Copy number alteration burden predicts prostate cancer relapse
Copy number alteration burden predicts prostate cancer relapse
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DOI：
10.1073/pnas.1411446111
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发表时间：
2014-07-29
影响因子：
11.1
通讯作者：
Sawyers, Charles L.
中科院分区：
文献类型：
--
作者：
Hieronymus, Haley;Schultz, Nikolaus;Sawyers, Charles L.
原发性前列腺癌是男性最常见的恶性肿瘤，但预后差异很大，这突显了需要生物标记物来确定哪些患者可以保守治疗。目前很少有大型前列腺癌基因组资源能够结合发现预后生物标志物所需的分子和临床结果数据。此前，我们在168例原发肿瘤中发现了复发与DNA拷贝数改变(CNA)模式之间的关联，增加了CNA作为预后生物标记物的可能性。在这里，我们通过描述另外104例原发性前列腺癌和更新最初的168例患者的长期临床结果来研究这个问题。我们发现，跨基因组的CNA负荷，定义为受CNA影响的肿瘤基因组的百分比，与这两个队列的术后生化复发和转移有关，与前列腺癌现有的主要组织病理学预后变量--前列腺特异性抗原生物标记物或Gleason分级无关。此外，CNA负荷与中等风险的Gleason 7前列腺癌患者的生化复发有关，与前列腺特异性抗原或诺模图评分无关。我们进一步证明，CNA的负担可以通过使用低输入全基因组测序的诊断性针吸活检来测量，为研究保守治疗的队列的预后影响奠定了基础。
Primary prostate cancer is the most common malignancy in men but has highly variable outcomes, highlighting the need for biomarkers to determine which patients can be managed conservatively. Few large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary to discover prognostic biomarkers. Previously, we found an association between relapse and the pattern of DNA copy number alteration (CNA) in 168 primary tumors, raising the possibility of CNA as a prognostic biomarker. Here we examine this question by profiling an additional 104 primary prostate cancers and updating the initial 168 patient cohort with long-term clinical outcome. We find that CNA burden across the genome, defined as the percentage of the tumor genome affected by CNA, was associated with biochemical recurrence and metastasis after surgery in these two cohorts, independent of the prostate-specific antigen biomarker or Gleason grade, a major existing histopathological prognostic variable in prostate cancer. Moreover, CNA burden was associated with biochemical recurrence in intermediate-risk Gleason 7 prostate cancers, independent of prostate-specific antigen or nomogram score. We further demonstrate that CNA burden can be measured in diagnostic needle biopsies using low-input whole-genome sequencing, setting the stage for studies of prognostic impact in conservatively treated cohorts.