60 岁以下 MLH1 甲基化子宫内膜癌作为携带高危种系 MLH1 表观遗传突变女性的“哨兵”癌。
MLH1-methylated endometrial cancer under 60 years of age as the "sentinel" cancer in female carriers of high-risk constitutional MLH1 epimutation.
机构信息
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.
出版信息
Gynecol Oncol. 2023 Apr;171:129-140. doi: 10.1016/j.ygyno.2023.02.017. Epub 2023 Mar 8.
OBJECTIVE
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.
METHODS
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).
RESULTS
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.
CONCLUSIONS
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.
目的
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。
方法
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）。
结果
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。
结论
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。
Zotero 插件