Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
Next Generation Sequencing Clinical Lab, UT Southwestern Medical Center, Dallas, TX, USA.
Mod Pathol. 2022 Nov;35(11):1702-1712. doi: 10.1038/s41379-022-01124-5. Epub 2022 Jul 7.
Endometrial polyps (EMPs) are common exophytic masses associated with abnormal uterine bleeding and infertility. Unlike normal endometrium, which is cyclically shed, EMPs persist over ovulatory cycles and after the menopause. Despite their usual classification as benign entities, EMPs are paradoxically associated with endometrial carcinomas of diverse histologic subtypes, which frequently arise within EMPs. The etiology and potential origins of EMPs as clonally-derived neoplasms are uncertain, but previous investigations suggested that EMPs are neoplasms of stromal origin driven by recurring chromosomal rearrangements. To better define benign EMPs at the molecular genetic level, we analyzed individual EMPs from 31 women who underwent hysterectomy for benign indications. The 31 EMPs were subjected to comprehensive genomic profiling by exome sequencing of a large panel of tumor-related genes including oncogenes, tumor suppressors, and chromosomal translocation partners. There were no recurring chromosomal rearrangements, and copy-number analyses did not reveal evidence of significant chromosome-level events. Surprisingly, there was a high incidence of single nucleotide variants corresponding to classic oncogenic drivers (i.e., definitive cancer drivers). The spectrum of known oncogenic driver events matched that of endometrial cancers more closely than any other common cancer. Further analyses including laser-capture microdissection showed that these mutations were present in the epithelial compartment at low allelic frequencies. These results establish a link between EMPs and the acquisition of endometrial cancer driver mutations. Based on these findings, we propose a model where the association between EMPs and endometrial cancer is explained by the age-related accumulation of endometrial cancer drivers in a protected environment that-unlike normal endometrium-is not subject to cyclical shedding.
子宫内膜息肉（EMPs）是常见的外生性肿块，与异常子宫出血和不孕有关。与周期性脱落的正常子宫内膜不同，EMPs 在排卵周期和绝经后持续存在。尽管通常将 EMP 归类为良性实体，但它们与不同组织学亚型的子宫内膜癌相关，这些癌症经常在 EMP 内发生。EMPs 作为克隆衍生的肿瘤的病因和潜在起源尚不确定，但先前的研究表明，EMPs 是由反复染色体重排驱动的基质起源的肿瘤。为了在分子遗传学水平上更好地定义良性 EMP，我们分析了 31 名因良性指征接受子宫切除术的妇女的单个 EMP。对 31 个 EMP 进行了大规模肿瘤相关基因外显子组测序的全面基因组分析，包括癌基因、肿瘤抑制基因和染色体易位伙伴。没有反复出现的染色体重排，拷贝数分析也没有显示出显著染色体水平事件的证据。令人惊讶的是，存在大量对应经典致癌驱动因素（即明确的癌症驱动因素）的单核苷酸变异。已知致癌驱动事件的频谱与子宫内膜癌更接近，而与任何其他常见癌症都更接近。包括激光捕获显微切割在内的进一步分析表明，这些突变以低等位基因频率存在于上皮细胞区室中。这些结果在 EMP 和获得子宫内膜癌驱动突变之间建立了联系。基于这些发现，我们提出了一个模型，其中 EMP 和子宫内膜癌之间的关联是由与年龄相关的子宫内膜癌驱动因素在受保护的环境中积累解释的，这种环境与正常子宫内膜不同，不受周期性脱落的影响。
