ETV5 expression positively correlates with promoter methylation and predicts response for 5-FU-based adjuvant therapy response in proximal colon cancer

Mapping Intimacies ◽

10.1101/2020.09.08.287953 ◽

2020 ◽

Author(s):

Anil K Giri

Keyword(s):

Colon Cancer ◽

Cellular Proliferation ◽

Locally Advanced ◽

Therapy Response ◽

Predictive Biomarker ◽

Therapy Resistance ◽

The Cancer Genome Atlas ◽

Stage Ii ◽

Epigenetic Mechanism ◽

Cancer Tissue

AbstractDiscovery of markers predictive for 5-Fluorouracil (5-FU)-based adjuvant chemotherapy (adjCTX) response in patients with locally advanced stage II and III colorectal cancer (CRC) is necessary for early identification of potential responders as only 20-65% of CRC patients benefit from the treatment. PEA3 subfamily of ETS transcription factors (ETV1, ETV4, and ETV5) are upregulated in multiple cancers including colon cancers. However, the underlying epigenetic mechanism regulating their overexpression and their role in predicting therapy response in colon cancer is largely unexplored. In this study, using gene expression and methylation data from The Cancer Genome Atlas (TCGA) project, we showed that promoter DNA methylation negatively correlates with ETV4 expression (ρ= -0.17, p=5.6×10−3) and positively correlates with ETV5 expression (ρ= 0.22, p=1.43×10−4) in colon cancer tissue. Further, our analysis in 662 colon cancer patients treated with 5-FU-based-adjCTX revealed that higher ETV5 expression associated with shorter relapse-free survival (RFS) of treated patients with proximal tumors (Hazard ratio = 3.30 - 6.22, p=0.005-0.02). We also observed higher expression of signaling molecules involved in cellular proliferation (e.g. GNB5, DUSP4, FYN) in patients with high ETV5 level, suggesting that the increased cellular proliferation due to overexpression of these genes could drive the therapy resistance. The present study suggests ETV5 expression as a strong predictive biomarker for 5-FU-based adjCTX response in stage II/III CRC patients with proximal tumors.

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Higher ETV5 Expression Associates With Poor 5-Florouracil-Based Adjuvant Therapy Response in Colon Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2020.620811 ◽

2021 ◽

Vol 11 ◽

Author(s):

Anil K. Giri

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Locally Advanced ◽

Therapy Response ◽

Predictive Biomarker ◽

The Cancer Genome Atlas ◽

Stage Ii ◽

Epigenetic Mechanism ◽

Cancer Tissue ◽

Colon Cancers

Discovery of markers predictive for 5-Fluorouracil (5-FU)-based adjuvant chemotherapy (adjCTX) response in patients with locally advanced stage II and III colon cancer (CC) is necessary for precise identification of potential therapy responders. PEA3 subfamily of ETS transcription factors (ETV1, ETV4, and ETV5) are upregulated in multiple cancers including colon cancers. However, the underlying epigenetic mechanism regulating their overexpression as well as their role in predicting therapy response in colon cancer are largely unexplored. In this study, using gene expression and methylation data from The Cancer Genome Atlas (TCGA) project, we showed that promoter DNA methylation negatively correlates with ETV4 expression (ρ = −0.17, p = 5.6 × 10–3) and positively correlates with ETV5 expression (ρ = 0.22, p = 1.43 × 10–4) in colon cancer tissue. Further, our analysis in 1,482 colon cancer patients from five different cohorts revealed that higher ETV5 expression associates with shorter relapse-free survival (RFS) of adjCTX treated colon cancer patients (Hazard ratio = 2.09–5.43, p = 0.004–0.01). The present study suggests ETV5 expression as a strong predictive biomarker for 5-FU-based adjCTX response in stage II/III CC patients.

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Platelets harbor prostate cancer biomarkers and the ability to predict therapeutic response in castration-resistant patients.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.e583 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. e583-e583

Author(s):

Camilla Thellenberg Karlsson ◽

Lee-ann Tjon-Kon-Fat ◽

Marie Lundholm ◽

Mona Schröder ◽

Thomas Wurdinger ◽

...

