Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy.
Genomic Heterogeneity Within Individual Prostate Cancer Foci Impacts Predictive Biomarkers of Targeted Therapy.
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DOI：
10.1016/j.euf.2018.01.006
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发表时间：
2019-05
影响因子：
5.4
通讯作者：
Nakagawa H
中科院分区：
文献类型：
--
作者：
VanderWeele DJ;Finney R;Katayama K;Gillard M;Paner G;Imoto S;Yamaguchi R;Wheeler D;Lack J;Cam M;Pontier A;Nguyen YTM;Maejima K;Sasaki-Oku A;Nakano K;Tanaka H;Vander Griend D;Kubo M;Ratain MJ;Miyano S;Nakagawa H
大多数致命的前列腺癌是由侵袭性原发病复发引起的。最近，全身性治疗在生存获益方面的最显著进展来自于将治疗管理转移到早期疾病状态。目前正朝着使用前列腺内指数病变的生物标志物来指导早期系统治疗的方向发展。确定未经治疗的前列腺癌指标焦点内的基因组异质性，包括预测性生物标志物的异质性。10例未经治疗的前列腺癌患者接受了前列腺切除术。从10个索引病灶的70个空间上不同的区域提取DNA。鉴定了单核苷酸突变、小插入缺失和拷贝数变化。确定病灶内基因组异质性和预测治疗反应的变异异质性。外显子组测序和拷贝数估计表明分支进化，其中>75%的点突变是亚克隆的，包括与去势抵抗性前列腺癌相关的许多途径。10名患者中有7名患者的五个基因之一发生了改变，这些基因预测了对前列腺癌靶向治疗的反应和生存益处。在生物标志物阳性病例中，25%的前列腺内区域生物标志物阴性，前列腺内区域和淋巴结转移之间不一致。未经治疗的非转移性前列腺癌具有明显的灶内异质性。与去势抵抗性前列腺癌相关的途径中的许多改变存在于亚克隆群体中，包括预测对靶向治疗的反应的生物标志物。未经治疗的患者的肿瘤具有预测对靶向治疗的反应的改变，但生物标志物的存在取决于评估的肿瘤区域。
Most lethal prostate cancers progress from relapse of aggressive primary disease. Recently, the most significant advances in survival benefit from systemic therapy have come from moving the administration of therapy to an earlier disease state. There is movement toward using biomarkers from the intraprostatic index lesion to guide early systemic therapy. To determine the genomic heterogeneity, including the heterogeneity of predictive biomarkers, within the index focus of treatment-naïve prostate cancer. Ten patients with treatment-naïve prostate cancer underwent prostatectomy. DNA was extracted from 70 spatially distinct regions of the 10 index foci. Single nucleotide mutations, small indels, and copy number changes were identified. Intrafocal genomic heterogeneity and heterogeneity of alterations that predict response to therapy was determined. Exome sequencing and copy number estimates demonstrate branched evolution with >75% of point mutations being subclonal, including numerous pathways associated with castrate-resistant prostate cancer. Seven of 10 patients harbor alterations in one of five genes that predict response to targeted therapies with survival benefit in prostate cancer. Within biomarker-positive cases, 25% of intraprostatic regions are biomarker negative, with discordance between intraprostatic regions and lymph node metastases. Treatment-naïve, nonmetastatic prostate cancer has marked intrafocal heterogeneity. Numerous alterations in pathways associated with castration-resistant prostate cancer are present in subclonal populations, including biomarkers predictive of response to targeted therapy. Untreated patients’ tumors have alterations that predict response to targeted therapies, but the presence of a biomarker is dependent on what region of the tumor was evaluated.
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影响因子：
4.8
作者：
Mroz, Edmund A.;Rocco, James W.
通讯作者：
Rocco, James W.
影响因子：
3.3
作者：
Morais CL;Guedes LB;Hicks J;Baras AS;De Marzo AM;Lotan TL
通讯作者：
Lotan TL
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
DOI：
10.1073/pnas.1411446111
发表时间：
2014-07-29
影响因子：
11.1
作者：
Hieronymus, Haley;Schultz, Nikolaus;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
4.8
作者：
Morgan, T. M.;Meng, M. V.;Lin, D. W.
通讯作者：
Lin, D. W.