Machuca-Aguado Jesús, Catherwood Mark, Houghton Oisin, Taylor Jennifer, Shah Rajeev, Ben-Mussa Ali, Gonzalez David, McCluggage W Glenn
Department of Pathology, Virgen Macarena University Hospital, Seville, Spain.
Regional Molecular Diagnostics Service, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.
Histopathology. 2025 Mar;86(4):611-626. doi: 10.1111/his.15365. Epub 2024 Nov 28.
Since the publication of The Cancer Genome Atlas (TCGA) molecular Classification of endometrial carcinomas in 2013, multiple studies have demonstrated the prognostic and therapeutic importance of this. However, there is great variability on whether and how this is undertaken in different institutions, and this is often dependent on resources and availability of molecular testing. Points of controversy include whether molecular classification is needed on all endometrial carcinomas and whether pure molecular testing is undertaken or a surrogate such as the ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) Classifier. Herein we report our experience instigating molecular classification of endometrial carcinomas in Northern Ireland.
From 1st March 2023, all endometrial carcinomas diagnosed on biopsy in the four pathology laboratories in Northern Ireland were referred to the central molecular pathology laboratory for genomic analysis using a custom next-generation sequencing (NGS) panel; the NGS panel included the entire coding regions of polymerase epsilon (POLE) and TP53 genes, as well as microsatellite instability (MSI) analysis. All cases also underwent immunohistochemical staining with oestrogen receptor (ER), p53, and the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. The molecular results were available by the time of surgery (if a hysterectomy was performed) allowing integration into the final pathology report where a TCGA molecular type was assigned. Two hundred and sixty-seven endometrial carcinomas underwent molecular testing; in five cases, there was insufficient material for testing, leaving 262 cases. The TCGA groups were POLEmut (19; 7.3%), MMRd (63; 24%), p53abn (62; 23.7%), and no specific molecular profile (NSMP) 118 (45%). Seventeen tumours (6.5%) were "multiple-classifiers": five POLEmut-p53abn, two POLEmut-MMRd, one POLE-MMRd-p53abn (all included in the POLEmut TCGA group), and nine MMRd-p53abn (included in the MMRd group).
This represents one of the first population-based studies investigating the prevalence of the different TCGA molecular groups of endometrial carcinomas in an unselected population. Performing molecular testing on biopsies enables management to be tailored to the molecular group and allows integration of the TCGA group into the report of the final resection specimen. We hope our experience will facilitate other laboratories in undertaking TCGA molecular classification.
自2013年《癌症基因组图谱》（TCGA）发布子宫内膜癌分子分类以来，多项研究已证明其在预后和治疗方面的重要性。然而，不同机构在是否以及如何进行此项工作上存在很大差异，这通常取决于资源和分子检测的可及性。争议点包括是否需要对所有子宫内膜癌进行分子分类，以及是进行单纯的分子检测还是采用替代方法，如子宫内膜癌前瞻性分子风险分类器（ProMisE）分类器。在此，我们报告我们在北爱尔兰开展子宫内膜癌分子分类的经验。
从2023年3月1日起，北爱尔兰四个病理实验室通过活检诊断的所有子宫内膜癌均被转至中央分子病理实验室，使用定制的二代测序（NGS） panel进行基因组分析；该NGS panel包括聚合酶ε（POLE）和TP53基因的全部编码区，以及微卫星不稳定性（MSI）分析。所有病例还进行了雌激素受体（ER）、p53以及错配修复（MMR）蛋白MLH1、PMS2、MSH2和MSH6的免疫组化染色。手术时（如果进行了子宫切除术）可获得分子检测结果，从而能够将其整合到最终病理报告中，并指定TCGA分子类型。267例子宫内膜癌接受了分子检测；5例因检测材料不足而未进行检测，剩余262例。TCGA分组为POLEmut（19例；7.3%）、MMRd（63例；24%）、p53abn（62例；23.7%）和无特定分子特征（NSMP）118例（45%）。17例肿瘤（6.5%）为“多分类器”：5例POLEmut-p53abn、2例POLEmut-MMRd、1例POLE-MMRd-p53abn（均包含在POLEmut的TCGA组中）以及9例MMRd-p53abn（包含在MMRd组中）。
这是首批基于人群的研究之一，旨在调查未选择人群中不同TCGA分子组的子宫内膜癌患病率。对活检标本进行分子检测能够根据分子组制定治疗方案，并将TCGA组整合到最终切除标本的报告中。我们希望我们的经验将有助于其他实验室进行TCGA分子分类。
