Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Eur Urol. 2017 Nov;72(5):665-674. doi: 10.1016/j.eururo.2017.04.034. Epub 2017 May 13.
Intraductal carcinoma (IDC) and cribriform architecture (CA) represent unfavorable subpathologies in localized prostate cancer. We recently showed that IDC shares a clonal ancestry with the adjacent glandular adenocarcinoma.
We investigated for the co-occurrence of "aggression" factors, genomic instability and hypoxia, and performed gene expression profiling of these tumors.
DESIGN, SETTING, AND PARTICIPANTS: A total of 1325 men were treated for localized prostate cancer from four academic institutions (University Health Network, CHU de Québec-Université Laval, Memorial Sloan Kettering Cancer Center [MSKCC], and Erasmus Medical Center). Pathological specimens were centrally reviewed. Gene copy number and expression, and intraprostatic oxygenation were assessed.
IDC/CA was separately assessed for biochemical relapse risk in the Canadian and MSKCC cohorts. Both cohorts were pooled for analyses on metastasis.
Presence of IDC/CA independently predicted for increased risks of biochemical relapse (HR 2.17, p<0.001; HR 2.32, p=0.0035) and metastasis (HR 3.31, p<0.001). IDC/CA+ cancers were associated with an increased percentage of genome alteration (PGA [median] 7.2 vs 3.0, p<0.001), and hypoxia (64.0% vs 45.5%, p=0.17). Combinatorial genomic-pathological indices offered the strongest discrimination for metastasis (C-index 0.805 [clinical+IDC/CA+PGA] vs 0.786 [clinical+IDC/CA] vs 0.761 [clinical]). Profiling of mRNA abundance revealed that long noncoding RNA, SChLAP1, was the only gene expressed at >3-fold higher (p<0.0001) in IDC/CA+ than in IDC/CA- tumors, independently corroborated by increased SChLAP1 RNA in situ hybridization signal. Optimal treatment intensification for IDC/CA+ prostate cancer requires prospective testing.
The poor outcome associated with IDC and CA subpathologies is associated with a constellation of genomic instability, SChLAP1 expression, and hypoxia. We posit a novel concept in IDC/CA+ prostate cancer, "nimbosus" (gathering of stormy clouds, Latin), which manifests as increased metastatic capacity and lethality.
A constellation of unfavorable molecular characteristics co-occur with intraductal and cribriform subpathologies in prostate cancer. Modern imaging for surveillance and treatment intensification trials should be considered in this adverse subgroup.
导管内癌（IDC）和筛状结构（CA）是局限性前列腺癌中不利的亚病理学表现。我们最近表明，IDC 与相邻的腺泡腺癌具有克隆起源。
我们研究了这些肿瘤中“侵袭性”因素、基因组不稳定性和缺氧的共同发生情况，并进行了基因表达谱分析。
设计、设置和参与者：共有 1325 名男性在四家学术机构（多伦多大学健康网络、魁北克大学拉瓦尔分校医疗中心、纪念斯隆凯特琳癌症中心 [MSKCC] 和伊拉斯谟医疗中心）接受局限性前列腺癌治疗。对病理标本进行了集中审查。评估了基因拷贝数和表达以及前列腺内氧合情况。
在加拿大和 MSKCC 队列中，分别评估 IDC/CA 对生化复发风险的影响。对两个队列进行了转移分析。
IDC/CA 的存在独立预测生化复发（HR 2.17，p<0.001；HR 2.32，p=0.0035）和转移（HR 3.31，p<0.001）的风险增加。IDC/CA+癌症与更高的基因组改变百分比相关（PGA[中位数]7.2%比 3.0%，p<0.001）和缺氧（64.0%比 45.5%，p=0.17）。组合基因组病理学指数为转移提供了最强的区分度（C 指数 0.805[临床+IDC/CA+PGA]比 0.786[临床+IDC/CA]比 0.761[临床]）。mRNA 丰度的分析显示，长非编码 RNA SChLAP1 在 IDC/CA+肿瘤中的表达水平比 IDC/CA-肿瘤高 3 倍以上（p<0.0001），这一结果通过原位杂交信号中 SChLAP1 RNA 的增加得到独立证实。IDC/CA+前列腺癌的最佳治疗强化需要前瞻性试验。
与 IDC 和 CA 亚病理学相关的不良预后与基因组不稳定性、SChLAP1 表达和缺氧的组合有关。我们提出了一个新的概念，即 IDC/CA+前列腺癌中的“nimbosus”（聚集的暴风云，拉丁语），它表现为转移能力增加和致命性增加。
在前列腺癌中，一系列不利的分子特征与导管内和筛状结构的亚病理学同时发生。在这个不利的亚组中，应该考虑现代成像进行监测和治疗强化试验。
