Gynecology Service, Departments of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Gynecol Oncol. 2023 Dec;179:16-23. doi: 10.1016/j.ygyno.2023.10.007. Epub 2023 Oct 25.
To assess the clinicopathologic, molecular profiles, and survival outcomes of patients with endometrial carcinomas (ECs) harboring telomerase reverse transcriptase (TERT) hotspot mutations or gene amplification.
ECs harboring somatic TERT promoter hotspot mutations or gene amplification (TERT-altered) were identified from 1944 ECs that underwent clinical tumor-normal sequencing from 08/2016-12/2021. Clinicopathologic variables, somatic mutation profiles, and survival outcomes of TERT-alt and TERT-wild-type EC were assessed.
We identified 66 TERT-altered ECs (43 TERT-mutated and 23 TERT-amplified), representing 3% of the unselected ECs across histologic subtypes. Most TERT-altered ECs were of copy number (CN)-high/TP53abn molecular subtype (n = 40, 60%), followed by microsatellite-unstable (MSI-H) or CN-low/no specific molecular profile (NSMP)(n = 13, 20% each). TERT-amplified and TERT-mutated ECs were molecularly distinct, with TERT-amplified ECs being more genomically instable and more frequently harboring TP53 and PPP2R1A alterations (q < 0.1). Compared to TERT-wild-type ECs, TERT-altered ECs were more commonly of CN-H/TP53abn molecular subtype (31% vs 57%, p = 0.001), serous histology (10% vs 26%, p = 0.004), and were significantly enriched for TP53, CDKN2A/B, and DROSHA somatic genetic alterations (q < 0.1). Median progression-free survival was 18.7 months (95% CI 11.8-not estimable [NE]) for patients with TERT-altered EC and 80.9 months (65.8-NE) for patients with TERT-wild-type EC (HR 0.33, 95% CI 0.21-0.51, p < 0.001). Similarly, median overall survival was 46.7 months (95% CI 30-NE) for TERT-altered EC patients and not reached for TERT-wild-type EC patients (HR 0.24, 95% CI 0.13-0.44, p < 0.001).
TERT-altered ECs, although rare, are enriched for CN-high/TP53abn tumors, TP53, CDKN2A/B and DROSHA somatic mutations, and independently predict worse survival outcomes.
评估携带端粒酶逆转录酶（TERT）热点突变或基因扩增的子宫内膜癌（ECs）患者的临床病理、分子谱和生存结局。
从 2016 年 8 月至 2021 年 12 月进行临床肿瘤-正常测序的 1944 例 EC 中鉴定出携带体细胞 TERT 启动子热点突变或基因扩增（TERT 改变）的 ECs。评估 TERT 改变和 TERT 野生型 EC 的临床病理变量、体细胞突变谱和生存结局。
我们鉴定出 66 例 TERT 改变的 EC（43 例 TERT 突变和 23 例 TERT 扩增），占所有组织学亚型中未经选择的 EC 的 3%。大多数 TERT 改变的 EC 为拷贝数（CN）高/TP53abn 分子亚型（n=40，60%），其次是微卫星不稳定（MSI-H）或 CN 低/无特定分子谱（NSMP）（n=13，各占 20%）。TERT 扩增和 TERT 突变的 EC 在分子上是不同的，TERT 扩增的 EC 具有更高的基因组不稳定性，并且更频繁地携带 TP53 和 PPP2R1A 改变（q<0.1）。与 TERT 野生型 EC 相比，TERT 改变的 EC 更常见于 CN-H/TP53abn 分子亚型（31%比 57%，p=0.001）、浆液性组织学（10%比 26%，p=0.004），并且显著富集 TP53、CDKN2A/B 和 DROSHA 体细胞遗传改变（q<0.1）。TERT 改变的 EC 患者的无进展生存期中位数为 18.7 个月（95%CI 11.8-不可估计[NE]），而 TERT 野生型 EC 患者的无进展生存期中位数为 80.9 个月（65.8-NE）（HR 0.33，95%CI 0.21-0.51，p<0.001）。同样，TERT 改变的 EC 患者的总生存期中位数为 46.7 个月（95%CI 30-NE），而 TERT 野生型 EC 患者的总生存期未达到（HR 0.24，95%CI 0.13-0.44，p<0.001）。
虽然罕见，但 TERT 改变的 EC 富含 CN 高/TP53abn 肿瘤、TP53、CDKN2A/B 和 DROSHA 体细胞突变，并独立预测更差的生存结局。