Keyword(s):

Prostate Cancer ◽

Best Practice ◽

Therapy Response ◽

Progression Free Survival ◽

Predictive Biomarker ◽

Therapy Resistance ◽

Castration Resistant Prostate Cancer ◽

Androgen Synthesis ◽

Castration Resistant ◽

Biomarker Analysis

e583 Background: Novel therapies for castration resistant prostate cancer (CRPC) have been introduced in the clinic with possibilities for individualized treatment plans. Best practice of those expensive drugs requires predictive biomarker monitoring. This study used circulating biomarker analysis to follow cancer-derived transcripts implicated in therapy resistance. Methods: The isolated platelet population of blood samples and QRT-PCR were used to identify selected biomarker transcripts in patients with CRPC prior chemo- or androgen synthesis directed therapies. The association between biomarker status in platelets (positive vs. negative) and therapy response, progression-free survival (PFS) and overall survival (OS) was examined. Results: Fifty patients received either docetaxel (n = 24) or abiraterone (n = 26) therapy, with therapy response rates of 54% and 48%, respectively. Transcripts for the PC-associated biomarkers kallikrein-related peptidase-3 ( KLK3), androgen receptor splice-variant 7 (ARV7), folate hydrolase 1 (FOLH1), and neuropeptide-Y ( NPY) were present within the platelet fraction. Analyzing biomarkers in the chemotherapy group did not add information about PFS, but FOLH1 was associated with short OS (p = 0.00015). In the abiraterone treated cohort, detectable FOLH1 (p = 0.009), KLK3 (p = 0.018), and NPY (p = 0.028) were all associated with short PFS. Patients with biomarker-negative platelets had the best outcome, while FOLH1 and NPY provided independent predictive information regarding PFS and KLK3 (p = 0.001) and FOLH1 (p = 0.002) were associated with short OS. Conclusions: Analyzing tumor-derived biomarkers in platelets of CRPC patients enabled prediction of the outcome after abiraterone therapy with high accuracy. Platelet-based analysis of FOLH1, NPY, and KLK3 may be used for treatment stratification of patients scheduled for treatment with abiraterone.

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Evolutionary genetic algorithm identifies IL2RB as a potential predictive biomarker for immune-checkpoint therapy in colorectal cancer

NAR Genomics and Bioinformatics ◽

10.1093/nargab/lqab016 ◽

2021 ◽

Vol 3 (2) ◽

Author(s):

Matthew Alderdice ◽

Stephanie G Craig ◽

Matthew P Humphries ◽

Alan Gilmore ◽

Nicole Johnston ◽

...

Keyword(s):

Colorectal Cancer ◽

Evolutionary Algorithm ◽

Immune Checkpoint ◽

Strong Association ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

The Cancer Genome Atlas ◽

Immune Checkpoints ◽

Cancer Tissue ◽

Specific Staining

Abstract Identifying robust predictive biomarkers to stratify colorectal cancer (CRC) patients based on their response to immune-checkpoint therapy is an area of unmet clinical need. Our evolutionary algorithm Atlas Correlation Explorer (ACE) represents a novel approach for mining The Cancer Genome Atlas (TCGA) data for clinically relevant associations. We deployed ACE to identify candidate predictive biomarkers of response to immune-checkpoint therapy in CRC. We interrogated the colon adenocarcinoma (COAD) gene expression data across nine immune-checkpoints (PDL1, PDCD1, CTLA4, LAG3, TIM3, TIGIT, ICOS, IDO1 and BTLA). IL2RB was identified as the most common gene associated with immune-checkpoint genes in CRC. Using human/murine single-cell RNA-seq data, we demonstrated that IL2RB was expressed predominantly in a subset of T-cells associated with increased immune-checkpoint expression (P < 0.0001). Confirmatory IL2RB immunohistochemistry (IHC) analysis in a large MSI-H colon cancer tissue microarray (TMA; n = 115) revealed sensitive, specific staining of a subset of lymphocytes and a strong association with FOXP3+ lymphocytes (P < 0.0001). IL2RB mRNA positively correlated with three previously-published gene signatures of response to immune-checkpoint therapy (P < 0.0001). Our evolutionary algorithm has identified IL2RB to be extensively linked to immune-checkpoints in CRC; its expression should be investigated for clinical utility as a potential predictive biomarker for CRC patients receiving immune-checkpoint blockade.

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The LIM Protein Ajuba Augments Tumor Metastasis in Colon Cancer

Cancers ◽

10.3390/cancers12071913 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1913

Author(s):

Noëlle Dommann ◽

Daniel Sánchez-Taltavull ◽

Linda Eggs ◽

Fabienne Birrer ◽

Tess Brodie ◽

...

