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

Graule, Janina; Uth, Kristin; Fischer, Elia; Centeno, Irene; Galván, José A.; Eichmann, Micha David; Rau, Tilman T.; Langer, Rupert; Dawson, Heather; Nitsche, Ulrich; Traeger, Peter; Berger, Martin D.; Schnüriger, Beat; Hädrich, Marion; Studer, Peter; Inderbitzin, Daniel; Lugli, Alessandro; Tschan, Mario P.; Zlobec, Inti

doi:10.1186/s13148-018-0548-2

Cited by 57 publications

(51 citation statements)

References 32 publications

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“…With regard to CDX2 expression, it should be noted that the CDX2‐negative tumors represent a larger fraction in this cohort compared with the original Dalerba et al cohort . Our results are in concordance with recent studies that exhibited higher expression rates of CDX2 absence/loss in stage II tumors . Nevertheless, our results confirm the role of CDX2 expression as a prognostic factor, as has been previously demonstrated, and also display its correlation to tumor location.…”

Section: Discussionsupporting

confidence: 93%

Sidedness Matters: Surrogate Biomarkers Prognosticate Colorectal Cancer upon Anatomic Location

et al. 2019

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Background Anatomic location of primary tumors across the colon correlate with survival in the metastatic setting, whereas left‐sided tumors may exhibit superior survival compared with right‐sided tumors. The Oncotype Recurrence Score (RS) assay is a clinically validated predictor of recurrence risk in patients with stage II colorectal cancer (CRC). Previous studies had indicated that without adjuvant chemotherapy, CDX2‐negative stage II CRC tumors are associated with a lower rate of disease‐free survival than CDX2‐positive stage II CRC tumors. We aimed to evaluate whether these two validated prognostic biomarkers may correlate with primary tumor location, and whether tumor location may reflect differential prognosis in stage II CRC. Materials and Methods We retrospectively analyzed patients with T3 mismatch repair‐proficient (MMR‐P) stage II CRC for whom RS assay was performed. Pathological report was reviewed for exact primary tumor location and CDX2 immunostaining. RS and CDX2 expression were correlated with primary tumor location. Results The analysis included 1,147 patients with MMR‐P stage II CRC (median age 69 years [range 29–93]). Tumor distribution across the colon was as follows: 46% (n = 551) were right‐sided and 54% (n = 596) were left‐sided. RS was higher in right‐sided tumors (p = .01). The RS results gradually decreased across the colon (cecum, highest score; sigmoid, lowest score; p = .04). Right‐sided tumors exhibited more CDX2‐negative tumors (p = .07). Conclusion Our study indicates that right‐sided colorectal tumors may display worse prognosis compared with left‐sided tumors in MMR‐P stage II CRC. Primary tumor location may serve as a prognostic factor that should be taken into account for recurrence risk assessment and consideration of adjuvant treatment. Implications for Practice Sidedness matters, even in stage II colorectal cancer (CRC). Using two previously established prognostic tools, the Oncotype DX assay and CDX2 expression, this study found that right‐sided tumors may display worse prognosis compared with left‐sided tumors in mismatch repair‐proficient stage II CRC. Therefore, primary tumor location should be taken into account for recurrence risk assessment and consideration of adjuvant treatment.

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Section: Discussionsupporting

confidence: 93%

Sidedness Matters: Surrogate Biomarkers Prognosticate Colorectal Cancer upon Anatomic Location

et al. 2019

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“…According to the CCLE data, however, CDX2 copy number is poorly correlated with gene expression, and furthermore, in a real patient dataset (TCGA), mRNA expression was not significantly different between patients harboring a gain or amplification of chr13q12.2. However, as a recent study described that CDX2 loss through demethylation and HDAC inhibition is an adverse prognostic factor and linked to molecular features of the serrated pathway [68], CDX2 may act as an oncogene in tumors with a high expression of CDX2, but this is not necessarily applicable to all cases of CRC with chr13q12.2 aberration.…”

