively diagnosed with localised CC were prospectively enrolled in our study. ctDNA was tracked to detect minimal residual disease by droplet digital PCR. CDX2 expression was analysed by immunostaining. Plasma levels of cytokines potentially involved in disease progression were measured using ELISAs. A 96 custom gene panel for nCounter assay was used to classify CC into colorectal cancer assigner and CMS.ResultsMost patients were classified into CMS4 (37%) and CMS2 (28%), followed by CMS1 (20%) and CMS3 (15%) groups. CDX2-negative tumours were enriched in CMS1 and CMS4 subtypes. In univariable analysis, prognosis was influenced by primary tumour location, stage, vascular and perineural invasion together with high interleukin-6 plasma levels at baseline, tumours belonging to CMS 1 vs CMS2 +CMS3, ctDNA presence in plasma and CDX2 loss. However, only positive ctDNA in plasma samples (HR 13.64; p=0.002) and lack of CDX2 expression (HR 23.12; p=0.001) were found to be independent prognostic factors for disease-free survival in the multivariable model.ConclusionsctDNA detection after surgery and lack of CDX2 expression identified patients at very high risk of recurrence in localised CC.

Colonic Adenocarcinomas Harboring NTRK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 16 Cases and Review of the Literature.

This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair-deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/β-catenin (APC, AMER1, CTNNB1), p53, and TGFβ (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.

CDX2 Loss With Microsatellite Stable Phenotype Predicts Poor Clinical Outcome in Stage II Colorectal Carcinoma.

Current risk factors in stage II colorectal carcinoma are insufficient to guide treatment decisions. Loss of CDX2 has been shown to associate with poor clinical outcome and predict benefit for adjuvant chemotherapy in stage II and III colorectal carcinoma. The prognostic relevance of CDX2 in stage II disease has not been sufficiently validated, especially in relation to clinical risk factors, such as microsatellite instability (MSI) status, BRAF mutation status, and tumor budding. In this study, we evaluated the protein expression of CDX2 in tumor center and front areas in a tissue microarrays material of stage II colorectal carcinoma patients (n=232). CDX2 expression showed a partial or total loss in respective areas in 8.6% and 10.9% of patient cases. Patients with loss of CDX2 had shorter disease-specific survival when scored independently either in tumor center or tumor front areas (log rank P=0.012; P=0.012). Loss of CDX2 predicted survival independently of other stage II risk factors, such as MSI status and BRAF mutation status, pT class, and tumor budding (hazard ratio=5.96, 95% confidence interval=1.55-22.95; hazard ratio=3.70, 95% confidence interval=1.30-10.56). Importantly, CDX2 loss predicted inferior survival only in patients with microsatellite stable, but not with MSI-high phenotype. Interestingly, CDX2 loss associated with low E-cadherin expression, tight junction disruption, and high expression of ezrin protein. The work demonstrates that loss of CDX2 is an independent risk factor of poor disease-specific survival in stage II colorectal carcinoma. Furthermore, the study suggests that CDX2 loss is linked with epithelial-to-mesenchymal transition independently of tumor budding.

Immunohistochemical pattern of liver metastases and paired sample analysis in patients with metastatic pancreatic cancer: Pronounced CDX2 expression and loss of SMAD4 indicate poor survival

Immunohistochemical pattern of liver metastases and paired sample analysis in patients with metastatic pancreatic cancer: Pronounced CDX2 expression and loss of SMAD4 indicate poor survival

CDX2 and Muc2 immunohistochemistry as prognostic markers in stage II colon cancer

The treatment for colorectal cancer is largely surgical followed by adjuvant chemotherapy in high-risk cases. In patients with stage II cancer, there is no clear benefit for chemotherapy, and the current tools for assessment of risk are inadequate. A recent study identified that colorectal cancer with a gene signature similar to undifferentiated colonic stem cells was associated with a worse outcome. It was later shown that loss of CDX2 detected by immunohistochemistry (IHC) alone resulted in a worse prognosis and that this could be used to predict patients who would benefit from chemotherapy. Having observed that CDX2 expression can be patchy, we elected to validate these prior results for clinical practice using whole-slide IHC. The pathology of all cases was reviewed, and 3 blocks were selected for CDX2 IHC. We also expanded the panel beyond CDX2 to assess whether other markers in the gene signature including CDX1, Muc2, GPX2, and villin could better predict outcome. Among 210 cases, CDX2 expression was diffusely lost in 11% and focally lost in 23% of cases. There was no difference in survival based on CDX2 expression, but Muc2 loss was associated with reduced survival (hazard ratio, 3.32; 95% confidence interval, 1.20 to 9.20). No significant differences in outcome were identified based on CDX1, GPX2, or villin expression. In keeping with this, assessment of The Cancer Genome Atlas gene expression data demonstrated that decreased Muc2 expression was associated with reduced overall survival. Our results with whole-slide IHC are different from the previous studies and caution against the use of CDX2 in isolation as a prognostic marker in clinical practice. We have identified that loss of Muc2 is associated with reduced survival. This supports the use of the colonic differentiation gene expression signature to identify high-risk patients but cautions against the use of any one IHC-based marker in isolation.

