Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer.
Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer.
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DOI：
10.18632/oncotarget.4494
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发表时间：
2015-09-22
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影响因子：
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通讯作者：
Pockaj BA
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文献类型：
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作者：
Barrett MT;Anderson KS;Lenkiewicz E;Andreozzi M;Cunliffe HE;Klassen CL;Dueck AC;McCullough AE;Reddy SK;Ramanathan RK;Northfelt DW;Pockaj BA
我们使用DNA含量流式细胞术，然后基于寡核苷酸阵列的比较基因组杂交来调查326个肿瘤的基因组，包括41个未经治疗的手术切除的三阴性乳腺癌（TNBC）。在TNBC（12/41）、胶质母细胞瘤（2/44）和结肠癌（2/68）中发现高水平（log 2 ratio ≥1）9 p24扩增子。扩增子的最短重叠区域靶向9p24.1，包括PD-L1、PD-L2和JAK 2（PDJ扩增子）的基因座。相反，ER+（0/8）和HER 2+（0/15）乳腺肿瘤和胰腺导管腺癌（0/150）中不存在该扩增子。通过连续变量的双样本t检验和分类变量的卡方检验，TNBC中的PDJ扩增子与组比较中的临床结果相关。携带PDJ扩增子的TNBC患者的预后更差，无病生存率和总生存率更差。定量RT-PCR证实TNBC中的PDJ扩增子与JAK 2和PD-1配体的表达升高相关。这些初步研究结果表明，PDJ扩增子富含TNBC，靶向激活PD-1介导的免疫检查点的信号传导途径，并鉴定预后不良的患者。
We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log2ratio ≥1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1, PD-L2, and JAK2 (PDJ amplicon). In contrast this amplicon was absent in ER+ (0/8) and HER2+ (0/15) breast tumors, and in pancreatic ductal adenocarcinomas (0/150). The PDJ amplicon in TNBCs was correlated with clinical outcomes in group comparisons by two-sample t-tests for continuous variables and chi-squared tests for categorical variables. TNBC patients with the PDJ amplicon had a worse outcome with worse disease-free and overall survival. Quantitative RT-PCR confirmed that the PDJ amplicon in TNBC is associated with elevated expression of JAK2 and of the PD-1 ligands. These initial findings demonstrate that the PDJ amplicon is enriched in TNBC, targets signaling pathways that activate the PD-1 mediated immune checkpoint, and identifies patients with a poor prognosis.