A nineteen gene‐based risk score classifier predicts prognosis of colorectal cancer patients

Colorectal cancer (CRC) patients frequently experience disease recurrence and distant metastasis. This study aimed to identify prognostic indicators, including individual responses to chemotherapy, in CRC patients. RNA‐seq data was generated using 54 samples (normal colon, primary CRC, and liver metastases) from 18 CRC patients and genes associated with CRC aggressiveness were identified. A risk score based on these genes was developed and validated in four independent CRC patient cohorts (n = 1063). Diverse statistical methods were applied to validate the risk scoring system, including a generalized linear model likelihood ratio test, Kaplan–Meier curves, a log‐rank test, and the Cox model. TREM1 and CTGF were identified as two activated regulators associated with CRC aggressiveness. A risk score based on 19 genes regulated by TREM1 or CTGF activation (TCA19) was a significant prognostic indicator. In multivariate and subset analyses based on pathological staging, TCA19 was an independent risk factor (HR = 1.894, 95% CI = 1.227–2.809, P = 0.002). Subset stratification in stage III patients revealed that TCA19 had prognostic potential and identified patients who would benefit from adjuvant chemotherapy, regardless of age. The TCA19 predictor represents a novel diagnostic tool for identifying high‐risk CRC patients and possibly predicting the response to adjuvant chemotherapy.

[1]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[2]  Jiang Qian,et al.  TiGER: A database for tissue-specific gene expression and regulation , 2008, BMC Bioinformatics.

[3]  B. Aggarwal,et al.  Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. , 2009, Trends in pharmacological sciences.

[4]  J. Fata,et al.  Altered tumor growth and metastasis of a T-cell lymphoma in Timp-1 transgenic mice. , 1997, Blood.

[5]  K. Lindor,et al.  Comparing the simplified and international autoimmune hepatitis group criteria in primary sclerosing cholangitis. , 2010, Gastroenterology & hepatology.

[6]  B. Binder,et al.  The plasminogen activator inhibitor "paradox" in cancer. , 2008, Immunology letters.

[7]  C. Croce,et al.  Integrated MicroRNA and mRNA Signatures Associated with Survival in Triple Negative Breast Cancer , 2013, PloS one.

[8]  Sun-Hee Kim,et al.  Expression level and glycan dynamics determine the net effects of TIMP-1 on cancer progression , 2012, BMB reports.

[9]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[10]  W. Frankel,et al.  Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles , 2004, Oncogene.

[11]  D. Kerr,et al.  Evolution of nonsurgical therapy for colorectal cancer , 2009, Nature Clinical Practice Gastroenterology &Hepatology.

[12]  Huanzhong Shi,et al.  Expression of soluble triggering receptor expression on myeloid cells-1 in pleural effusion. , 2008, Chinese medical journal.

[13]  Ling Xia,et al.  Overexpression of Snail induces epithelial–mesenchymal transition and a cancer stem cell–like phenotype in human colorectal cancer cells , 2012, Cancer medicine.

[14]  A. Harris,et al.  REporting recommendations for tumour MARKer prognostic studies (REMARK) , 2005, British Journal of Cancer.

[15]  G. Kang.  Four molecular subtypes of colorectal cancer and their precursor lesions. , 2011, Archives of pathology & laboratory medicine.

[16]  Ju-Seog Lee,et al.  Comparison of Prognostic Genomic Predictors in Colorectal Cancer , 2013, PloS one.

[17]  R. Dhir,et al.  Plasma fibronectin promotes lung metastasis by contributions to fibrin clots and tumor cell invasion. , 2010, Cancer research.

[18]  Lewis C Cantley,et al.  A colorectal cancer classification system that associates cellular phenotype and responses to therapy , 2013, Nature Medicine.

[19]  T. Ørntoft,et al.  Metastasis-Associated Gene Expression Changes Predict Poor Outcomes in Patients with Dukes Stage B and C Colorectal Cancer , 2009, Clinical Cancer Research.

[20]  J. Thiery,et al.  Complex networks orchestrate epithelial–mesenchymal transitions , 2006, Nature Reviews Molecular Cell Biology.

