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.
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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DOI：
10.18632/oncotarget.2374
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发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
Camargo AA
中科院分区：
文献类型：
--
作者：
Donnard E;Asprino PF;Correa BR;Bettoni F;Koyama FC;Navarro FC;Perez RO;Mariadason J;Sieber OM;Strausberg RL;Simpson AJ;Jardim DL;Reis LF;Parmigiani RB;Galante PA;Camargo AA
我们对23种结直肠癌细胞系中编码细胞表面蛋白（Surfaceome）的3，594个基因进行了突变分析，寻找新的改变途径，可药物突变和突变表位，用于结直肠癌的靶向治疗。共有3,944个体细胞非同义替换和595个InDel，发生在2,061个（57%）表面体基因中。我们在TCGA数据库中鉴定了48个先前未在结直肠肿瘤中描述为突变的基因，包括突变并在>10%的细胞系中表达的基因（SEMA 4C、FGFRL 1、PKD 1、FAM 38 A、WDR 81、TMEM 136、SLC 36 A1、SLC 26 A6、IGFLR 1）。对这些基因的分析揭示了FGF和SEMA 4信号在结直肠癌中的重要作用，可能具有治疗意义。我们还发现，细胞系平均表达11个可药用突变，包括受体酪氨酸激酶AXL和EPHA 2中的频繁突变（>20%），这些突变以前未被认为是结直肠癌的潜在靶点。最后，我们鉴定了82个细胞表面突变的表位，然而在我们的细胞系中仅检测到这些表位的30%的表达。尽管如此，这些表位中有92%在具有突变表型的细胞系中表达，为在这一患者亚群中使用“通用”免疫检查点药物开辟了新的途径。
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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影响因子：
11.5
作者：
Carlos Montero, Juan;Seoane, Samuel;Pandiella, Atanasio
通讯作者：
Pandiella, Atanasio
影响因子：
4
作者：
Brahmer JR
通讯作者：
Brahmer JR
影响因子：
--
作者：
da Cunha JP;Galante PA;de Souza JE;Pieprzyk M;Carraro DM;Old LJ;Camargo AA;de Souza SJ
通讯作者：
de Souza SJ
影响因子：
8
作者：
Brantley, DM;Cheng, N;Chen, J
通讯作者：
Chen, J
影响因子：
5.7
作者：
Dienstmann, Rodrigo;Serpico, Danila;Tabernero, Josep
通讯作者：
Tabernero, Josep