Dysregulation of X Chromosome Inactivation in High Grade Ovarian Serous Adenocarcinoma

Background
One of the two copies of the X chromosome is randomly inactivated in females as a means of dosage compensation. Loss of X chromosome inactivation (XCI) is observed in breast and ovarian cancers, and is frequent in basal-like subtype and BRCA1 mutation-associated breast cancers. We investigated the clinical implications of the loss of XCI in ovarian cancer and the association between the loss of XCI and BRCA1 dysfunction.
Materials and Methods
We used open source data generated by The Cancer Genome Atlas (TCGA) Genome Data Analysis Centers. Ward’s hierarchical clustering method was used to classify the methylation status of the X chromosome.
Results
We grouped 584 high grade serous ovarian adenocarcinomas (HG-SOA) according to methylation status, loss of heterozygosity and deletion or gain of X chromosome into the following five groups: preserved inactivated X chromosome (Xi) group (n = 175), partial reactivation of Xi group (n = 100), p arm deletion of Xi group (n = 35), q arm deletion of Xi group (n = 44), and two copies of active X group (n = 230). We found four genes (XAGE3, ZNF711, MAGEA4, and ZDHHC15) that were up-regulated by loss of XCI. HG-SOA with loss of XCI showed aggressive behavior (overall survival of partial reactivation of Xi group: HR 1.7, 95% CI 1.1–2.5, two copies of active X group: HR 1.4, 95% CI 1.0–1.9). Mutation and hypermethylation of BRCA1 were not frequent in HG-SOA with loss of XCI.
Conclusions
Loss of XCI is common in HG-SOA and is associated with poor clinical outcome. The role of BRCA1 in loss of XCI might be limited. XCI induced aberrant expression of cancer-testis antigens, which may have a role in tumor aggressiveness.

## 背景
女性体内两条X染色体中的一条会随机发生失活，以此实现剂量补偿效应。X染色体失活（X chromosome inactivation, XCI）的丢失可见于乳腺癌与卵巢癌，在基底样亚型乳腺癌以及BRCA1突变相关乳腺癌中尤为常见。本研究旨在探讨卵巢癌中XCI丢失的临床意义，以及XCI丢失与BRCA1功能异常之间的关联。

## 材料与方法
本研究使用了由癌症基因组图谱（The Cancer Genome Atlas, TCGA）基因组数据分析中心生成的开源数据。采用沃德分层聚类法（Ward’s hierarchical clustering method）对X染色体的甲基化状态进行分类。

## 结果
本研究依据甲基化状态、杂合性缺失以及X染色体的缺失或扩增情况，将584例高级别浆液性卵巢腺癌（high grade serous ovarian adenocarcinomas, HG-SOA）分为以下五组：保留失活X染色体（inactivated X chromosome, Xi）组（n=175）、Xi部分重激活组（n=100）、Xi短臂缺失组（n=35）、Xi长臂缺失组（n=44）以及双拷贝活性X染色体组（n=230）。本研究发现4个基因（XAGE3、ZNF711、MAGEA4及ZDHHC15）的表达因XCI丢失而上调。伴随XCI丢失的HG-SOA表现出侵袭性生物学行为：Xi部分重激活组的总生存期风险比（HR）为1.7，95%置信区间（CI）为1.1~2.5；双拷贝活性X染色体组的HR为1.4，95% CI为1.0~1.9。在伴随XCI丢失的HG-SOA中，BRCA1突变与高甲基化的发生率并不高。

## 结论
XCI丢失在HG-SOA中较为常见，且与不良临床预后相关。BRCA1在XCI丢失过程中的作用可能较为有限。XCI丢失会诱导癌-睾丸抗原的异常表达，这可能与肿瘤的侵袭性相关。