Histopathological and Immunohistochemical Study of the Prognostic Significance of Cox2 and CDX2 Expression in the Available Cases of Colorectal Carcinoma

AbstractBackground: Colorectal cancer is the third most common cancer worldwide. In Egypt, the relative frequency of colorectal cancer is about 9-12% with high male predominance 3:1. Several proteins are associated with the development and progression of colorectal cancer including Cox2 and CDX2 proteins. However, it is still controversial whether Cox2 and CDX2 expression can be regarded as prognostic factors for colorectal cancer patients.Aim of Study: The purpose of this study is to detect the immunohistochemical expression of Cox2 and CDX2 in colorectal carcinoma and correlate their expression with the available clinicopathological parameters to illustrate their prognostic role.Material and Methods: Fifty cases of colorectal carcinoma in colectomy specimens were collected retrospectively. They were stained by H & E, Cox2 and CDX2 for immunohisto-chemical study. The relations between their expression and the available clinicopathological parameters were evaluated.Results: Cox2 expression in colorectal carcinoma showed statistically significant relation with depth of tumor invasion, lymph node status, distant metastasis and tumor stage. CDX2 expression showed statistically significant inverse relation with histopathological grade, depth of tumor invasion, lymph node status, distant metastasis, tumor stage and vascular invasion. There was statistically significant relation between the immunohistochemical expression of Cox2 and CDX2 in colorectal carcinoma.Conclusions: Expression of Cox2 and loss of CDX2 are usually related to poor outcome and metastasis in colorectal cancer.

CDX2 in colorectal cancer is an independent prognostic factor and regulated by promoter methylation and histone deacetylation in tumors of the serrated pathway

BackgroundIn colorectal cancer, CDX2 expression is lost in approximately 20% of cases and associated with poor outcome. Here, we aim to validate the clinical impact of CDX2 and investigate the role of promoter methylation and histone deacetylation in CDX2 repression and restoration.MethodsCDX2 immunohistochemistry was performed on multi-punch tissue microarrays (n = 637 patients). Promoter methylation and protein expression investigated on 11 colorectal cancer cell lines identified two CDX2 low expressors (SW620, COLO205) for treatment with decitabine (DNA methyltransferase inhibitor), trichostatin A (TSA) (general HDAC inhibitor), and LMK-235 (specific HDAC4 and HDAC5 inhibitor). RNA and protein levels were assessed. HDAC5 recruitment to the CDX2 gene promoter region was tested by chromatin immunoprecipitation.ResultsSixty percent of tumors showed focal CDX2 loss; 5% were negative. Reduced CDX2 was associated with lymph node metastasis (p = 0.0167), distant metastasis (p = 0.0123), and unfavorable survival (multivariate analysis: p = 0.0008; HR (95%CI) 0.922 (0.988–0.997)) as well as BRAFV600E, mismatch repair deficiency, and CpG island methylator phenotype. Decitabine treatment alone induced CDX2 RNA and protein with values from 2- to 25-fold. TSA treatment ± decitabine also led to successful restoration of RNA and/or protein. Treatment with LMK-235 alone had marked effects on RNA and protein levels, mainly in COLO205 cells that responded less to decitabine. Lastly, decitabine co-treatment was more effective than LMK-235 alone at restoring CDX2.ConclusionCDX2 loss is an adverse prognostic factor and linked to molecular features of the serrated pathway. RNA/protein expression is restored in CDX2 low-expressing CRC cell lines by demethylation and HDAC inhibition. Importantly, our data underline HDAC4 and HDAC5 as new epigenetic CDX2 regulators that warrant further investigation.

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer.

We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I–IV primary CRCs by gene expression (n = 403) or immunohistochemistry (n = 642) and in relation to 5‐year relapse‐free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I–III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF‐mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5‐year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2‐negative cell lines were significantly more sensitive to chemotherapeutics than CDX2‐positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2‐negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early‐stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF.

