Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Medicine (Oncology), Stanford University, Stanford, CA, USA.
Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Gynecol Oncol. 2023 Apr;171:129-140. doi: 10.1016/j.ygyno.2023.02.017. Epub 2023 Mar 8.
Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to determine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1-methylated tumors.
We screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4, <60 years), and (ii) two population-based cohorts; "Columbus-area" (n = 68, all ages) and "Ohio Colorectal Cancer Prevention Initiative (OCCPI)" (n = 24, <60 years).
Constitutional MLH1 methylation was identified in three out of four patients diagnosed between 36 and 59 years from cancer clinics. Two had mono-/hemiallelic epimutation (∼50% alleles methylated). One with multiple primaries had low-level mosaicism in normal tissues and somatic "second-hits" affecting the unmethylated allele in all tumors, demonstrating causation. In the population-based cohorts, all 68 cases from the Columbus-area cohort were negative and low-level mosaic constitutional MLH1 methylation was identified in one patient aged 36 years out of 24 from the OCCPI cohort, representing one of six (∼17%) patients <50 years and one of 45 patients (∼2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three patients with underlying constitutional MLH1 methylation.
A correct diagnosis at first presentation of cancer is important as it will significantly alter clinical management. Screening for constitutional MLH1 methylation is warranted in patients with early-onset EC or synchronous/metachronous tumors (any age) displaying MLH1 methylation.
子宫内膜癌（EC）错配修复缺陷（MMRd）和林奇综合征的通用筛查使用 MLH1 甲基化的存在来排除后续种系测试中的常见散发性病例。然而，这忽略了具有高风险种系 MLH1 甲基化（表观遗传）的罕见病例，这是一种较差识别的机制，易导致 MLH1 甲基化的林奇型癌症。我们旨在确定 MMRd、MLH1 甲基化肿瘤的 EC 病例中种系 MLH1 甲基化的作用和频率。
我们使用焦磷酸测序和实时甲基化特异性 PCR 筛查来自癌症诊所（n=4，<60 岁）和两个基于人群的队列的 MMRd、MLH1 甲基化 EC 患者的血液中的种系 MLH1 甲基化；“哥伦布地区”（n=68，所有年龄段）和“俄亥俄州结直肠癌预防倡议（OCCPI）”（n=24，<60 岁）。
在从癌症诊所诊断为 36 至 59 岁之间的 4 名患者中的 3 名中发现了种系 MLH1 甲基化。两名患者存在单等位基因/半等位基因表观遗传（约 50%的等位基因甲基化）。一名有多个原发性肿瘤的患者在正常组织中有低水平嵌合体，并且在所有肿瘤中影响未甲基化等位基因的体细胞“二次打击”，证明了病因。在基于人群的队列中，哥伦布地区队列的 68 例均为阴性，OCCPI 队列的 24 例中有 1 例 36 岁患者存在低水平镶嵌种系 MLH1 甲基化，这是合并队列中 6 例（约 17%）<50 岁患者和 45 例（约 2%）<60 岁患者中的 1 例。有 3 名存在基础种系 MLH1 甲基化的患者的 EC 是首发性/双重首发性癌症。
在癌症初次表现时做出正确的诊断非常重要，因为这将显著改变临床管理。应在有早发性 EC 或同时性/异时性肿瘤（任何年龄）显示 MLH1 甲基化的患者中筛查种系 MLH1 甲基化。
