Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use.
Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use.
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DOI：
10.1016/j.ebiom.2016.08.036
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发表时间：
2016-10
期刊：
影响因子：
11.1
通讯作者：
Czerniak, Bogdan
中科院分区：
文献类型：
--
作者：
Dadhania, Vipulkumar;Zhang, Miao;Zhang, Li;Bondaruk, Jolanta;Majewski, Tadeusz;Siefker-Radtke, Arlene;Guo, Charles C.;Dinney, Colin;Cogdell, David E.;Zhang, Shizhen;Lee, Sangkyou;Lee, June G.;Weinstein, John N.;Baggerly, Keith;McConkey, David;Czerniak, Bogdan
有人建议，膀胱癌可分为两种分子亚型，称为管腔癌和基底癌，具有不同的临床行为和对化疗的敏感性。我们的目的是在几个临床队列中验证这些亚型，并确定特征性免疫组织化学标记物，以便在初级保健中心对疾病进行简单且经济高效的分类。我们分析了三组新鲜冷冻肿瘤样本中膀胱癌的基因组表达谱：MD Anderson (n = 132)、Lund (n = 308) 和癌症基因组图谱 (TCGA) (n = 408)，以验证腔亚型和基底亚型的表达特征并将其与临床随访数据联系起来。我们还使用 MD 安德森档案膀胱肿瘤样本队列 (n = 89) 和平行组织微阵列来识别允许对膀胱癌进行分子分类的免疫组织化学标记物。在所有分析的数据集中，膀胱癌可以分为两种候选内在分子亚型，此处称为管腔癌和基底癌。管腔肿瘤的特征在于与正常尿路上皮的中间/浅层相似的表达特征。他们显示 PPARγ 靶基因的上调以及 FGFR3、ELF3、CDKN1A 和 TSC1 突变的富集。此外，管腔肿瘤的特点是 E-Cadherin、HER2/3、Rab-25 和 Src 的过度表达。基底肿瘤表现出与正常尿路上皮基底层相似的表达特征。他们显示了 p63 靶基因的上调、TP53 和 RB1 突变的富集以及 CD49、Cyclin B1 和 EGFR 的过度表达。生存分析表明，与管腔癌相比，肌肉浸润性基底膀胱癌更具侵袭性。仅 luminal (GATA3) 和 basal (KRT5/6) 两种标记物的免疫组织化学表达就足以鉴定膀胱癌的分子亚型，准确度超过 90%。膀胱癌的分子亚型具有不同的临床行为和对化疗的敏感性，简单的双标记免疫组织化学分类器可用于预后和治疗分层。美国国家癌症研究所和国家健康研究所。膀胱癌可分为两种内在分子亚型，称为管腔癌和基底癌。管腔肿瘤的特征是正常尿路上皮中/表层的表达特征，并且它们显示 PARγ 靶基因的上调，并富集 FGFR3、ELF3、CDKN1A 和 TSC1 突变。基底肿瘤表现出与正常尿路上皮基底层相似的表达特征，并且显示出 p63 靶基因的上调以及 TP53 和 RB1 突变的富集。与腔内癌症相比，基底型肌肉浸润性肿瘤更具侵袭性。仅 luminal (GATA3) 和 basal (KRT5/6) 两种标记物的免疫组织化学表达就足以鉴定膀胱癌的分子亚型，准确度超过 90%。我们对包括总共 937 个膀胱癌肿瘤样本和注释临床数据的几个大型队列进行的分析表明，膀胱癌可以分为分子亚型，称为管腔癌和基底癌。管腔肿瘤的基因表达模式与正常尿路上皮分化程度更高的中间层和浅层相似。基底癌再现了分化程度较低的尿路上皮基底层的基因表达特征。这些分子亚型具有明显的转录因子上调作用，调节其靶基因的表达模式，并富含特定突变。与管腔类型相比，深入侵犯膀胱壁的基底肿瘤更具侵袭性，并且它们对一线化疗表现出明显的敏感性。将膀胱癌分类为其内在分子亚型可以通过两种免疫组织化学标记来完成，例如用于管腔肿瘤的 GATA3 和用于基底肿瘤的 KRT5/6，这可以在初级保健中心进行。
It has been suggested that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to chemotherapy. We aimed to validate these subtypes in several clinical cohorts and identify signature immunohistochemical markers that would permit simple and cost-effective classification of the disease in primary care centers. We analyzed genomic expression profiles of bladder cancer in three cohorts of fresh frozen tumor samples: MD Anderson (n = 132), Lund (n = 308), and The Cancer Genome Atlas (TCGA) (n = 408) to validate the expression signatures of luminal and basal subtypes and relate them to clinical follow-up data. We also used an MD Anderson cohort of archival bladder tumor samples (n = 89) and a parallel tissue microarray to identify immunohistochemical markers that permitted the molecular classification of bladder cancer. Bladder cancers could be assigned to two candidate intrinsic molecular subtypes referred to here as luminal and basal in all of the datasets analyzed. Luminal tumors were characterized by the expression signature similar to the intermediate/superficial layers of normal urothelium. They showed the upregulation of PPARγ target genes and the enrichment for FGFR3, ELF3, CDKN1A, and TSC1 mutations. In addition, luminal tumors were characterized by the overexpression of E-Cadherin, HER2/3, Rab-25, and Src. Basal tumors showed the expression signature similar to the basal layer of normal urothelium. They showed