Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets.
Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets.
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DOI：
10.1158/2159-8290.cd-15-0369
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发表时间：
2015-11
期刊：
影响因子：
28.2
通讯作者：
Hahn WC
中科院分区：
文献类型：
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作者：
Brastianos PK;Carter SL;Santagata S;Cahill DP;Taylor-Weiner A;Jones RT;Van Allen EM;Lawrence MS;Horowitz PM;Cibulskis K;Ligon KL;Tabernero J;Seoane J;Martinez-Saez E;Curry WT;Dunn IF;Paek SH;Park SH;McKenna A;Chevalier A;Rosenberg M;Barker FG 2nd;Gill CM;Van Hummelen P;Thorner AR;Johnson BE;Hoang MP;Choueiri TK;Signoretti S;Sougnez C;Rabin MS;Lin NU;Winer EP;Stemmer-Rachamimov A;Meyerson M;Garraway L;Gabriel S;Lander ES;Beroukhim R;Batchelor TT;Baselga J;Louis DN;Getz G;Hahn WC
脑转移与预后不佳有关。脑转移瘤是否存在与原发肿瘤不同的基因改变尚不清楚。我们对86例匹配的脑转移瘤、原发肿瘤和正常组织进行了全外显子组测序。在所有克隆相关的癌症样本中，我们观察到分支进化，其中所有转移和原发部位共享共同的祖先，但继续独立进化。在53%的病例中，我们在匹配的原发肿瘤样本中未发现的脑转移瘤中发现了潜在的临床信息变化。相反，在空间和时间上分离的脑转移灶在基因上是同质的。远端颅外和区域淋巴结转移与脑转移高度不同。我们在脑转移瘤中检测到与PI3K/AKT/mTOR、CDK和HER2/EGFR抑制剂的敏感性相关的变化。脑转移的基因组分析提供了一个机会来识别在临床采样的原发肿瘤、区域淋巴结或颅外转移中未检测到的潜在的临床信息性变化。
Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases.