Mutational analysis of genes coding for cell surface proteins in colorectal cancer cell lines reveal novel altered pathways, druggable mutations and mutated epitopes for targeted therapy.
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Elisa Donnard1,2,§, Paula F. Asprino1,§, Bruna R. Correa1, Fabiana Bettoni1, Fernanda C. Koyama1,3, Fabio C.P. Navarro1,2, Rodrigo O. Perez3,4, John Mariadason5, Oliver M. Sieber6,7, Robert L. Strausberg8, Andrew J.G. Simpson8, Denis L.F. Jardim1, Luiz Fernando L. Reis1, Raphael B. Parmigiani1, Pedro A.F. Galante1, Anamaria A. Camargo1,3
1 Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil.
2 Programa de Pós Graduação do Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
3 Laboratory of Molecular Biology and Genomics, Ludwig Institute for Cancer Research, São Paulo, Brazil.
4 Instituto Angelita & Joaquim Gama, São Paulo, Brazil.
5 Oncogenic Transcription Laboratory, Ludwig Institute for Cancer Research, Melbourne, Australia.
6 Colorectal Cancer Genetics Laboratory, Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
7 Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, Australia
8 Ludwig Institute for Cancer Research, New York, USA.
§ These Authors contributed equally to this work
Dr. Anamaria A. Camargo, email: [email protected]
Keywords: colorectal cancer, targeted therapy, cell surface proteins, somatic mutations.
Received: July 03, 2014 Accepted: August 20, 2014 Published: August 25, 2014
We carried out a mutational analysis of 3,594 genes coding for cell surface proteins (Surfaceome) in 23 colorectal cancer cell lines, searching for new altered pathways, druggable mutations and mutated epitopes for targeted therapy in colorectal cancer. A total of 3,944 somatic non-synonymous substitutions and 595 InDels, occurring in 2,061 (57%) Surfaceome genes were catalogued. We identified 48 genes not previously described as mutated in colorectal tumors in the TCGA database, including genes that are mutated and expressed in >10% of the cell lines (SEMA4C, FGFRL1, PKD1, FAM38A, WDR81, TMEM136, SLC36A1, SLC26A6, IGFLR1). Analysis of these genes uncovered important roles for FGF and SEMA4 signaling in colorectal cancer with possible therapeutic implications. We also found that cell lines express on average 11 druggable mutations, including frequent mutations (>20%) in the receptor tyrosine kinases AXL and EPHA2, which have not been previously considered as potential targets for colorectal cancer. Finally, we identified 82 cell surface mutated epitopes, however expression of only 30% of these epitopes was detected in our cell lines. Notwithstanding, 92% of these epitopes were expressed in cell lines with the mutator phenotype, opening new venues for the use of “general” immune checkpoint drugs in this subset of patients.
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