the upregulation of p63 target genes, the enrichment for TP53 and RB1 mutations, and overexpression of CD49, Cyclin B1, and EGFR. Survival analyses showed that the muscle-invasive basal bladder cancers were more aggressive when compared to luminal cancers. The immunohistochemical expressions of only two markers, luminal (GATA3) and basal (KRT5/6), were sufficient to identify the molecular subtypes of bladder cancer with over 90% accuracy. The molecular subtypes of bladder cancer have distinct clinical behaviors and sensitivities to chemotherapy, and a simple two-marker immunohistochemical classifier can be used for prognostic and therapeutic stratification. U.S. National Cancer Institute and National Institute of Health. Bladder cancer can be assigned to two intrinsic molecular subtypes referred to as luminal and basal. Luminal tumors are characterized by the expression signature of intermediate/superficial layers of normal urothelium and they show up-regulation of PARγ target genes with enrichment for FGFR3, ELF3, CDKN1A, and TSC1 mutations. Basal tumors show the expression signature similar to the basal layer of normal urothelium and they show the up-regulation of p63 target genes with the enrichment of TP53 and RB1 mutations. Muscle invasive tumors of basal type are more aggressive when compared to luminal cancers. The immunohistochemical expression of only two markers, luminal (GATA3) and basal (KRT5/6) is sufficient to identify the molecular subtypes of bladder cancer with over 90% accuracy. Our analyses of several large cohorts comprising of a total of 937 bladder cancer tumors samples with annotated clinical data showed that bladder cancers can be classified into molecular subtypes referred to as luminal and basal. Luminal tumors are similar in their gene expression pattern to more differentiated intermediate and superficial layers of normal urothelium. Basal cancers recapitulate the gene expression signature of the less differentiated basal layer of the urothelium. These molecular subtypes have distinct up-regulation of transcription factors that regulate the expression pattern of their target genes and are enriched for specific mutations. Basal tumors which deeply invade the bladder wall are more aggressive when compared to luminal types and they show distinct sensitivities to frontline chemotherapy. The classification of bladder cancer into its intrinsic molecular subtypes can be accomplished with two immunohistochemical markers such as GATA3 for luminal tumors and KRT5/6 for basal tumors which can be performed in primary care centers.
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影响因子：
4.6
作者：
Aine M;Eriksson P;Liedberg F;Sjödahl G;Höglund M
通讯作者：
Höglund M
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1038/modpathol.2015.68
发表时间：
2015-09
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
Singh RR;Murugan P;Patel LR;Voicu H;Yoo SY;Majewski T;Mehrotra M;Wani K;Tannir N;Karam JA;Jonasch E;Wood CG;Creighton CJ;Medeiros LJ;Broaddus RR;Tamboli P;Baggerly KA;Aldape KD;Czerniak B;Luthra R;Sircar K
通讯作者：
Sircar K
影响因子：
23.4
作者：
Groenendijk, Floris H.;de Jong, Jeroen;van der Heijden, Michiel S.
通讯作者：
van der Heijden, Michiel S.
影响因子：
21.3
作者：
Van Batavia, Jason;Yamany, Tammer;Mendelsohn, Cathy
通讯作者：
Mendelsohn, Cathy