title: 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.
abstract: 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.
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil; Programa de Pós Graduação do Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil; These Authors contributed equally to this work.
authors.forename: Elisa
authors.initials: E
authors.lastname: Donnard
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil; These Authors contributed equally to this work.
authors.forename: Paula F
authors.initials: PF
authors.lastname: Asprino
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil;
authors.forename: Bruna R
authors.initials: BR
authors.lastname: Correa
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil;
authors.forename: Fabiana
authors.initials: F
authors.lastname: Bettoni
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil; Laboratory of Molecular Biology and Genomics, Ludwig Institute for Cancer Research, São Paulo, Brazil.
authors.forename: Fernanda C
authors.initials: FC
authors.lastname: Koyama
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil; Programa de Pós Graduação do Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Fabio C P
authors.initials: FC
authors.lastname: Navarro
authors.affiliation: Laboratory of Molecular Biology and Genomics, Ludwig Institute for Cancer Research, São Paulo, Brazil; Instituto Angelita & Joaquim Gama, São Paulo, Brazil.
authors.forename: Rodrigo O
authors.initials: RO
authors.lastname: Perez
authors.affiliation: Oncogenic Transcription Laboratory, Ludwig Institute for Cancer Research, Melbourne, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Mariadason
authors.affiliation: Colorectal Cancer Genetics Laboratory, Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Faculty of Medicine, Dentistry and Health Sciences, Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Sieber
authors.affiliation: Ludwig Institute for Cancer Research, New York, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Strausberg
authors.affiliation: Ludwig Institute for Cancer Research, New York, USA.
authors.forename: Andrew J G
authors.initials: AJ
authors.lastname: Simpson
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil.
authors.forename: Denis L F
authors.initials: DL
authors.lastname: Jardim
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil.
authors.forename: Luiz Fernando L
authors.initials: LF
authors.lastname: Reis
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil.
authors.forename: Raphael B
authors.initials: RB
authors.lastname: Parmigiani
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil.
authors.forename: Pedro A F
authors.initials: PA
authors.lastname: Galante
authors.affiliation: Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil; Laboratory of Molecular Biology and Genomics, Ludwig Institute for Cancer Research, São Paulo, Brazil.
authors.forename: Anamaria A
authors.initials: AA
authors.lastname: Camargo
mesh_terms: D001483:Base Sequence; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D055808:Drug Discovery; D000939:Epitopes / Q000235:genetics; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D058990:Molecular Targeted Therapy; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D000939:Epitopes; D008565:Membrane Proteins