Davidson Ben, Teien Lande Karin, Nebdal Daniel, Nesbakken Anne Jorunn, Holth Arild, Lindemann Kristina, Zahl Eriksson Ane Gerda, Sørlie Therese
Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310, Oslo, Norway.
Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, N-0316, Oslo, Norway.
Virchows Arch. 2025 Apr;486(4):697-705. doi: 10.1007/s00428-024-03912-7. Epub 2024 Sep 5.
The objective of the present study was to characterize the molecular features of endometrial carcinomas with ambiguous histology. Eighteen carcinomas that could not be conclusively typed based on morphology and immunohistochemistry underwent analysis of mismatch repair (MMR) status, microsatellite status, and whole-exome sequencing. None of the tumors had pathogenic POLE mutation. Twelve tumors (67%) were microsatellite stable, and 6 (33%) had microsatellite instability. Fourteen tumors (78%) harbored TP53 mutations, and 2 (11%) had mutations in MMR genes. Eleven carcinomas (61%) were classified as copy number high and 7 (39%) as MSI-hypermutated, the latter including 3 tumors with TP53 mutation who concomitantly had MSI or mutation in a MMR gene. Other mutations that were found in > 1 tumor affected MUC16 (7 tumors), PIK3CA (6 tumors), PPP2R1A (6 tumors), ARID1A (5 tumors), PTEN (5 tumors), FAT1 (4 tumors), FAT4 (3 tumors), BRCA2 (2 tumors), ERBB2 (2 tumors), FBXW7 (2 tumors), MET (2 tumors), MTOR (2 tumors), JAK1 (2 tumors), and CSMD3 (2 tumors). At the last follow-up (median = 68.6 months), 8 patients had no evidence of disease, 1 patient was alive with disease, 8 patients were dead of disease, and 1 patient died of other cause. In conclusion, based on this series, the molecular landscape of endometrial carcinomas with ambiguous histology is dominated by TP53 mutations and the absence of POLE mutations, with heterogeneous molecular profile with respect to other genes. A high proportion of these tumors is clinically aggressive.
本研究的目的是描述组织学不明确的子宫内膜癌的分子特征。18例基于形态学和免疫组化无法明确分型的癌进行了错配修复（MMR）状态、微卫星状态和全外显子测序分析。所有肿瘤均无致病性POLE突变。12例肿瘤（67%）微卫星稳定，6例（33%）微卫星不稳定。14例肿瘤（78%）存在TP53突变，2例（11%）存在MMR基因突变。11例癌（61%）分类为拷贝数高，7例（39%）为微卫星高度突变，后者包括3例伴有微卫星不稳定或MMR基因突变的TP53突变肿瘤。在超过1例肿瘤中发现的其他突变影响MUC16（7例肿瘤）、PIK3CA（6例肿瘤）、PPP2R1A（6例肿瘤）、ARID1A（5例肿瘤）、PTEN（5例肿瘤）、FAT1（4例肿瘤）、FAT4（3例肿瘤）、BRCA2（2例肿瘤）、ERBB2（2例肿瘤）、FBXW7（2例肿瘤）、MET（2例肿瘤）、MTOR（2例肿瘤）、JAK1（2例肿瘤）和CSMD3（2例肿瘤）。在最后一次随访时（中位数=68.6个月），8例患者无疾病证据，1例患者带瘤生存，8例患者死于疾病，1例患者死于其他原因。总之，基于本系列研究，组织学不明确的子宫内膜癌的分子格局以TP53突变和无POLE突变为主要特征，其他基因的分子谱具有异质性。这些肿瘤中有很大一部分在临床上具有侵袭性。
