'Druggable' alterations detected by Ion Torrent in metastatic colorectal cancer patients.
'Druggable' alterations detected by Ion Torrent in metastatic colorectal cancer patients.
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DOI：
10.3892/ol.2014.2047
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发表时间：
2014-06
期刊：
影响因子：
2.9
通讯作者：
Zheng S
中科院分区：
文献类型：
--
作者：
Fang W;Radovich M;Zheng Y;Fu CY;Zhao P;Mao C;Zheng Y;Zheng S
转移性结直肠癌（metastatic colorectal cancer, mCRC）患者的多发性和不良预后强调了对用于治疗和预后的生物标志物的改进需求。在本研究中，在mCRC患者中发现了关键癌症基因外显子区域的体细胞变异。收集mCRC患者转移灶活检获得的福尔马林固定石蜡包埋组织，提取DNA并使用Ion Torrent个人基因组机进行测序。对于已知癌症基因的靶向扩增，使用Ion AmpliSeq™癌症面板，该面板设计用于检测来自46个癌基因和肿瘤抑制基因的604个位点的739个体细胞突变目录（COSMIC）突变，只需10 ng的输入DNA。然后使用Ion Torrent Suite软件中的Ampliseq™Variant Caller插件分析测序结果。此外，使用Ingenuity Pathway软件进行通路分析。并进行Cox回归分析，探讨变异数与临床因素（有效率、无病生存期和总生存期）之间的潜在相关性。在10个样本中，在使用SNP数据库排除种系突变后，鉴定出24个基因中的65个遗传改变，其中41%的改变也存在于COSMIC数据库中。经统计分析，未发现临床因素与患者的变异数有显著相关。然而，通路分析发现“结直肠癌转移信号”是最常见的突变典型通路。该分析进一步揭示了Wnt、磷酸肌肽3激酶(PI3K)/AKT和转化生长因子(TGF)-β/SMAD信号通路中的突变基因。值得注意的是，包括预期的APC、BRAF、KRAS、PIK3CA和TP53基因在内的11个基因在至少两个样本中发生了突变。值得注意的是，90%（9/10）的mCRC患者至少有一种“可药物”改变（范围，1-6种改变），这些改变与临床治疗方案有关，或者目前正在研究新的靶向治疗的临床试验。这些结果表明，关键癌基因和肿瘤抑制基因的DNA测序能够识别个体结直肠癌患者的“可药物”改变。
The frequency and poor prognosis of patients with metastatic colorectal cancer (mCRC) emphasizes the requirement for improved biomarkers for use in the treatment and prognosis of mCRC. In the present study, somatic variants in exonic regions of key cancer genes were identified in mCRC patients. Formalin-fixed, paraffin-embedded tissues obtained by biopsy of the metastases of mCRC patients were collected, and the DNA was extracted and sequenced using the Ion Torrent Personal Genome Machine. For the targeted amplification of known cancer genes, the Ion AmpliSeq™ Cancer Panel, which is designed to detect 739 Catalogue of Somatic Mutations in Cancer (COSMIC) mutations in 604 loci from 46 oncogenes and tumor suppressor genes using as little as 10 ng of input DNA, was used. The sequencing results were then analyzed using the Ampliseq™ Variant Caller plug-in within the Ion Torrent Suite software. In addition, Ingenuity Pathway software was used to perform a pathway analysis. The Cox regression analysis was also conducted to investigate the potential correlation between alteration numbers and clinical factors, including response rate, disease-free survival and overall survival. Among 10 specimens, 65 genetic alterations were identified in 24 genes following the exclusion of germline mutations using the SNP database, whereby 41% of the alterations were also present in the COSMIC database. No clinical factors were found to significantly correlate with the alteration numbers in the patients by statistical analysis. However, pathway analysis identified ‘colorectal cancer metastasis signaling’ as the most commonly mutated canonical pathway. This analysis further revealed mutated genes in the Wnt, phosphoinositide 3-kinase (PI3K)/AKT and transforming growth factor (TGF)-β/SMAD signaling pathways. Notably, 11 genes, including the expected APC, BRAF, KRAS, PIK3CA and TP53 genes, were mutated in at least two samples. Notably, 90% (9/10) of mCRC patients harbored at least one ‘druggable’ alteration (range, 1–6 alterations) that has been linked to a clinical treatment option or is currently being investigated in clinical trials of novel targeted therapies. These results indicated that DNA sequencing of key oncogenes and tumor suppressors enables the identification of ‘druggable’ alterations for individual colorectal cancer patients.
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影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
3.5
作者：
Cho, Kwang-Hyun;Baek, Songjoon;Sung, Myong-Hee
通讯作者：
Sung, Myong-Hee
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA
影响因子：
254.7
作者：
Siegel, Rebecca;Naishadham, Deepa;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin
影响因子：
11.2
作者：
Traxler, P;Allegrini, PR;Caravatti, G
通讯作者：
Caravatti, G