Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making.
Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making.
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DOI：
10.1200/po.17.00029
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发表时间：
2017-07
影响因子：
4.6
通讯作者：
Scher HI
中科院分区：
文献类型：
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作者：
Abida W;Armenia J;Gopalan A;Brennan R;Walsh M;Barron D;Danila D;Rathkopf D;Morris M;Slovin S;McLaughlin B;Curtis K;Hyman DM;Durack JC;Solomon SB;Arcila ME;Zehir A;Syed A;Gao J;Chakravarty D;Vargas HA;Robson ME;Joseph V;Offit K;Donoghue MTA;Abeshouse AA;Kundra R;Heins ZJ;Penson AV;Harris C;Taylor BS;Ladanyi M;Mandelker D;Zhang L;Reuter VE;Kantoff PW;Solit DB;Berger MF;Sawyers CL;Schultz N;Scher HI
长期的自然病史和主要的骨转移扩散模式是前列腺癌患者采用精准医学的障碍。为了确定临床基因组分析在疾病中的可行性，我们对来自局部、转移性非去势和转移性去势抵抗性前列腺癌（CRPC）患者的肿瘤和正常DNA进行了靶向深度测序。患者同意对其肿瘤和生殖系DNA进行基因组分析。采用基于杂交捕获的临床测定来鉴定肿瘤和匹配的正常血液中超过300个癌症相关基因中的单核苷酸变异、小插入和缺失、拷贝数改变和结构重排。我们成功地对来自451名前列腺癌患者的504个肿瘤进行了测序。在DNA损伤修复（DDR）、PI3K和MAP激酶途径中鉴定了潜在的可操作的改变。27%的患者在DDR基因中存在种系或体细胞改变，这可能预测对PARP抑制的反应。对个体患者的匹配肿瘤的分析显示，最终发展为转移性疾病的患者的肿瘤早期出现体细胞TP53和BRCA2改变。相反，疾病状态的比较分析显示，APC改变在转移性肿瘤中富集，而ATM改变在CRPC中特异性富集。通过对代表疾病临床谱的前列腺肿瘤进行基因组分析，我们发现了高频率的潜在可操作的改变以及疾病发生、转移和去势抵抗的可能驱动因素。我们的研究结果支持常规使用肿瘤和生殖系DNA分析晚期前列腺癌患者，目的是指导有针对性的临床试验的招募和咨询恶性肿瘤风险增加的家庭。
A long natural history and a predominant osseous pattern of metastatic spread are impediments to the adoption of precision medicine in patients with prostate cancer. To establish the feasibility of clinical genomic profiling in the disease, we performed targeted deep sequencing of tumor and normal DNA from patients with locoregional, metastatic non-castrate, and metastatic castration-resistant prostate cancer (CRPC). Patients consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based clinical assay was employed to identify single nucleotide variations, small insertions and deletions, copy number alterations and structural rearrangements in over 300 cancer-related genes in tumors and matched normal blood. We successfully sequenced 504 tumors from 451 patients with prostate cancer. Potentially actionable alterations were identified in DNA damage repair (DDR), PI3K, and MAP kinase pathways. 27% of patients harbored a germline or a somatic alteration in a DDR gene that may predict for response to PARP inhibition. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease. In contrast, comparative analysis across disease states revealed that APC alterations were enriched in metastatic tumors, while ATM alterations were specifically enriched in CRPC. Through genomic profiling of prostate tumors representing the disease clinical spectrum, we identified a high frequency of potentially actionable alterations and possible drivers of disease initiation, metastasis and castration-resistance. Our findings support the routine use of tumor and germline DNA profiling for patients with advanced prostate cancer, for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy.