BACKGROUND: Colon cancer has a huge incidence and mortality worldwide every year. Immunotherapy could be a new therapeutic option for patients with advanced colon cancer. Tumor mutation burden (TMB) and immune infiltration are considered critical in immunotherapy but their characteristics in colon cancer are still controversial. METHODS: The somatic mutation, transcriptome, and clinical data of patients with colon cancer were obtained from the TCGA database. Patients were divided into low or high TMB groups using the median TMB value. Somatic mutation landscape, differentially expressed genes, and immune-related hub genes, Gene Ontology and KEGG, gene set enrichment, and immune infiltration analyses were investigated between the two TMB groups. Univariate and multivariate Cox analyses were utilized to construct a prognostic gene signature. The differences in immune infiltration, and the expression of HLA-related genes and checkpoint genes were investigated between the two immunity groups based on single sample gene set enrichment analysis. Finally, a nomogram of the prognostic prediction model integrating TMB, immune infiltration, and clinical parameters was established. Calibration plots and receiver operating characteristic curves (ROC) were drawn, and the C-index was calculated to assess the predictive ability. RESULTS: Missense mutations and single nucleotide polymorphisms were the major variant characteristics in colon cancer. The TMB level showed significant differences in N stage, M stage, pathological stage, and immune infiltration. CD8+ T cells, activated memory CD4+ T cells, activated NK cells, and M1 macrophages infiltrated more in the high-TMB group. The antigen processing and presentation signaling pathway was enriched in the high-TMB group. Two immune related genes (CHGB and SCT) were identified to be correlated with colon cancer survival (HR = 1.39, P = 0.01; HR = 1.26, P = 0.02, respectively). Notably, the expression of SCT was identified as a risk factor in the immune risk model, in which high risk patients showed poorer survival (P = 0.04). High immunity status exhibited significant correlations with immune response pathways, HLA-related genes, and immune checkpoint genes. Finally, including nine factors, our nomogram prediction model showed better calibration (C-index = 0.764) and had an AUC of 0.737. CONCLUSION: In this study, we investigated the patterns and prognostic roles of TMB and immune infiltration in colon cancer, which provided new insights into the tumor microenvironment and immunotherapies and the development of a novel nomogram prognostic prediction model for patients with colon cancer.
BACKGROUND: Colon cancer has a huge incidence and mortality worldwide every year. Immunotherapy could be a new therapeutic option for patients with advanced colon cancer. Tumor mutation burden (TMB) and immune infiltration are considered critical in immunotherapy but their characteristics in colon cancer are still controversial. METHODS: The somatic mutation, transcriptome, and clinical data of patients with colon cancer were obtained from the TCGA database. Patients were divided into low or high TMB groups using the median TMB value. Somatic mutation landscape, differentially expressed genes, and immune-related hub genes, Gene Ontology and KEGG, gene set enrichment, and immune infiltration analyses were investigated between the two TMB groups. Univariate and multivariate Cox analyses were utilized to construct a prognostic gene signature. The differences in immune infiltration, and the expression of HLA-related genes and checkpoint genes were investigated between the two immunity groups based on single sample gene set enrichment analysis. Finally, a nomogram of the prognostic prediction model integrating TMB, immune infiltration, and clinical parameters was established. Calibration plots and receiver operating characteristic curves (ROC) were drawn, and the C-index was calculated to assess the predictive ability. RESULTS: Missense mutations and single nucleotide polymorphisms were the major variant characteristics in colon cancer. The TMB level showed significant differences in N stage, M stage, pathological stage, and immune infiltration. CD8+ T cells, activated memory CD4+ T cells, activated NK cells, and M1 macrophages infiltrated more in the high-TMB group. The antigen processing and presentation signaling pathway was enriched in the high-TMB group. Two immune related genes (CHGB and SCT) were identified to be correlated with colon cancer survival (HR = 1.39, P = 0.01; HR = 1.26, P = 0.02, respectively). Notably, the expression of SCT was identified as a risk factor in the immune risk model, in which high risk patients showed poorer survival (P = 0.04). High immunity status exhibited significant correlations with immune response pathways, HLA-related genes, and immune checkpoint genes. Finally, including nine factors, our nomogram prediction model showed better calibration (C-index = 0.764) and had an AUC of 0.737. CONCLUSION: In this study, we investigated the patterns and prognostic roles of TMB and immune infiltration in colon cancer, which provided new insights into the tumor microenvironment and immunotherapies and the development of a novel nomogram prognostic prediction model for patients with colon cancer.
