Genomic, Transcriptomic, and Proteomic Profiling of Metastatic Breast Cancer.
Genomic, Transcriptomic, and Proteomic Profiling of Metastatic Breast Cancer.
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转移性乳腺癌的基因组，转录组和蛋白质组学分析。
DOI：
10.1158/1078-0432.ccr-20-4048
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发表时间：
2021-06-01
期刊：
影响因子：
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通讯作者：
Meric-Bernstam F
中科院分区：
文献类型：
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作者：
Akcakanat A;Zheng X;Cruz Pico CX;Kim TB;Chen K;Korkut A;Sahin A;Holla V;Tarco E;Singh G;Damodaran S;Mills GB;Gonzalez-Angulo AM;Meric-Bernstam F
转移性乳腺癌（MBC）是不可治愈的，人们对个性化治疗方案越来越感兴趣。在这里，我们报告MBC的分子分析，重点是可操作的改变中的分子进化。入选62例MBC患者。进行DNA、RNA和功能蛋白质组学分析，并在可行时比较匹配的原发性和转移性肿瘤。41例肿瘤的靶向外显子组测序确定了TP 53（21; 51%）、PIK 3CA（20; 49%）的常见改变，以及几种新兴生物标志物的改变，如NF 1突变/缺失（6; 15%）、PTEN突变（4; 10%）、ARID 1A突变/缺失（6; 15%）。在27例激素受体阳性患者中，我们确定了MDM 2扩增（3; 11%），FGFR 1扩增（5; 19%），ATM突变（2; 7%）和ESR 1突变（4; 15%）。在10例接受靶向外显子组测序的原发性和转移性肿瘤匹配患者中，可操作改变的不一致性很常见，包括3例患者的NF 1丢失，1例患者的PIK 3CA突变丢失和3例患者的获得性ESR 1突变。在匹配的样品中的RNA-seq证实了NF 1表达的丧失和基因组NF 1的丧失。在33名具有匹配的原发性和转移性样本并进行RNA分析的患者中，14个可操作的基因差异表达，包括抗体药物缀合物靶标LIV-1和B7-H3。MBC中的分子分析揭示了多种常见的以及不太常见的但可能可行的改变。基因组和转录谱显示了肿瘤间的异质性和随着肿瘤进展可操作靶点的潜在演变。需要进一步的工作，以优化测试和综合分析的治疗选择。
Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations. Sixty-two patients with MBC were included. An analysis of DNA, RNA and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible. Targeted exome sequencing of 41 tumors identified common alterations in TP53 (21; 51%), PIK3CA (20; 49%), as well as alterations in several emerging biomarkers such as NF1 mutations/deletions (6; 15%), PTEN mutations (4; 10%), ARID1A mutations/deletions (6; 15%). Among 27 hormone receptor-positive patients, we identified MDM2 amplifications (3; 11%), FGFR1 amplifications (5; 19%), ATM mutations (2; 7%), and ESR1 mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including NF1 loss in 3 patients, loss of PIK3CA mutation in 1 patient, and acquired ESR1 mutations in 3 patients. RNA-seq in matched samples confirmed loss of NF1 expression with genomic NF1 loss. Among 33 patients with matched primary and metastatic samples that underwent RNA profiling, 14 actionable genes were differentially expressed, including antibody drug conjugate targets LIV-1 and B7-H3. Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.