Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Pathology and Laboratory Medicine, Sinai Health System, Toronto, Ontario, Canada.
Cancer. 2021 Aug 1;127(15):2666-2673. doi: 10.1002/cncr.33542. Epub 2021 Mar 31.
Leiomyosarcoma (LMS) is the most common soft tissue and uterine sarcoma, but no standard therapy is available for recurrent or metastatic LMS. TP53, p16/RB1, and PI3K/mTOR pathway dysregulations are recurrent events, and some LMS express estrogen receptor (ER) and/or progesterone receptor (PR). To characterize relationships between these pathway perturbations, the authors evaluated protein expression in soft tissue and uterine nonprimary leiomyosarcoma (np-LMS), including local recurrences and distant metastases.
TP53, RB1, p16, and PTEN expression aberrations were determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) from 227 np-LMS and a comparison group of 262 primary leiomyosarcomas (p-LMS). Thirty-five of the np-LMS had a matched p-LMS specimen in the TMAs. Correlative studies included differentiation scoring, ER and PR IHC, and CDKN2A/p16 fluorescence in situ hybridization.
Dysregulation of TP53, p16/RB1, and PTEN was demonstrated in 90%, 95%, and 41% of np-LMS, respectively. PTEN inactivation was more common in soft tissue np-LMS than uterine np-LMS (55% vs 31%; P = .0005). Moderate-strong ER expression was more common in uterine np-LMS than soft tissue np-LMS (50% vs 7%; P < .0001). Co-inactivation of TP53 and RB1 was found in 81% of np-LMS and was common in both soft tissue and uterine np-LMS (90% and 74%, respectively). RB1, p16, and PTEN aberrations were nearly always conserved in p-LMS and np-LMS from the same patients.
These studies show that nearly all np-LMS have TP53 and/or RB1 aberrations. Therefore, therapies targeting cell cycle and DNA damage checkpoint vulnerabilities should be prioritized for evaluations in LMS.
平滑肌肉瘤（LMS）是最常见的软组织和子宫肉瘤，但对于复发性或转移性 LMS，尚无标准疗法。TP53、p16/RB1 和 PI3K/mTOR 通路失调是复发性事件，一些 LMS 表达雌激素受体（ER）和/或孕激素受体（PR）。为了描述这些通路改变之间的关系，作者评估了软组织和子宫非原发性平滑肌肉瘤（np-LMS）的蛋白表达，包括局部复发和远处转移。
采用组织微阵列（TMA）的免疫组化（IHC）方法检测 227 例 np-LMS 和 262 例原发性平滑肌肉瘤（p-LMS）的组织中 TP53、RB1、p16 和 PTEN 表达异常。在 TMA 中，有 35 例 np-LMS 与匹配的 p-LMS 标本。相关性研究包括分化评分、ER 和 PR IHC 以及 CDKN2A/p16 荧光原位杂交。
分别有 90%、95%和 41%的 np-LMS 存在 TP53、p16/RB1 和 PTEN 失调。软组织 np-LMS 中 PTEN 失活比子宫 np-LMS 更常见（55%比 31%；P =.0005）。子宫 np-LMS 中中等至强的 ER 表达比软组织 np-LMS 更常见（50%比 7%；P <.0001）。在 81%的 np-LMS 中发现了 TP53 和 RB1 的共失活，在软组织和子宫 np-LMS 中均很常见（分别为 90%和 74%）。在来自同一患者的 p-LMS 和 np-LMS 中，RB1、p16 和 PTEN 异常几乎总是保守的。
这些研究表明，几乎所有 np-LMS 都存在 TP53 和/或 RB1 异常。因此，针对细胞周期和 DNA 损伤检查点脆弱性的治疗方法应优先在 LMS 中进行评估。
