Endometrial polyps are non-neoplastic but harbor epithelial mutations in endometrial cancer drivers at low allelic frequencies.
Endometrial polyps are non-neoplastic but harbor epithelial mutations in endometrial cancer drivers at low allelic frequencies.
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DOI：
10.1038/s41379-022-01124-5
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发表时间：
2022-11
期刊：
影响因子：
7.5
通讯作者：
Castrillon, Diego H.
中科院分区：
文献类型：
--
作者：
Sahoo, Subhransu S.;Aguilar, Mitzi;Xu, Yan;Lucas, Elena;Miller, Valerie;Chen, Hao;Zheng, Wenxin;Cuevas, Ileana C.;Li, Hao-Dong;Hitrys, David;Wachsmann, Megan B.;Bishop, Justin A.;Cantarell, Brandi;Gagan, Jeffrey;Koduru, Prasad;SoRelle, Jeffrey A.;Castrillon, Diego H.
子宫内膜息肉（EMPs）是一种常见的外生性肿块，与子宫异常出血和不孕有关。与周期性脱落的正常子宫内膜不同，emp在排卵周期和绝经后持续存在。尽管emp通常被归类为良性实体，但矛盾的是，emp与不同组织学亚型的子宫内膜癌相关，这些亚型经常出现在emp中。emp作为克隆源性肿瘤的病因和潜在起源尚不确定，但先前的研究表明，emp是由反复发生的染色体重排驱动的基质源性肿瘤。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名因良性指征而接受子宫切除术的女性的个体emp。通过对大量肿瘤相关基因（包括致癌基因、肿瘤抑制基因和染色体易位伴侣）的外显子组测序，对31个emp进行了全面的基因组分析。没有反复出现的染色体重排，拷贝数分析也没有发现显著的染色体水平事件的证据。令人惊讶的是，与经典致癌驱动因素（即确定的癌症驱动因素）相对应的单核苷酸变异的发生率很高。已知的致癌驱动事件的范围与子宫内膜癌比其他任何常见癌症更接近。包括激光捕获显微解剖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室中。这些结果建立了emp与子宫内膜癌驱动突变获得之间的联系。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可以通过子宫内膜癌驱动因子在受保护的环境中与年龄相关的积累来解释，与正常子宫内膜不同，这种环境不受周期性脱落的影响。
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.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.1911310116
发表时间：
2019-12-17
影响因子：
11.1
作者：
Cuevas, Ileana C.;Sahoo, Subhransu S.;Castrillon, Diego H.
通讯作者：
Castrillon, Diego H.
影响因子：
--
作者：
Bol, S;Wanschura, S;Bullerdiek, J
通讯作者：
Bullerdiek, J
DOI：
10.1016/0020-7292(91)90767-y
发表时间：
1991-10-01
影响因子：
3.8
作者：
DEMUYLDER, X;NEVEN, P;DEMUYLDER, E
通讯作者：
DEMUYLDER, E