Personalized genomic analyses for cancer mutation discovery and interpretation.
Personalized genomic analyses for cancer mutation discovery and interpretation.
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DOI：
10.1126/scitranslmed.aaa7161
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发表时间：
2015-04-15
影响因子：
17.1
通讯作者：
Velculescu VE
中科院分区：
文献类型：
--
作者：
Jones S;Anagnostou V;Lytle K;Parpart-Li S;Nesselbush M;Riley DR;Shukla M;Chesnick B;Kadan M;Papp E;Galens KG;Murphy D;Zhang T;Kann L;Sausen M;Angiuoli SV;Diaz LA Jr;Velculescu VE
大规模平行测序方法开始在临床上用于表征个体患者肿瘤并基于所鉴定的突变选择疗法。这些分析中的一个主要问题是这些方法在多大程度上识别了临床上可采取行动的改变，以及单独检查肿瘤组织是否足够，或者是否还应该分析匹配的正常DNA以准确识别肿瘤特异性（体细胞）改变。为了解决这些问题，我们全面评估了来自15种肿瘤类型患者的815个肿瘤-正常配对样本。我们使用下一代全外显子组测序或111个靶基因鉴定了基因组改变，其灵敏度分别为>95%和> 99%，特异性> 99.99%。这些分析分别揭示了每个外显子组和靶向分析平均140和4.3个体细胞突变。超过75%的病例存在与已知疗法或当前临床试验相关的基因体细胞改变。匹配的正常DNA分析确定了3%的明显散发性癌症患者的癌症易感基因的种系改变。相比之下，仅肿瘤测序方法无法明确识别癌症易感基因的种系变化，并导致额外的假阳性结果，分别包括靶向和外显子组分析中识别的31%和65%的改变，包括潜在的可操作基因。这些数据表明，匹配的肿瘤正常测序分析是必不可少的体细胞和生殖系的改变的精确识别和解释，并有重要的意义，癌症患者的诊断和治疗管理。
Massively parallel sequencing approaches are beginning to be used clinically to characterize individual patient tumors and to select therapies based on the identified mutations. A major question in these analyses is the extent to which these methods identify clinically actionable alterations and whether the examination of the tumor tissue alone is sufficient or whether matched normal DNA should also be analyzed to accurately identify tumor-specific (somatic) alterations. To address these issues, we comprehensively evaluated 815 tumor-normal paired samples from patients of 15 tumor types. We identified genomic alterations using next-generation sequencing of whole exomes or 111 targeted genes that were validated with sensitivities >95% and >99%, respectively, and specificities >99.99%. These analyses revealed an average of 140 and 4.3 somatic mutations per exome and targeted analysis, respectively. More than 75% of cases had somatic alterations in genes associated with known therapies or current clinical trials. Analyses of matched normal DNA identified germline alterations in cancer-predisposing genes in 3% of patients with apparently sporadic cancers. In contrast, a tumor-only sequencing approach could not definitively identify germline changes in cancer-predisposing genes and led to additional false-positive findings comprising 31% and 65% of alterations identified in targeted and exome analyses, respectively, including in potentially actionable genes. These data suggest that matched tumor-normal sequencing analyses are essential for precise identification and interpretation of somatic and germline alterations and have important implications for the diagnostic and therapeutic management of cancer patients.
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影响因子：
11.2
作者：
Carter H;Chen S;Isik L;Tyekucheva S;Velculescu VE;Kinzler KW;Vogelstein B;Karchin R
通讯作者：
Karchin R
胰腺神经内分泌肿瘤中经常改变DAXX/ATRX，MEN1和MTOR途径基因。
DOI：
10.1126/science.1200609
发表时间：
2011-03-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jiao Y;Shi C;Edil BH;de Wilde RF;Klimstra DS;Maitra A;Schulick RD;Tang LH;Wolfgang CL;Choti MA;Velculescu VE;Diaz LA Jr;Vogelstein B;Kinzler KW;Hruban RH;Papadopoulos N
通讯作者：
Papadopoulos N
DOI：
10.1073/pnas.0712345105
发表时间：
2008-03-18
影响因子：
11.1
作者：
Jones, Sian;Chen, Wei-dong;Markowitz, Sanford D.
通讯作者：
Markowitz, Sanford D.
影响因子：
46.9
作者：
Frampton GM;Fichtenholtz A;Otto GA;Wang K;Downing SR;He J;Schnall-Levin M;White J;Sanford EM;An P;Sun J;Juhn F;Brennan K;Iwanik K;Maillet A;Buell J;White E;Zhao M;Balasubramanian S;Terzic S;Richards T;Banning V;Garcia L;Mahoney K;Zwirko Z;Donahue A;Beltran H;Mosquera JM;Rubin MA;Dogan S;Hedvat CV;Berger MF;Pusztai L;Lechner M;Boshoff C;Jarosz M;Vietz C;Parker A;Miller VA;Ross JS;Curran J;Cronin MT;Stephens PJ;Lipson D;Yelensky R
通讯作者：
Yelensky R
影响因子：
30.8
作者：
Jiao, Yuchen;Pawlik, Timothy M.;Anders, Robert A.;Selaru, Florin M.;Streppel, Mirte M.;Lucas, Donald J.;Niknafs, Noushin;Guthrie, Violeta Beleva;Maitra, Anirban;Argani, Pedram;Offerhaus, G. Johan A.;Roa, Juan Carlos;Roberts, Lewis R.;Gores, Gregory J.;Popescu, Irinel;Alexandrescu, Sorin T.;Dima, Simona;Fassan, Matteo;Simbolo, Michele;Mafficini, Andrea;Capelli, Paola;Lawlor, Rita T.;Ruzzenente, Andrea;Guglielmi, Alfredo;Tortora, Giampaolo;de Braud, Filippo;Scarpa, Aldo;Jarnagin, William;Klimstra, David;Karchin, Rachel;Velculescu, Victor E.;Hruban, Ralph H.;Vogelstein, Bert;Kinzler, Kenneth W.;Papadopoulos, Nickolas;Wood, Laura D.
通讯作者：
Wood, Laura D.