Keyword(s):

Colon Cancer ◽

Cell Lines ◽

Human Colon ◽

Tumor Burden ◽

The Cancer Genome Atlas ◽

Cancer Tissue ◽

Potential Candidate ◽

Sequencing Data ◽

Human Colon Cancer ◽

Cancer Genome Atlas

Colorectal cancer, along with its high potential for recurrence and metastasis, is a major health burden. Uncovering proteins and pathways required for tumor cell growth is necessary for the development of novel targeted therapies. Ajuba is a member of the LIM domain family of proteins whose expression is positively associated with numerous cancers. Our data shows that Ajuba is highly expressed in human colon cancer tissue and cell lines. Publicly available data from The Cancer Genome Atlas shows a negative correlation between survival and Ajuba expression in patients with colon cancer. To investigate its function, we transduced SW480 human colon cancer cells, with lentiviral constructs to knockdown or overexpress Ajuba protein. The transcriptome of the modified cell lines was analyzed by RNA sequencing. Among the pathways enriched in the differentially expressed genes, were cell proliferation, migration and differentiation. We confirmed our sequencing data with biological assays; cells depleted of Ajuba were less proliferative, more sensitive to irradiation, migrated less and were less efficient in colony formation. In addition, loss of Ajuba expression decreased the tumor burden in a murine model of colorectal metastasis to the liver. Taken together, our data supports that Ajuba promotes colon cancer growth, migration and metastasis and therefore is a potential candidate for targeted therapy.

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CTCs as a prognostic and predictive biomarker for stage II/III Colon Cancer: a companion study to the PePiTA trial

BMC Cancer ◽

10.1186/s12885-019-5528-1 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Françoise Rothé ◽

Marion Maetens ◽

Ghizlane Rouas ◽

Marianne Paesmans ◽

Marc Van den Eynde ◽

...

Keyword(s):

Colon Cancer ◽

Predictive Biomarker ◽

Stage Ii

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Relationship between tumor gene expression and recurrence in stage II/III colon cancer: Quantitative RT-PCR assay of 757 genes in fixed paraffin-embedded (FPE) tissue

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.3518 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 3518-3518 ◽

Cited By ~ 3

Author(s):

M. J. O’Connell ◽

S. Paik ◽

G. Yothers ◽

J. P. Costantino ◽

J. W. Cowens ◽

...

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Stage Ii ◽

Stage Iii ◽

P Value ◽

Cancer Tissue ◽

Matrix Remodeling ◽

Rt Pcr ◽

Pcr Assay ◽

Curative Surgery

3518 Background: As an initial step in developing abetter method of assessing prognosis following potentially curative surgery for colon cancer, we performed an exploratory gene identification study. Methods: RNA was extracted from three 10-micron sections of the FPE tumor tissue obtained at the initial diagnosis from 353 patients entered between 1977 and 1984 into the surgery-only or surgery-plus BCG arms of NSABP C-01/C-02. Expression was quantified for 757 cancer-related and reference genes with RT-PCR. Results: Blocks from 270 patients were evaluable after pre-specified exclusions: 128 were stage II and 142 were stage III. All patients had ≥ 5-year follow up. In univariate Cox proportional hazard analyses, 148 genes exhibited a nominally significant (unadjusted p-value <0.05) linear association with recurrence-free interval (RFI) (7 genes p≤0.001, 66 genes 0.001<p<0.01; 75 genes 0.01≤p<0.05). False discovery rate calculations suggest that about 25% of the 148 genes are expected to be false positives. Higher expression was associated with shorter RFI for 118 genes including SERPINB5, DUSP1, AKT3, TIMP1, ANXA2, RHOB (p≤ 0.001) and with longer RFI for 30 genes including BRCA1 (p≤0.001). The relationship between gene expression and RFI was similar for stage II and stage III patients for 143 of the 148 genes found to be significant. The largest cluster of genes is functionally related to extracellular matrix remodeling. The magnitude of the hazard ratios is similar to that observed in the early Oncotype DX studies in breast cancer and should allow clinically useful separation into low/intermediate/high risk groups. Conclusions: Quantitative RT-PCR assay of FPE colon cancer tissue can be used to identify large numbers of genes associated with RFI in patients with stage II and III colon cancer. If these results are confirmed by additional studies in progress, this technique has promise to improve selection of colon cancer patients for adjuvant chemotherapy. Funded in part as a collaborative arrangement under contract between the NSABP Foundation, Inc., and Genomic Health, Inc. [Table: see text]

