Dataset Information

SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance.

ABSTRACT: PURPOSE:SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. RESULTS:The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. CONCLUSIONS:Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.

SUBMITTER: Wasserman I

PROVIDER: S-EPMC6421131 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance.

Wasserman Isaac I Lee Lik Hang LH Ogino Shuji S Marco Michael R MR Wu Chao C Chen Xi X Datta Jashodeep J Sadot Eran E Szeglin Bryan B Guillem Jose G JG Paty Philip B PB Weiser Martin R MR Nash Garrett M GM Saltz Leonard L Barlas Afsar A Manova-Todorova Katia K Uppada Srijaya Prakash Babu SPB Elghouayel Arthur E AE Ntiamoah Peter P Glickman Jonathan N JN Hamada Tsuyoshi T Kosumi Keisuke K Inamura Kentaro K Chan Andrew T AT Nishihara Reiko R Cercek Andrea A Ganesh Karuna K Kemeny Nancy E NE Dhawan Punita P Yaeger Rona R Sawyers Charles L CL Garcia-Aguilar Julio J Giannakis Marios M Shia Jinru J Smith J Joshua JJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20181226 6

<h4>Purpose</h4>SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.<b>Experimental Design:</b> A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance.<h4>Results</h4>The discovery cohort co ...[more]

PMID: 30587545

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Project description:ObjectiveAn oncogenic protein, pituitary tumor transforming gene 1 binding factor (PTTG1IP, also called PBF), has been found to be expressed in various cancers. However, few studies have explored its prognostic significance and biologic function in epithelial ovarian cancer (EOC).MethodsBased on the Cancer Genome Atlas (TCGA) database, this study determined the differential expression of PBF at the mRNA level in EOC and normal tissues, which was then verified using real-time PCR and western blotting. Moreover, the Kaplan-Meier method and the Cox regression method were adopted to assess the clinical value of PBF in EOC. A nomogram model was constructed to evaluate the prognostic performance of PBF in EOC. Gene set enrichment analysis (GSEA) was employed to evaluate the signaling and pathway enrichment of PBF in EOC. The association between PBF expression and tumor-infiltrating immune cells (TIICs) in EOC was examined by single-sample GSEA and TIMER.ResultsPBF was significantly higher in EOC than normal tissues as shown through TCGA database, and this result was verified by qRT-PCR and western blotting of EOC tissues and different cell lines. High PBF was associated with tumor size and lymphatic metastasis status. Kaplan-Meier (KM) analysis indicated that high PBF expression correlated with poor prognosis in patients with EOC (P < 0.0001). Moreover, multivariate Cox regression analysis was used to verify that PBF is an independent prognostic factor for EOC. The nomogram model exhibited moderate predictive accuracy and clinical utility in predicting EOC prognosis. The GSEA revealed that the expression of signaling pathways, such DNA damage replication, p53 pathway, Akt phosphorylation pathway, and estrogen-dependent nuclear pathway, were increased in the phenotype with high PBF expression. PBF expression was associated with neutrophil cells, iDC cells, NK cells, and Tem cells.ConclusionAs a prognostic biomarker for EOC, PBF was found to be correlated with immune infiltration, and may therefore be a promising target for immunotherapy for EOC.

Project description:Growing evidence has revealed that the E2F family of transcription factor 2 (E2F2) participates in the tumorigenesis and progression of various tumors, but its role in colorectal cancer (CRC) remains largely unknown. Herein, the aim of our study was to investigate the exact role of E2F2 in CRC. The expression levels of E2F2 in CRC were appraised based on the Tumor Immune Estimate Resource (TIMER), Oncomine, The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) database. The results were further confirmed using CRC tumor tissues and normal controls by experimental assays including immunohistochemistry, qRT-PCR and western blot. The survival analysis of E2F2 in CRC was analyzed using PrognoScan database and TCGA data sets. In addition, the functional roles of E2F2 were examined by Gene Set Enrichment Analysis (GSEA) and immune infiltration analysis. Our results illustrated that E2F2 was significantly downregulated in CRC samples. The low E2F2 expression in CRC was prominently correlated with N, M stage and pathological stage. Decreased E2F2 expression had an unfavorable overall survivial (OS), disease free survival (DFS), disease specific survival (DSS) and progress free interval (PFI). Multivariate cox regression showed E2F2 could be an independent prognostic factors of OS in CRC. Receiver operating characteristic (ROC) analysis showed that E2F2 may serve as a potential diagnostic biomarker for CRC patients. GSEA disclosed that E2F2 was probably involved in several pathways, including ATR pathway, ATM signalling pathway, mismatch repair, base excision repair, homologous recomibination, Fanconi Anemia pathway, multicancer invasiveness signature, and cancer stem cells. Moreover, E2F2 was significantly correlated with the infiltration level of Th2, aDC, Th17, NK CD56dim, T helper and pDC cells. The current study demonstrates that decreased E2F2 expression is closely associated with poor prognosis and immune cell infiltration in CRC, which can be a promising independent prognostic biomarker and potential treatment target for CRC.

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Dataset Information

SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance.

Publications

SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance.

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