Toboni Michael D, Wu Sharon, Farrell Alex, Xiu Joanne, Ribeiro Jennifer R, Oberley Matthew J, Arend Rebecca, Erickson Britt K, Herzog Thomas J, Thaker Premal H, Powell Matthew A
University of Alabama at Birmingham, Division of Gynecologic Oncology, Birmingham, AL, USA.
Caris Life Sciences, Phoenix, AZ, USA.
Gynecol Oncol. 2023 Oct;177:132-141. doi: 10.1016/j.ygyno.2023.08.015. Epub 2023 Sep 8.
To identify differential survival outcomes and immune checkpoint inhibitor (ICI) response in MLH1 hypermethylated versus MLH1 mutated ("Lynch-like") endometrial tumors and determine whether their molecular profiles can elucidate the differential outcomes.
1673 mismatch repair deficient endometrial tumors were analyzed by next-generation sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ). PD-L1, ER, and PR were tested by immunohistochemistry and immune cell infiltrates were calculated using MCP-counter. Significance was determined using Chi-square and Mann-Whitney U tests and adjusted for multiple comparisons. Overall survival (OS) was depicted using Kaplan-Meier survival curves.
The endometrial cancer cohort comprised 89.2% patients with MLH1 hypermethylated tumors and 10.8% with MLH1 mutated tumors, with median ages of 67 and 60 years, respectively (p < 0.01). Patients with MLH1 hypermethylated tumors had significantly worse OS and trended toward worse OS following ICI treatment than patients with MLH1 mutated tumors. The immune microenvironment of MLH1 hypermethylated relative to MLH1 mutated was characterized by decreased PD-L1 positivity, immune checkpoint gene expression, immune cell infiltration, T cell inflamed scores, and interferon gamma (IFNγ) scores. MLH1 hypermethylation was also associated with decreased mutation rates in TP53 and DNA damage repair genes, but increased rates of JAK1, FGFR2, CCND1, and PTEN mutations, as well as increased ER and PR positivity.
Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors.
确定错配修复缺陷（dMMR）的子宫内膜癌中，MLH1基因启动子高甲基化与MLH1基因功能缺陷型突变（“林奇样”）肿瘤患者的生存差异及免疫检查点抑制剂（ICI）疗效差异，并确定它们的分子特征是否能解释这种差异。
采用二代测序和全转录组测序（Caris生命科学公司，凤凰城，亚利桑那州）分析1673例错配修复缺陷的子宫内膜癌肿瘤样本。通过免疫组化检测PD-L1、雌激素受体（ER）和孕激素受体（PR），并使用MCP-counter计算免疫细胞浸润情况。采用卡方检验和曼-惠特尼U检验确定差异显著性，并对多重比较进行校正。采用Kaplan-Meier生存曲线描述总生存期（OS）。
子宫内膜癌队列中，89.2%为MLH1高甲基化肿瘤患者，10.8%为MLH1突变肿瘤患者，中位年龄分别为67岁和60岁（p<0.01）。与MLH1突变肿瘤患者相比，MLH1高甲基化肿瘤患者的OS显著更差，且接受ICI治疗后的OS有更差的趋势。相对于MLH1突变肿瘤，MLH1高甲基化肿瘤的免疫微环境表现为PD-L1阳性率降低、免疫检查点基因表达降低、免疫细胞浸润减少、T细胞炎症评分降低和干扰素γ（IFNγ）评分降低。MLH1高甲基化还与TP53和DNA损伤修复基因的突变率降低有关，但JAK1、FGFR2、CCND1和PTEN的突变率增加，以及ER和PR阳性率增加。
与MLH1突变肿瘤患者相比，MLH1高甲基化的子宫内膜癌患者生存率显著降低，免疫治疗反应存在差异，这与不同的突变谱、更免疫冷的表型以及MLH1高甲基化肿瘤中ER/PR表达增加有关。对于MLH1高甲基化肿瘤患者，医疗人员可考虑早期从单药ICI治疗过渡到多药方案或激素治疗。
