Analysis in epithelial ovarian cancer identifies KANSL1 as a biomarker and target gene for immune response and HDAC inhibition
Analysis in epithelial ovarian cancer identifies KANSL1 as a biomarker and target gene for immune response and HDAC inhibition
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DOI：
10.1016/j.ygyno.2020.11.008
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发表时间：
2021-01-23
影响因子：
4.7
通讯作者：
Slamon, Dennis J.
中科院分区：
文献类型：
--
作者：
Fejzo, Marlena S.;Chen, Hsiao-Wang;Slamon, Dennis J.
Objective.卵巢癌有一种免疫反应性亚型，预后良好，但大多数卵巢癌的免疫反应性有限。其原因尚不清楚。本研究的目的是通过鉴定与基因组事件相关的预后mRNA表达水平的遗传相关基因来探讨这一问题。170个卵巢肿瘤的表达微阵列和5年生存数据以及45个卵巢癌细胞系的aCGH数据被用于鉴定与预后相关的扩增/缺失基因。鉴定了定位于表观遗传修饰的染色体6p21.3的三个免疫应答基因。搜索基因在表观遗传修饰中的作用，鉴定KANSL 1。搜索全基因组关联研究以鉴定与改变的免疫谱相关的KANSL 1中的遗传变异。研究了具有KANSL 1扩增/重排的细胞系对HDAC抑制的敏感性。196个基因的表达与生存率有统计学意义，其中82个基因的表达水平与拷贝数变异相关。其中，3个免疫应答基因（HCP 5、PSMB 8、PSMB 9）聚集在表观遗传修饰的染色体6p21.3处，并且它们的表达与表观遗传修饰基因KANSL 1负相关。KANSL 1在卵巢癌中扩增/重排，与淋巴细胞特征相关，是HDAC抑制反应的生物标志物，可能驱动免疫反应基因的表达。这项研究确定了82个与卵巢癌预后相关的基因和基因组改变。其中，免疫应答基因具有与5年生存相关的相关表达。KANSL 1可能是一个主基因，改变6p21.3的免疫应答基因表达，并驱动对HDAC抑制剂的应答。未来的研究应该调查KANSL 1，并确定靶向它是否会改变卵巢癌的免疫特征，并改善生存率，HDAC抑制和/或免疫治疗反应。(c)2020爱思唯尔公司All rights reserved.
Objective. There is an immunoreactive subtype of ovarian cancer with a favorable prognosis, but the majority of ovarian cancers have limited immune reactivity. The reason for this is poorly understood. This study aimed to approach this question by identifying prognostically relevant genes whose prognostic mRNA expression levels correlated with a genomic event.Methods. Expression microarray and 5-year survival data on 170 ovarian tumors and aCGH data on 45 ovarian cancer cell lines were used to identify amplified/deleted genes associated with prognosis. Three immune response genes were identified mapping to epigenetically modified chromosome 6p21.3. Genes were searched for roles in epigenetic modification, identifying KANSL1. Genome-wide association studies were searched to identify genetic variants in KANSL1 associated with altered immune profile. Sensitivity to HDAC inhibition in cell lines with KANSL1 amplification/rearrangement was studied.Results. Expression of 196 genes was statistically significantly associated with survival, and expression levels correlated with copy number variations for 82 of them. Among these, 3 immune-response genes (HCP5, PSMB8, PSMB9) clustered together at epigenetically modified chromosome 6p21.3 and their expression was inversely correlated to epigenetic modification gene KANSL1. KANSL1 is amplified/rearranged in ovarian cancer, associated with lymphocyte profile, a biomarker for response to HDAC inhibition, and may drive expression of immune response genes.Conclusion. This study identifies 82 genes with prognostic relevance and genomic alteration in ovarian cancer. Among these, immune-response genes have correlated expression which is associated with 5-year survival. KANSL1 may be a master gene altering immune-response gene expression at 6p21.3 and drive response to HDAC inhibitors. Future research should investigate KANSL1 and determine whether targeting it alters the immune profile of ovarian cancer and improves survival, HDAC inhibition, and/or immunotherapy response.(c) 2020 Elsevier Inc. All rights reserved.