Authors: Paolo Onori; Candace Wise; Eugenio Gaudio; Antonio Franchitto; Heather Francis; Guido Carpino; Vien Lee; Ian Lam; Timothy Miller; David E Dostal; Shannon S Glaser Journal: Int J Cancer Date: 2010-07-01 Impact factor: 7.396
Authors: Hossein Borghaei; Luis Paz-Ares; Leora Horn; David R Spigel; Martin Steins; Neal E Ready; Laura Q Chow; Everett E Vokes; Enriqueta Felip; Esther Holgado; Fabrice Barlesi; Martin Kohlhäufl; Oscar Arrieta; Marco Angelo Burgio; Jérôme Fayette; Hervé Lena; Elena Poddubskaya; David E Gerber; Scott N Gettinger; Charles M Rudin; Naiyer Rizvi; Lucio Crinò; George R Blumenschein; Scott J Antonia; Cécile Dorange; Christopher T Harbison; Friedrich Graf Finckenstein; Julie R Brahmer Journal: N Engl J Med Date: 2015-09-27 Impact factor: 91.245
Authors: Zachary R Chalmers; Caitlin F Connelly; David Fabrizio; Laurie Gay; Siraj M Ali; Riley Ennis; Alexa Schrock; Brittany Campbell; Adam Shlien; Juliann Chmielecki; Franklin Huang; Yuting He; James Sun; Uri Tabori; Mark Kennedy; Daniel S Lieber; Steven Roels; Jared White; Geoffrey A Otto; Jeffrey S Ross; Levi Garraway; Vincent A Miller; Phillip J Stephens; Garrett M Frampton Journal: Genome Med Date: 2017-04-19 Impact factor: 11.117
Authors: Ludmil B Alexandrov; Serena Nik-Zainal; David C Wedge; Samuel A J R Aparicio; Sam Behjati; Andrew V Biankin; Graham R Bignell; Niccolò Bolli; Ake Borg; Anne-Lise Børresen-Dale; Sandrine Boyault; Birgit Burkhardt; Adam P Butler; Carlos Caldas; Helen R Davies; Christine Desmedt; Roland Eils; Jórunn Erla Eyfjörd; John A Foekens; Mel Greaves; Fumie Hosoda; Barbara Hutter; Tomislav Ilicic; Sandrine Imbeaud; Marcin Imielinski; Marcin Imielinsk; Natalie Jäger; David T W Jones; David Jones; Stian Knappskog; Marcel Kool; Sunil R Lakhani; Carlos López-Otín; Sancha Martin; Nikhil C Munshi; Hiromi Nakamura; Paul A Northcott; Marina Pajic; Elli Papaemmanuil; Angelo Paradiso; John V Pearson; Xose S Puente; Keiran Raine; Manasa Ramakrishna; Andrea L Richardson; Julia Richter; Philip Rosenstiel; Matthias Schlesner; Ton N Schumacher; Paul N Span; Jon W Teague; Yasushi Totoki; Andrew N J Tutt; Rafael Valdés-Mas; Marit M van Buuren; Laura van 't Veer; Anne Vincent-Salomon; Nicola Waddell; Lucy R Yates; Jessica Zucman-Rossi; P Andrew Futreal; Ultan McDermott; Peter Lichter; Matthew Meyerson; Sean M Grimmond; Reiner Siebert; Elías Campo; Tatsuhiro Shibata; Stefan M Pfister; Peter J Campbell; Michael R Stratton Journal: Nature Date: 2013-08-14 Impact factor: 49.962