Abstract 574: BRAF V600E mutation and loss of CDX2 synergize in serrated colorectal tumorigenesis

Abstract While many CRCs arise from adenomatous polyps through what we call “adenoma-carcinoma sequence,” it has been estimated that up to 20% of CRCs likely evolve from an alternative pathway, so-called ‘‘serrated pathway.' However, only 8-10% of CRCs display definitive serrated morphology at diagnosis. We previously examined expression of differentiation and molecular markers that are most likely to be involved in serrated tumor development by using 36 serrated CRCs and found CDX2 loss or BRAF mutations often together. We then generated a mouse model that can be induced concurrent biallelic inactivation of Cdx2 (Cdx2-/-) and expression of mutant BRAFV600E in adult mouse colon epithelium, and the Cdx2-/-/BrafV600E tumors showed a quite similar phenotype to that of CDX2-negative serrated CRCs. Through the validation of global gene expression profile including the mouse models and human CRCs, we focused on ADAM28 as a candidate because ADAM28 was significantly upregulated in Cdx2-/-/BrafV600E tumor and CRCs with low CDX2 expression and BRAFV600E mutation. We examined ADAM28 expression using 12 CRC cases with BRAFV600E mutation (8 of 12 displayed serrated feature) and 12 CRC cases with KRAS codon 12/13 mutation and found that ADAM28 was specifically upregulated in BRAF mutant CRC cases. Among 10 CRC cell lines (DLD-1, Lovo, SW48, SW480, SW837, SW1116, Caco2, RKO, HT-29, HCT-116), only HT-29, which has many phenotypic and genetic similarities to serrated CRC, showed a robust expression of membranous type ADAM28, and 9 of 10 CRC cells, except for RKO, showed weak to modest expression of active-form ADAM28. Further in-depth studies are ongoing to clarify the solid evidences, especially the utility of ADAM28 as a diagnostic marker for serrated CRCs and the direct effect of ADAM28 onto cell growth of CRC cells using ADAM28-specific antibody. We present a novel transgenic model of human serrated CRC to highlight the suitability of centering on CDX2 loss and BRAFV600E in the pathogenesis. This model has a great potential to figure out the mechanisms underlying in serrated tumor progression and identify the candidates of new biomarkers and therapeutic targets of CRCs with serrated morphology. Citation Format: Naoya Sakamoto, Ying Feng, Takuya Hattori, Masayuki Shimoda, Akira Ishikawa, Ririno Honma, Takao Hinoi, Hiroyuki Egi, Hideki Ohdan, Yasunori Okada, Eric Fearon, Wataru Yasui. BRAFV600E mutation and loss of CDX2 synergize in serrated colorectal tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 574.

Prognostic significance of CDX2 immunoexpression in poorly differentiated clusters of colorectal carcinoma.

CDX2 is a transcription factor that acts as a tumor suppressor in colorectal cancer (CRC). Its loss triggers metastatic process and tumor progression; however, its prognostic role in patients with CRC is still controversial. Poorly differentiated clusters (PDCs) are aggregates of neoplastic cells which likely have high metastatic potential in CRC. In this study, we analyzed and compared CDX2 expression in PDC (CDX2-PDC) and corresponding main tumor (CDX2 main tumor) in 42 CRCs showing at least 10 PDC (PDC G3). Five of 42 CRCs (12%) were classified as CDX2 main tumor negative (4/5 were also PDC-CDX2 negative); all had tumor recurrence and died of CRC. Twenty nine of 42 cases were CDX2-PDC negative. Among CRC CDX2 main tumor positive, 15 had recurrences and 13 died from CRC; 13 and 11 of them, respectively, were CDX2-PDC negative. By assigning one point to CDX2 main tumor or CDX2-PDC positivity, we assessed CDX2-staining score for each case. Twelve cases had CDX2-staining score 2 (CDX2 positive in main tumor and PDC); 26 had score 1 (CDX2 positive in main tumor or PDC), and 4 had CDX2 score 0 (CDX2 negative in main tumor and PDC). In our patients, CDX2-staining score had higher prognostic value compared to CDX2 main tumor or CDX2-PDC alone. In addition, it represented a significant and independent prognostic variable for disease-free survival (DFS) and cancer-specific survival (CSS). Our findings suggest that, although loss of CDX2 in the main tumor identifies high-risk patients with high specificity, CDX2-PDC should also be considered in CDX2 main tumor positive cases to predict prognosis.

