Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki, Finland.
Mod Pathol. 2018 Aug;31(8):1291-1301. doi: 10.1038/s41379-018-0044-4. Epub 2018 Mar 27.
Molecular alterations preceding endometrial and ovarian cancer and the sequence of events are unknown. Consecutive specimens from lifelong surveillance for Lynch syndrome provides a natural setting to address such questions. To molecularly define the multistep gynecological tumorigenesis, DNA mismatch repair gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nation-wide registry and endometrial biopsy specimens taken from these individuals during 20 years of screening were collected. A total of 213 endometrial and ovarian specimens from Lynch syndrome individuals and 197 histology-matched (non-serous) samples from sporadic cases were available for this investigation. The specimens were profiled for markers linked to endometrial and ovarian tumorigenesis, including ARID1A protein expression, mismatch repair status, and tumor suppressor gene promoter methylation. In Lynch syndrome-associated endometrial and ovarian carcinomas, ARID1A protein was lost in 61-100% and mismatch repair was deficient in 97-100%, compared to 0-17% and 14-44% in sporadic cases (P = 0.000). ARID1A loss appeared in complex hyperplasia and deficient mismatch repair and tumor suppressor gene promoter methylation in histologically normal endometrium. Despite quantitative differences between Lynch syndrome and sporadic cases, ARID1A expression, mismatch repair, and tumor suppressor gene promoter methylation divided endometrial samples from both patient groups into three categories of increasing abnormality, comprising normal endometrium and simple hyperplasia (I), complex hyperplasia with or without atypia (II), and endometrial cancer (III). Complex hyperplasias without vs. with atypia were molecularly indistinguishable. In conclusion, surveillance specimens from Lynch syndrome identify mismatch repair deficiency, tumor suppressor gene promoter methylation, and ARID1A loss as early changes in tumor development. Our findings are clinically relevant for the classification of endometrial hyperplasias and have potential implications in cancer prevention in Lynch syndrome and beyond.
子宫内膜癌和卵巢癌发生之前的分子改变及其发生顺序尚不清楚。林奇综合征的终身监测中连续采集的标本为解决这些问题提供了一个自然的环境。为了从分子水平上阐明妇科肿瘤的多步骤发生机制，我们从全国性的登记处确定了患有子宫内膜癌或卵巢癌或子宫内膜增生的 DNA 错配修复基因突变携带者，并收集了这些个体在 20 年筛查期间的子宫内膜活检标本。本研究共纳入 213 例林奇综合征个体的子宫内膜和卵巢标本以及 197 例组织学匹配（非浆液性）的散发性病例标本。对这些标本进行了与子宫内膜和卵巢肿瘤发生相关的标志物分析，包括 ARID1A 蛋白表达、错配修复状态和肿瘤抑制基因启动子甲基化。与散发性病例相比（0-17%和 14-44%），林奇综合征相关的子宫内膜癌和卵巢癌中 ARID1A 蛋白缺失率为 61-100%，错配修复缺陷率为 97-100%（P = 0.000）。在组织学正常的子宫内膜中，ARID1A 缺失发生于复杂增生和错配修复缺陷以及肿瘤抑制基因启动子甲基化中。尽管林奇综合征和散发性病例之间存在定量差异，但 ARID1A 表达、错配修复和肿瘤抑制基因启动子甲基化将来自两组患者的子宫内膜样本分为三个异常程度递增的类别，包括正常子宫内膜和单纯性增生（I）、伴或不伴非典型性的复杂性增生（II）和子宫内膜癌（III）。无非典型性的复杂性增生与有非典型性的复杂性增生在分子上无法区分。总之，林奇综合征的监测标本确定了错配修复缺陷、肿瘤抑制基因启动子甲基化和 ARID1A 缺失是肿瘤发生的早期变化。我们的研究结果与子宫内膜增生的分类具有临床相关性，并可能对林奇综合征及其他疾病的癌症预防具有潜在意义。
