Genomics of lethal prostate cancer at diagnosis and castration resistance
Genomics of lethal prostate cancer at diagnosis and castration resistance
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DOI：
10.1172/jci132031
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发表时间：
2020-04-01
影响因子：
15.9
通讯作者：
de Bono, Johann S.
中科院分区：
文献类型：
--
作者：
Mateo, Joaquin;Seed, George;de Bono, Johann S.
原发性前列腺癌的基因组学不同于转移性去势耐药前列腺癌(MCRPC)。我们研究了患有mCRPC的患者的前列腺癌活检组织的基因组异常。还研究了配对、同一患者、诊断和治疗后的mCRPC活检。我们描述了470例未经治疗的前列腺癌诊断活检组织，以及61例mCRPC活检组织，使用有针对性的低通全基因组测序(n=52)。描述性统计用于总结突变和拷贝数分布。采用Fisher‘s精确检验比较患病率。生存相关分析采用对数等级检验。常见的有TP53(27%)、PTEN(12%)和DDR基因缺陷(BRCA27%；031(125%；ATM 4%)。TPS3、BRCA2和CDI(12个突变比TCGA队列中描述的更常见。原发灶P81缺失的患者预后较差。在61名激素初治和mCRPC匹配的男性患者中，AR、TP53、P81和PI3K/AKT突变状态在同一患者样本之间存在差异。总之，从患有mCRPC的男性获得的诊断性前列腺活检的基因组学不同于那些非致命性的原发性前列腺癌。Rb1/TP53/AR异常在晚期较丰富，但诊断样本中DDR缺陷的发生率与mCRPC相似。
The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC. also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; 031(12 5%; ATM 4%) were commonly detected. TPS3, BRCA2, and CDI(12 mutations were ma rkedly more common than described in the TCGA cohort. Patients with P81 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, P81, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.