Loss of CDX2 is correlated to high grade and advanced stage in colorectal carcinoma pathology department of FSI Hospital Tunisia

Loss of CDX2 is correlated to high grade and advanced stage in colorectal carcinoma pathology department of FSI Hospital Tunisia

Clinicopathologic profile, immunophenotype, and genotype of CD274 (PD-L1)-positive colorectal carcinomas

The CD274 (PD-L1)/PDCD1 (PD-1) pathway is crucial for the modulation of immune responses and self-tolerance. Aberrantly expressed CD274 allows tumor cells to evade host immune system and is considered to be a mechanism of adaptive immune resistance. Inhibition of the CD274/PDCD1 immune checkpoint offers a promising new therapeutic strategy. Although CD274-expressing tumor cells have been identified in different types of tumors including colorectal cancer, clinicopathologic profile of these CD274-positive tumors has not been extensively studied. In this study, 454 primary colorectal carcinomas were analyzed histologically and immunohistochemically for CD274, mismatch repair (MMR) proteins, intestinal differentiation marker (CDX2), and stem cell markers (ALCAM, ALDH1A1, and SALL4). CD274-positive colorectal carcinomas (54/454 (12%)) usually (83%) involved the right or transverse colon with poorly differentiated and solid/medullary histology. On the basis of multivariate logistic regression analysis, CD274 positivity was significantly associated with poorly differentiated histotype (OR: 3.32; 95% CI: 1.46–7.51; P=0.004), MMR deficiency (OR: 10.0; 95% CI: 4.66–21.5; P<0.001), and ‘stem-like’ immunophenotype defined by the loss or weak expression of CDX2 and ALCAM-positivity (OR: 5.51; 95% CI: 1.66–18.3; P=0.005). Mutation analysis of 66 arbitrary selected colorectal carcinomas revealed that CD274-positive tumors usually (88%) carried the BRAF V600E mutation. Thus, colorectal carcinomas defined by CD274 positivity displayed features associated with tumors arising via the serrated neoplasia pathway. Moreover, colorectal carcinomas characterized by lack of CDX2 and prominent expression of ALCAM frequently (71%) showed CD274 positivity. This might suggest association of CD274 expression with ‘stem-like’ phenotype. Further evaluation of a larger cohort or experimental analyses would be needed to confirm this notion.

BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis.

While 20-30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8-10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from 'serrated' versus 'conventional adenoma' precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss or BRAF mutations in ~60% of cases and often together (p=0.04). CDX2Null/BRAFV600E expression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAFV600E potently interacted with CDX2 silencing to alter gene expression. Like human serrated lesions, CDX2Null/BRAFV600E-mutant epithelium expressed gastric markers. Organoids from CDX2Null/BRAFV600E-mutant colon epithelium showed serrated features, and partially recapitulated the gene expression pattern in mouse colon tissues. We present a novel mouse tumor model based on signature defects seen in many human serrated CRCs - CDX2 loss and BRAFV600E. The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis.

Essential roles for Cdx in murine primitive hematopoiesis

The Cdx transcription factors play essential roles in primitive hematopoiesis in the zebrafish where they exert their effects, in part, through regulation of hox genes. Defects in hematopoiesis have also been reported in Cdx mutant murine embryonic stem cell models, however, to date no mouse model reflecting the zebrafish Cdx mutant hematopoietic phenotype has been described. This is likely due, in part, to functional redundancy among Cdx members and the early lethality of Cdx2 null mutants. To circumvent these limitations, we used Cre-mediated conditional deletion to assess the impact of concomitant loss of Cdx1 and Cdx2 on murine primitive hematopoiesis. We found that Cdx1/Cdx2 double mutants exhibited defects in primitive hematopoiesis and yolk sac vasculature concomitant with reduced expression of several genes encoding hematopoietic transcription factors including Scl/Tal1. Chromatin immunoprecipitation analysis revealed that Scl was occupied by Cdx2 in vivo, and Cdx mutant hematopoietic yolk sac differentiation defects could be rescued by expression of exogenous Scl. These findings demonstrate critical roles for Cdx members in murine primitive hematopoiesis upstream of Scl.

561P - CDX2 loss as a prognostic and predictive biomarker in metastatic colorectal cancer

561P - CDX2 loss as a prognostic and predictive biomarker in metastatic colorectal cancer

Early marker of DNA damage response, atm, as a predictor of clinical outcome following radiotherapy in rectal cancer patients

Early marker of DNA damage response, atm, as a predictor of clinical outcome following radiotherapy in rectal cancer patients

Histopathology of interspincteric resection specimens of low rectal cancer: An institutional experience of a series of 41 patients

Histopathology of interspincteric resection specimens of low rectal cancer: An institutional experience of a series of 41 patients