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Tumor sidedness and intrinsic subtypes in patients with stage II/III colon cancer: Analysis of NSABP C-07 (NRG Oncology).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3514 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3514-3514 ◽

Cited By ~ 1

Author(s):

S. Rim Kim ◽

Nan Song ◽

Greg Yothers ◽

Patrick Gavin ◽

Carmen Joseph Allegra ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Therapy Response ◽

Stage Ii ◽

Intrinsic Subtypes ◽

Treatment Benefit ◽

Cancer Subtypes ◽

Metastatic Setting

3514 Background: The predictive value of tumor sidedness in colorectal cancer is currently of interest especially in metastatic setting for anti-EGFR therapy response. We tested whether intrinsic molecular subtype classification predictive of treatment benefit in stage II/III colon cancer is an independent novel marker in association with tumor sidedness. Methods: All available cases included in the NSABP/NRG C-07 trial for which we had both gene expression data and anatomical data (n=1603) were used to determine the molecular subtypes using the following classifiers; the Colorectal Cancer Assigner (CRCA), the Colon Cancer Subtypes (CCS) and the Consensus Molecular Subtypes (CMS). Frequency of tumor sidedness in each subtype and recurrence-free survival were analyzed. Results: Intrinsic subtypes were differentially distributed in right- and left-colon tumors with the exception of the stem-like or CMS4 (mesenchymal) subtype (Table 1). Sidedness was not associated with prognosis (p=0.82, HR: 1.022 [CI: 0.851-1.227]) or prediction of patients with greater benefit from oxaliplatin when combined with 5-Fu+LV (interaction p=0.484). Conclusions: Although tumor sidedness is associated with distribution of intrinsic subtypes in stage II/III colon cancer, it is not predictive of survival benefit from oxaliplatin in C-07. Support: -180868, -180822, U24-CA196067; HI13C2162; PA DOH; Sanofi-Synthelabo Clinical trial information: NCT00004931. [Table: see text]

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Prognostic and Predictive Value of the Tumor-Stroma Ratio in STAGE II Colon Cancer

Clinical Oncology and Research ◽

10.31487/j.cor.2020.04.12 ◽

2020 ◽

pp. 1-8

Author(s):

Wilma E. Mesker ◽

Armin Gerger ◽

Austrian Breast and Colorectal Cancer Study Group (ABCSG) ◽

Evelyne Bareck ◽

Gabi W. van Pelt ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Predictive Value ◽

Cox Regression ◽

Tumor Stroma ◽

Predictive Biomarker ◽

Distant Recurrence ◽

Stage Ii ◽

Cox Regression Analysis ◽

Stage Ii Colon Cancer

Background: Tumor-stroma ratio (TSR) is an independent prognosticator in colon cancer. Objective: We set out to investigate the predictive power, as well as to validate the prognostic power of TSR in stage II colon cancer patients. Better identification of patients who could benefit from adjuvant chemotherapy remains an important issue in stage II disease. Methods: TSR was microscopically determined on haematoxylin and eosin-stained primary tumor tissue slides of 212 patients who received either adjuvant chemotherapy or surveillance after curative resection in a prospective randomized clinical trial (ABCSG-91). Results: Stroma-high tumors were associated with significantly more cancer-related death ((CaDeath) HR 2.30, 95% CI 1.05−5.03; p=0.037) and significantly shorter distant recurrence-free survival ((DRFS) HR 2.32, 95% CI 1.10−4.87; p=0.027) compared to stroma-low tumors. Backward multivariate Cox-regression analysis demonstrated TSR as an independent prognosticator for DRFS (p=0.027) and CaDeath (p=0.031). TSR did not validate as a predictive biomarker; CaDeath (HR 0.87, 95% CI 0.18−4.17; p=0.87), DRFS (HR 0.76, 95% CI 0.17−3.36; p=0.71) and OS (HR 0.96, 95% CI 0.29−3.21; p=0.95) for the type of chemotherapy given in ABCSG-91. Conclusions: TSR, an easily applicable and inexpensive observer-based method, is an independent predictor of poor prognosis in stage II colon cancer. Predictive value for adjuvant 5-FU/leucovorin could not be demonstrated.

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