Foundation Medicine Inc., Cambridge, MA, United States of America.
Foundation Medicine Inc., Morrisville, NC, United States of America.
Gynecol Oncol. 2020 May;157(2):357-366. doi: 10.1016/j.ygyno.2020.02.024. Epub 2020 Mar 7.
Genomic alterations of BCOR via ZC3H7B-BCOR fusion or BCOR internal tandem duplication (ITD) define a subset of endometrial stromal sarcoma (ESS). The goals of this study were to: 1) determine the molecular landscape of BCOR-rearranged ESS, 2) to identify novel BCOR fusion gene partners in ESS and their associated clinicopathological characteristics, and 3) to potentially unravel targetable genomic alterations in BCOR-mutated ESS.
A retrospective database search of a CLIA-certified molecular laboratory was performed for uterine sarcomas that contained BCOR rearrangements or BCOR ITD. The cases were previously assayed by comprehensive genomic profiling via both DNA- and RNA-based targeted next generation sequencing during the course of clinical care. Clinicopathological and genomic data was centrally re-reviewed.
We identify largest cohort of BCOR-rearranged ESS to date (n = 40), which included 31 cases with canonical ZC3H7B-BCOR fusion as well as 8 cases with novel BCOR gene rearrangement partners, such as BCOR-L3MBTL2, EP300-BCOR, BCOR-NUTM2G, BCOR-RALGPS1, BCOR-MAP7D2, RGAG1-BCOR, ING3-BCOR, BCOR-NUGGC, KMT2D-BCOR, CREBBP-BCOR and 1 case with BCOR internal rearrangement. Re-review of cases with novel rearrangements demonstrated sarcomas with spindle, epithelioid or small round cell components and frequent myxoid stromal change. Comprehensive genomic profiling revealed high frequency of CDK4 and MDM2 amplification in 38% and 45% of BCOR-rearranged cases, respectively, and homozygous deletion of CDKN2A, which encodes an inhibitor of CDK4 in 28% of cases. Notably, CDK4 and MDM2 amplification was absent in all cases from 15 different ESS cases harboring BCOR ITD.
Alterations of CDK4 pathway members, for which targeted therapy is clinically available (i.e. palbociclib), via CDK4 amplification or CDKN2A loss, contributes to the pathogenesis of BCOR-rearranged uterine sarcomas, which may have therapeutic implications.
BCOR 通过 ZC3H7B-BCOR 融合或 BCOR 内部串联重复（ITD）的基因组改变定义了子宫内膜间质肉瘤（ESS）的一个亚组。本研究的目的是：1）确定 BCOR 重排的 ESS 的分子图谱，2）鉴定 ESS 中新型 BCOR 融合基因伙伴及其相关的临床病理特征，3）可能揭示 BCOR 突变的 ESS 中可靶向的基因组改变。
对 CLIA 认证的分子实验室进行了回顾性数据库搜索，以寻找包含 BCOR 重排或 BCOR ITD 的子宫肉瘤病例。这些病例在临床治疗过程中通过基于 DNA 和 RNA 的综合基因组分析进行了综合基因组分析。集中重新审查了临床病理和基因组数据。
我们确定了迄今为止最大的 BCOR 重排 ESS 队列（n=40），其中包括 31 例具有典型 ZC3H7B-BCOR 融合的病例，以及 8 例具有新型 BCOR 基因重排伙伴的病例，例如 BCOR-L3MBTL2、EP300-BCOR、BCOR-NUTM2G、BCOR-RALGPS1、BCOR-MAP7D2、RGAG1-BCOR、ING3-BCOR、BCOR-NUGGC、KMT2D-BCOR、CREBBP-BCOR 和 1 例具有 BCOR 内部重排的病例。对具有新型重排的病例进行重新审查显示，肉瘤具有梭形、上皮样或小圆细胞成分，并且经常有粘液样基质变化。综合基因组分析显示，在 38%和 45%的 BCOR 重排病例中分别高频出现 CDK4 和 MDM2 扩增，以及 28%的病例中 CDKN2A 的纯合缺失，CDKN2A 编码 CDK4 的抑制剂。值得注意的是，在 15 例不同的 ESS 病例中，所有携带 BCOR ITD 的病例均未出现 CDK4 和 MDM2 扩增。
通过 CDK4 扩增或 CDKN2A 缺失导致 CDK4 通路成员改变，这些改变是 BCOR 重排的子宫肉瘤发病机制的一部分，这可能具有治疗意义。
