在卵巢上皮癌分析中，KANSL1 被鉴定为免疫反应和 HDAC 抑制的生物标志物和靶基因。

Analysis in epithelial ovarian cancer identifies KANSL1 as a biomarker and target gene for immune response and HDAC inhibition.

机构信息

David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA.

出版信息

Gynecol Oncol. 2021 Feb;160(2):539-546. doi: 10.1016/j.ygyno.2020.11.008. Epub 2020 Nov 20.

DOI:10.1016/j.ygyno.2020.11.008

PMID:33229045

Abstract

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.

摘要

目的

卵巢癌存在一种免疫反应亚型，其预后良好，但大多数卵巢癌的免疫反应有限。其原因尚不清楚。本研究旨在通过鉴定与预后相关的基因来解决这个问题，这些基因的预后 mRNA 表达水平与基因组事件相关。

方法

使用 170 例卵巢肿瘤的表达微阵列和 5 年生存数据以及 45 例卵巢癌细胞系的 aCGH 数据，鉴定与预后相关的扩增/缺失基因。在表观遗传修饰的染色体 6p21.3 上鉴定出三个免疫反应基因。搜索基因在表观遗传修饰中的作用，确定 KANSL1。搜索全基因组关联研究，以确定与免疫谱改变相关的 KANSL1 遗传变异。研究了 KANSL1 扩增/重排的细胞系对 HDAC 抑制的敏感性。

结果

196 个基因的表达与生存统计学显著相关，其中 82 个基因的表达水平与拷贝数变化相关。在这些基因中，3 个免疫反应基因（HCP5、PSMB8、PSMB9）在表观遗传修饰的染色体 6p21.3 上聚集在一起，它们的表达与表观遗传修饰基因 KANSL1 呈负相关。KANSL1 在卵巢癌中扩增/重排，与淋巴细胞谱相关，是对 HDAC 抑制反应的生物标志物，可能驱动免疫反应基因的表达。

结论

本研究鉴定了 82 个与卵巢癌预后相关的基因和基因组改变。在这些基因中，免疫反应基因的表达与 5 年生存率相关。KANSL1 可能是一个主基因，改变 6p21.3 处免疫反应基因的表达，并驱动对 HDAC 抑制剂的反应。未来的研究应研究 KANSL1，确定是否靶向它可以改变卵巢癌的免疫谱，提高生存率、HDAC 抑制和/或免疫治疗反应。