Section: Discussionmentioning

confidence: 99%

Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer

et al. 2020

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Background: Bevacizumab, a monoclonal antibody against soluble VEGFA, is an approved and commonly administered anti-angiogenic drug in patients with metastasized colorectal cancer (mCRC). The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months, and acquired resistance mechanisms are largely unknown. Here, we employed whole-genome sequencing of plasma DNA to evaluate the tumor genome of patients undergoing treatment with bevacizumab to determine novel aberrations associated with resistance. Methods: Using longitudinal plasma analyses, we studied the evolution of tumor genomes in a mCRC cohort (n = 150) and conducted analyses of CRC cases from The Cancer Genome Atlas (TCGA) database (n = 619) to identify associations between genomic aberrations and clinical features. We employed whole-genome sequencing to identify the most frequently occurring focal somatic copy number alterations (SCNAs). Using the TCGA data as a comparative and supporting dataset, we defined the minimally amplified overlapping region and studied the mechanistic consequences of copy number gain of the involved genes in this segment. In addition, we established an in vitro cell model and conducted downstream gene expression and cell viability assays to confirm our findings from the patient dataset. Results:We observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of CRC cases from the TCGA database suggested that this amplicon is associated with more advanced stages. We confirmed that this 13q12.2 amplicon frequently emerges later during the clinical course of disease. After defining the minimally amplified region, we observed that the amplification and expression of one gene, POLR1D, impacted cell proliferation and resulted in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab treatment. In fact, in several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with therapy resistance. Conclusions: Non-invasive analyses of cell-free DNA from patients undergoing treatment with bevacizumab enabled the tracking of evolving tumor genomes and helped identify a recurrent focal SCNA of clinical relevance. Here, we describe a novel resistance mechanism against a widely applied treatment in patients with mCRC which will impact the clinical management of patients.

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“…Our current studies also highlights the detailed mechanism of Wnt/β-catenin pathway regulated by JARID1B in CRC cells. Caudal-type homeobox transcription factor 2 (CDX2), an essential intestinespecific regulator, is involved in the development and differentiation of intestinal epithelial cells and regulates the balance between cell proliferation and differentiation [33]. In the present study, many studies revealed that CDX2 expression level was associated with CRC cells proliferation and poor prognosis for patients with CRC [34].…”

Section: Discussionmentioning

confidence: 60%

JARID1B promotes colorectal cancer proliferation and Wnt/β-catenin signaling via decreasing CDX2 level

Huang

Xiao

Hua

et al. 2020

Preprint

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Background: Jumonji AT-rich interactive domain 1B(JARID1B) has been shown to be upregulated in many human cancers and plays a critical role in the development of cancers cells. Nevertheless, its functional role in colorectal cancer (CRC) progression is not fully understood. Methods: Herein, JARID1B expression levels were detected in clinical CRC samples by western blotting and qRT-PCR. DLD-1 cells with JARID1B knockdown or overexpression by stably transfected plasmids were used in vitro and in vivo study. Colony formation, 5-ethynyl-20-deoxyuridine (EdU) and Real Time Cellular Analysis(RTCA) assays were used to detect cell proliferation and growth. Transcriptome and CHIP assays were used to examine the molecular biology changes and molecular interaction in these cells. Nude mice was utilized to study the correlation of JARID1B and tumor growth in vivo. Results: Here, we first observed that JARID1B was significantly upregulated in CRC tissue compared to adjacent normal tissues. In CRC patients, JARID1B high expression was positively relation with poor overall survival. Multivariate analyses revealed that high JARID1B expression was an independent predictive marker for the poor prognosis of CRC. In addition, we found that JARID1B promoted CRC cells proliferation by Wnt/β-catenin signaling pathway. Further studies demonstrated CDX2 as a downstream target of JARID1B, and our data demonstrated that CDX2 is crucial for JARID1B -mediated Wnt/β-catenin signaling pathway. Mechanistically, we demonstrated that JARID1B regulated CDX2 expression through demethylation of H3K4me3. Conclusions: CDX2 inhibited by JARID1B-derived H3K4me3 methylation promoted cells proliferation of CRC via Wnt/β-catenin signaling pathway. Therefore, our studies provided a novel insight into the role of JARID1B in CRC cells proliferation and potential new molecular target for treating CRC.

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

Cited by 57 publications

References 32 publications

Sidedness Matters: Surrogate Biomarkers Prognosticate Colorectal Cancer upon Anatomic Location

Sidedness Matters: Surrogate Biomarkers Prognosticate Colorectal Cancer upon Anatomic Location

Cell-free DNA analysis reveals POLR1D-mediated resistance to bevacizumab in colorectal cancer

JARID1B promotes colorectal cancer proliferation and Wnt/β-catenin signaling via decreasing CDX2 level

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