Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases.
Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases.
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DOI：
10.18632/oncotarget.25041
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发表时间：
2018-04-17
期刊：
影响因子：
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通讯作者：
Reis-Filho JS
中科院分区：
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作者：
De Mattos-Arruda L;Ng CKY;Piscuoglio S;Gonzalez-Cao M;Lim RS;De Filippo MR;Fusco N;Schultheis AM;Ortiz C;Viteri S;Arias A;Macedo GS;Oliveira M;Gomez P;Teixidó C;Nuciforo P;Peg V;Saura C;Ramon Y Cajal S;Casas FT;Weigelt B;Cortes J;Seoane J;Reis-Filho JS
脑转移对接受抗her2全身治疗的her2阳性乳腺癌患者的管理构成挑战。在这里，我们试图定义her2阳性脑转移中私有或富集的突变库。针对254个在乳腺癌中经常发生突变和/或与DNA修复相关的基因的所有外显子进行大规模平行测序，以表征6例her2阳性乳腺癌及其脑转移的时空异质性。采用最先进的生物信息学算法对数据进行分析，并采用正交法对选定的突变进行验证。空间和时间的病变间遗传异质性被观察到her2阳性脑转移患者的快速尸检。局限于脑转移的遗传改变包括癌症基因FGFR2、PIK3CA和ATR的突变，CDKN2A的纯合缺失和KRAS的扩增。在另外5例患者中研究了抗her2治疗后从原发性her2阳性乳腺癌到脑转移的进展中克隆组成的变化和额外突变的获得。脑部病变中可能存在或富集的致病突变影响癌症和临床可操作的基因，包括ATR、BRAF、FGFR2、MAP2K4、PIK3CA、RAF1和TP53。脑转移瘤中克隆组成的变化和额外突变的获得可能影响her2阳性乳腺癌中潜在的可动基因。鉴于脑转移性疾病患者的治疗决策仍然主要基于原发肿瘤中评估的生物标志物，我们的观察结果具有潜在的临床意义。
Brain metastases constitute a challenge in the management of patients with HER2-positive breast cancer treated with anti-HER2 systemic therapies. Here we sought to define the repertoire of mutations private to or enriched for in HER2-positive brain metastases. Massively parallel sequencing targeting all exons of 254 genes frequently mutated in breast cancers and/or related to DNA repair was used to characterize the spatial and temporal heterogeneity of HER2-positive breast cancers and their brain metastases in six patients. Data were analyzed with state-of-the-art bioinformatics algorithms and selected mutations were validated with orthogonal methods. Spatial and temporal inter-lesion genetic heterogeneity was observed in the HER2-positive brain metastases from an index patient subjected to a rapid autopsy. Genetic alterations restricted to the brain metastases included mutations in cancer genes FGFR2, PIK3CA and ATR, homozygous deletion in CDKN2A and amplification in KRAS. Shifts in clonal composition and the acquisition of additional mutations in the progression from primary HER2-positive breast cancer to brain metastases following anti-HER2 therapy were investigated in additional five patients. Likely pathogenic mutations private to or enriched in the brain lesions affected cancer and clinically actionable genes, including ATR, BRAF, FGFR2, MAP2K4, PIK3CA, RAF1 and TP53. Changes in clonal composition and the acquisition of additional mutations in brain metastases may affect potentially actionable genes in HER2-positive breast cancers. Our observations have potential clinical implications, given that treatment decisions for patients with brain metastatic disease are still mainly based on biomarkers assessed in the primary tumor.