[21]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[22]  M. Cronin,et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. , 2004, The New England journal of medicine.

[23]  M. Koch,et al.  Expression of an ASCL2 related stem cell signature and IGF2 in colorectal cancer liver metastases with 11p15.5 gain , 2010, Gut.

[24]  X. Wang,et al.  Sixty‐five gene‐based risk score classifier predicts overall survival in hepatocellular carcinoma , 2012, Hepatology.

[25]  J. Verbeek.  Moose Consort Strobe and Miame Stard Remark or how can we improve the quality of reporting studies. , 2008, Scandinavian journal of work, environment & health.

[26]  M. Sim,et al.  AJCC Cancer Staging Manual 7th edition criteria for colon cancer: do the complex modifications improve prognostic assessment? , 2013, Journal of the American College of Surgeons.

[27]  T. Yeatman,et al.  Prognostic gene expression signature associated with two molecularly distinct subtypes of colorectal cancer , 2011, Gut.

[28]  M. J. van de Vijver,et al.  Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. , 2011, Cell stem cell.

[29]  Walter Krämer,et al.  Review of Modern applied statistics with S, 4th ed. by W.N. Venables and B.D. Ripley. Springer-Verlag 2002 , 2003 .

[30]  R. Labianca,et al.  DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. , 2011, Journal of the National Cancer Institute.

[31]  Florian Markowetz,et al.  Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions , 2013, Nature Medicine.

[32]  Y. Jeng,et al.  Connective tissue growth factor modulates oral squamous cell carcinoma invasion by activating a miR-504/FOXP1 signalling , 2012, Oncogene.

[33]  A. Sabatini,et al.  Monitoring of levels of polycyclic aromatic hydrocarbons in bees caught from beekeeping: remark 1 , 2009, Veterinary Research Communications.

[34]  A. Thor,et al.  Systemic Gene Delivery Expands the Repertoire of Effective Antiangiogenic Agents* , 1999, The Journal of Biological Chemistry.

[35]  D. Watson,et al.  Translating tumor biology into personalized treatment planning: analytical performance characteristics of the Oncotype DX® Colon Cancer Assay , 2010, BMC Cancer.

[36]  Peter Beighton,et al.  de la Chapelle, A. , 1997 .

[37]  Minoru Toyota,et al.  Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer , 2007, Proceedings of the National Academy of Sciences.

[38]  T. Lumley,et al.  Time‐Dependent ROC Curves for Censored Survival Data and a Diagnostic Marker , 2000, Biometrics.

[39]  T. Fleming,et al.  Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic. , 1989, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  Rolf I. Skotheim,et al.  Anticipating the Clinical Use of Prognostic Gene Expression–Based Tests for Colon Cancer Stage II and III: Is Godot Finally Arriving? , 2013, Clinical Cancer Research.

[41]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[42]  Rohan Kumar,et al.  Expression of CTGF and Cyr61 in colorectal cancer , 2010, Journal of Clinical Pathology.

[43]  William N. Venables,et al.  Modern Applied Statistics with S , 2010 .

[44]  R. Weinberg,et al.  Activation of miR-31 function in already-established metastases elicits metastatic regression. , 2011, Genes & development.

[45]  V. Findlay,et al.  Epithelial to mesenchymal transition and the cancer stem cell phenotype: Insights from cancer biology with therapeutic implications for colorectal cancer , 2014, Cancer Gene Therapy.

[46]  J. Jass.  Classification of colorectal cancer based on correlation of clinical, morphological and molecular features , 2007, Histopathology.

[47]  Douglas G Altman,et al.  REporting recommendations for tumour MARKer prognostic studies (REMARK). , 2005, European journal of cancer.

[48]  V. Seshan,et al.  A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis , 2012, Cell.

[49]  F. Seibold,et al.  TREM-1--expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. , 2007, The Journal of clinical investigation.

[50]  Mira Ayadi,et al.  Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value , 2013, PLoS medicine.

[51]  Å. Lasson,et al.  Recurrence rates after curative surgery for rectal carcinoma, with special reference to their accuracy , 1987, Diseases of the colon and rectum.

[52]  T R Fleming,et al.  Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. , 1990, The New England journal of medicine.