Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA.
Cancer. 2013 Aug 15;119(16):3027-33. doi: 10.1002/cncr.28152. Epub 2013 Jun 12.
The authors hypothesized that Lynch syndrome (LS)-associated endometrial cancer (EC) develops from morphologically normal endometrium that accumulates enough molecular changes to progress through a continuum of hyperplasia to carcinoma, similar to sporadic EC. The primary objective of the current study was to determine whether LS-associated EC involves progression through a preinvasive lesion. The secondary objective was to identify molecular changes that contribute to endometrial carcinogenesis in patients with LS.
Women with a confirmed mismatch repair gene mutation for LS who were undergoing a prophylactic or therapeutic hysterectomy were eligible. Cases and controls were matched for EC and hyperplasia based preferentially on age and histology. Mutation status of phosphatidylinositol 3-kinase (PIK3CA); KRAS; AKT; LKB1; catenin (cadherin-associated protein), beta 1, 88kDa (CTNNB1); and phosphatase and tensin homolog (PTEN) protein loss was assessed.
Concurrent complex atypical hyperplasia (CAH) was found in EC in 11 cases of LS (39.3%) and 21 sporadic cases (46.6%). Loss of PTEN expression was common in both sporadic (69%) and LS-associated EC (86.2%). There was no significant difference noted with regard to the frequency of KRAS mutations in cases of sporadic EC (10.3%) compared with LS-associated EC (3.4%). AKT and LKB1 mutations were rarely observed. Mutations in PIK3CA and CTNNB1 occurred more frequently in cases of sporadic EC compared with LS-associated EC.
Hyperplasia, particularly CAH, is part of the preinvasive spectrum of disease in LS-associated EC, as indicated by the presence of complex hyperplasia and CAH in cases of LS. Although loss of PTEN is common in both LS and sporadic EC cases, there was a lack of additional mutations in LS-associated EC cases. This suggests that in the context of the mismatch repair defects in LS, fewer additional molecular changes are required to progress from preinvasive lesions to cancer.
作者假设林奇综合征（LS）相关的子宫内膜癌（EC）源自形态正常的子宫内膜，该子宫内膜累积了足够的分子变化，从而通过增生到癌的连续过程进展，类似于散发性 EC。本研究的主要目的是确定 LS 相关 EC 是否涉及到癌前病变的进展。次要目的是确定导致 LS 患者子宫内膜发生癌变的分子变化。
本研究纳入了正在接受预防性或治疗性子宫切除术且经证实存在 LS 错配修复基因突变的女性。病例和对照基于年龄和组织学优先匹配 EC 和增生。评估了磷酸肌醇 3-激酶（PIK3CA）、KRAS、AKT、LKB1、连环蛋白（钙粘蛋白相关蛋白）β1、88kDa（CTNNB1）和磷酸酶及张力蛋白同源物（PTEN）蛋白缺失的突变状态。
在 11 例 LS（39.3%）和 21 例散发性病例（46.6%）的 EC 中发现同时存在复杂非典型增生（CAH）。PTEN 表达缺失在散发性 EC（69%）和 LS 相关 EC（86.2%）中均很常见。在散发性 EC（10.3%）与 LS 相关 EC（3.4%）中 KRAS 突变的频率方面，无显著差异。AKT 和 LKB1 突变很少观察到。PIK3CA 和 CTNNB1 的突变在散发性 EC 中比 LS 相关 EC 更常见。
增生，特别是 CAH，是 LS 相关 EC 癌前病变谱的一部分，这表现为 LS 病例中存在复杂增生和 CAH。尽管 LS 和散发性 EC 病例中均常见 PTEN 缺失，但 LS 相关 EC 病例中缺乏其他突变。这表明在 LS 的错配修复缺陷背景下，从癌前病变进展到癌症需要较少的额外分子变化。
