Jakab Anna, Patai Árpád V, Darvas Mónika, Tormássi-Bély Karolina, Micsik Tamás
Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Hungary.
Pathol Oncol Res. 2024 Apr 5;30:1611574. doi: 10.3389/pore.2024.1611574. eCollection 2024.
Colorectal carcinomas (CRC) are one of the most frequent malignancies worldwide. Based on gene expression profile analysis, CRCs can be classified into four distinct subtypes also known as the consensus molecular subtypes (CMS), which predict biological behaviour. Besides CMS, several other aspects of tumor microenvironment (TME) and systemic inflammatory response (SIR) influence the outcome of CRC patients. TME and inflammation have important role in the immune (CMS1) and mesenchymal (CMS4) subtypes, however, the relationship between these and systemic inflammation has not been assessed yet. Our objective was to evaluate the connection between CMS, TME and SIR, and to analyze the correlation between these markers and routinely used tumor markers, such as CEA (Carcinoembryonic Antigen) and CA19-9 (Carbohydrate Antigen 19-9). FFPE (Formalin Fixed Paraffin Embedded) samples of 185 CRC patients were collected. TME was described using tumor-stroma ratio (TSR), Klintrup-Makinen (KM) grade, and Glasgow Microenvironment Score (GMS). CMS classification was performed on tissue microarray using MLH1, PMS2, MSH2 and MSH6, and pan-cytokeratin, CDX2, FRMD6, HTR2B and ZEB1 immunohistochemical stains. Pre-operative tumor marker levels and inflammatory markers [C-reactive protein - CRP, albumin, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute platelet count (APC)] and patient history were retrieved using MedSolution database. Amongst TME-markers, TSR correlated most consistently with adverse clinicopathological features ( < 0.001) and overall survival ( < 0.001). Elevated CRP and modified Glasgow Prognostic Score (mGPS) were associated with worse outcome and aggressive phenotype, similarly to tumor markers CEA and CA19-9. Stroma-Tumor Marker score (STM score), a new combined score of CA19-9 and TSR delivered the second best prognostication after mGPS. Furthermore, CMS4 showed association with TSR and several laboratory markers (albumin and platelet derived factors), but not with other SIR descriptors. CMS did not show any association with CEA and CA19-9 tumor markers. More routinely available TME, SIR and tumor markers alone and in combination deliver reliable prognostic data for choosing the patients with higher risk for propagation. CMS4 is linked with high TSR and poor prognosis, but in overall, CMS-classification showed only limited effect on SIR- and tumor-markers.
结直肠癌（CRC）是全球最常见的恶性肿瘤之一。基于基因表达谱分析，CRC可分为四种不同的亚型，也称为共识分子亚型（CMS），这些亚型可预测生物学行为。除了CMS，肿瘤微环境（TME）和全身炎症反应（SIR）的其他几个方面也会影响CRC患者的预后。TME和炎症在免疫（CMS1）和间充质（CMS4）亚型中起重要作用，然而，它们与全身炎症之间的关系尚未得到评估。我们的目的是评估CMS、TME和SIR之间的联系，并分析这些标志物与常用肿瘤标志物（如癌胚抗原（CEA）和糖类抗原19-9（CA19-9））之间的相关性。收集了185例CRC患者的福尔马林固定石蜡包埋（FFPE）样本。使用肿瘤-基质比（TSR）、克林特鲁普-马基宁（KM）分级和格拉斯哥微环境评分（GMS）来描述TME。使用错配修复蛋白（MLH1）、错配修复蛋白（PMS2）、错配修复蛋白（MSH2）和错配修复蛋白（MSH6）以及全细胞角蛋白、尾型同源盒转录因子2（CDX2）、FERM结构域蛋白6（FRMD6）、5-羟色胺受体2B（HTR2B）和锌指E盒结合蛋白1（ZEB1）免疫组化染色在组织芯片上进行CMS分类。使用MedSolution数据库获取术前肿瘤标志物水平和炎症标志物[C反应蛋白（CRP）、白蛋白、绝对中性粒细胞计数（ANC）、绝对淋巴细胞计数（ALC）、绝对血小板计数（APC）]以及患者病史。在TME标志物中，TSR与不良临床病理特征（<0.001）和总生存期（<0.001）的相关性最为一致。CRP升高和改良格拉斯哥预后评分（mGPS）与较差的预后和侵袭性表型相关，与肿瘤标志物CEA和CA19-9相似。基质-肿瘤标志物评分（STM评分），一种CA19-9和TSR的新综合评分，在mGPS之后提供了第二好的预后评估。此外，CMS4与TSR和几种实验室标志物（白蛋白和血小板衍生因子）相关，但与其他SIR描述符无关。CMS与CEA和CA19-9肿瘤标志物无任何关联。单独或联合使用更常规可用的TME、SIR和肿瘤标志物可为选择具有更高转移风险的患者提供可靠的预后数据。CMS4与高TSR和不良预后相关，但总体而言，CMS分类对SIR和肿瘤标志物的影响有限。
