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Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer.
Cancer Cell ( IF 48.8 ) Pub Date : 2018-01-08 , DOI: 10.1016/j.ccell.2017.12.004 Rona Yaeger 1 , Walid K Chatila 2 , Marla D Lipsyc 1 , Jaclyn F Hechtman 3 , Andrea Cercek 1 , Francisco Sanchez-Vega 2 , Gowtham Jayakumaran 3 , Sumit Middha 3 , Ahmet Zehir 3 , Mark T A Donoghue 2 , Daoqi You 2 , Agnes Viale 2 , Nancy Kemeny 1 , Neil H Segal 1 , Zsofia K Stadler 1 , Anna M Varghese 1 , Ritika Kundra 2 , Jianjiong Gao 2 , Aijazuddin Syed 3 , David M Hyman 1 , Efsevia Vakiani 3 , Neal Rosen 1 , Barry S Taylor 4 , Marc Ladanyi 5 , Michael F Berger 6 , David B Solit 7 , Jinru Shia 3 , Leonard Saltz 1 , Nikolaus Schultz 4
Cancer Cell ( IF 48.8 ) Pub Date : 2018-01-08 , DOI: 10.1016/j.ccell.2017.12.004 Rona Yaeger 1 , Walid K Chatila 2 , Marla D Lipsyc 1 , Jaclyn F Hechtman 3 , Andrea Cercek 1 , Francisco Sanchez-Vega 2 , Gowtham Jayakumaran 3 , Sumit Middha 3 , Ahmet Zehir 3 , Mark T A Donoghue 2 , Daoqi You 2 , Agnes Viale 2 , Nancy Kemeny 1 , Neil H Segal 1 , Zsofia K Stadler 1 , Anna M Varghese 1 , Ritika Kundra 2 , Jianjiong Gao 2 , Aijazuddin Syed 3 , David M Hyman 1 , Efsevia Vakiani 3 , Neal Rosen 1 , Barry S Taylor 4 , Marc Ladanyi 5 , Michael F Berger 6 , David B Solit 7 , Jinru Shia 3 , Leonard Saltz 1 , Nikolaus Schultz 4
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Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1, increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutations, and enrichment of oncogenic alterations in KRAS, BRAF, PIK3CA, AKT1, RNF43, and SMAD4 compared with left-sided primaries. Left-sided tumors frequently had no identifiable genetic alteration in mitogenic signaling, but exhibited higher mitogenic ligand expression. Our results suggest different pathways to tumorigenesis in right- and left-sided microsatellite stable CRC that may underlie clinical differences.
中文翻译：
临床测序定义了转移性结直肠癌的基因组景观。
转移性结直肠癌（mCRC）在临床上具有异质性，但这种变异的基因组基础仍然知之甚少。我们对 1,134 个 CRC 进行了前瞻性靶向测序。我们发现了 APC 内含子区域的剪接改变和 CTNNB1 中的大框内缺失，增加了 96% CRC 的致癌 WNT 通路改变。与左侧原发部位相比，微卫星稳定转移性结直肠癌的右侧原发部位与生存期较短、诊断时年龄较大、突变增加以及 KRAS、BRAF、PIK3CA、AKT1、RNF43 和 SMAD4 致癌改变丰富相关。左侧肿瘤在促有丝分裂信号传导方面通常没有可识别的遗传改变，但表现出较高的促有丝分裂配体表达。我们的结果表明，右侧和左侧微卫星稳定结直肠癌的肿瘤发生途径不同，这可能是临床差异的基础。
更新日期：2018-01-08
中文翻译：
临床测序定义了转移性结直肠癌的基因组景观。
转移性结直肠癌（mCRC）在临床上具有异质性，但这种变异的基因组基础仍然知之甚少。我们对 1,134 个 CRC 进行了前瞻性靶向测序。我们发现了 APC 内含子区域的剪接改变和 CTNNB1 中的大框内缺失，增加了 96% CRC 的致癌 WNT 通路改变。与左侧原发部位相比，微卫星稳定转移性结直肠癌的右侧原发部位与生存期较短、诊断时年龄较大、突变增加以及 KRAS、BRAF、PIK3CA、AKT1、RNF43 和 SMAD4 致癌改变丰富相关。左侧肿瘤在促有丝分裂信号传导方面通常没有可识别的遗传改变，但表现出较高的促有丝分裂配体表达。我们的结果表明，右侧和左侧微卫星稳定结直肠癌的肿瘤发生途径不同，这可能是临床差异的基础。
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