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Abstract：
BACKGROUND: Colorectal cancer is a complex disease with high mortality rates. Over time, the treatment of metastatic colorectal cancer (mCRC) has gradually improved due to the development of modern chemotherapy and targeted therapy regimens. However, due to the inherent heterogeneity of this condition, identifying reliable predictive biomarkers for targeted therapies remains challenging. A recent promising classification system-the consensus molecular subtype (CMS) system-offers the potential to categorize mCRC patients based on their unique biological and molecular characteristics. Four distinct CMS categories have been defined: immune (CMS1), canonical (CMS2), metabolic (CMS3), and mesenchymal (CMS4). Nevertheless, there is currently no standardized protocol for accurately classifying patients into CMS categories. To address this challenge, reverse transcription polymerase chain reaction (RT-qPCR) and next-generation genomic sequencing (NGS) techniques may hold promise for precisely classifying mCRC patients into their CMSs.
OBJECTIVE: To investigate if mCRC patients can be classified into CMS categories using a standardized molecular biology workflow.
METHODS: This observational study was conducted at the University of Chile Clinical Hospital and included patients with unresectable mCRC who were undergoing systemic treatment with chemotherapy and/or targeted therapy. Molecular biology techniques were employed to analyse primary tumour samples from these patients. RT-qPCR was utilized to assess the expression of genes associated with fibrosis (TGF-β and β-catenin) and cell growth pathways (c-MYC). NGS using a 25-gene panel (TumorSec) was performed to identify specific genomic mutations. The patients were then classified into one of the four CMS categories according to the clinical consensus of a Tumour Board. Informed consent was obtained from all the patients prior to their participation in this study. All techniques were conducted at University of Chile.
RESULTS: Twenty-six patients were studied with the techniques and then evaluated by the Tumour Board to determine the specific CMS. Among them, 23% (n = 6), 19% (n = 5), 31% (n = 8), and 19% (n = 5) were classified as CMS1, CMS2, CMS3, and CMS4, respectively. Additionally, 8% of patients (n = 2) could not be classified into any of the four CMS categories. The median overall survival of the total sample was 28 mo, and for CMS1, CMS2, CMS3 and CMS4 it was 11, 20, 30 and 45 mo respectively, with no statistically significant differences between groups.
CONCLUSIONS: A molecular biology workflow and clinical consensus analysis can be used to accurately classify mCRC patients. This classification process, which divides patients into the four CMS categories, holds significant potential for improving research strategies and targeted therapies tailored to the specific characteristics of mCRC.
OBJECTIVE: To investigate if mCRC patients can be classified into CMS categories using a standardized molecular biology workflow.
METHODS: This observational study was conducted at the University of Chile Clinical Hospital and included patients with unresectable mCRC who were undergoing systemic treatment with chemotherapy and/or targeted therapy. Molecular biology techniques were employed to analyse primary tumour samples from these patients. RT-qPCR was utilized to assess the expression of genes associated with fibrosis (TGF-β and β-catenin) and cell growth pathways (c-MYC). NGS using a 25-gene panel (TumorSec) was performed to identify specific genomic mutations. The patients were then classified into one of the four CMS categories according to the clinical consensus of a Tumour Board. Informed consent was obtained from all the patients prior to their participation in this study. All techniques were conducted at University of Chile.
RESULTS: Twenty-six patients were studied with the techniques and then evaluated by the Tumour Board to determine the specific CMS. Among them, 23% (n = 6), 19% (n = 5), 31% (n = 8), and 19% (n = 5) were classified as CMS1, CMS2, CMS3, and CMS4, respectively. Additionally, 8% of patients (n = 2) could not be classified into any of the four CMS categories. The median overall survival of the total sample was 28 mo, and for CMS1, CMS2, CMS3 and CMS4 it was 11, 20, 30 and 45 mo respectively, with no statistically significant differences between groups.
CONCLUSIONS: A molecular biology workflow and clinical consensus analysis can be used to accurately classify mCRC patients. This classification process, which divides patients into the four CMS categories, holds significant potential for improving research strategies and targeted therapies tailored to the specific characteristics of mCRC.
摘要：
背景：结直肠癌是一种复杂的疾病，死亡率很高。随着时间的推移,随着现代化疗和靶向治疗方案的发展,转移性结直肠癌(mCRC)的治疗方法逐渐得到改善.然而,由于这种情况固有的异质性，为靶向治疗确定可靠的预测性生物标志物仍然具有挑战性.最近有希望的分类系统-共有分子亚型（CMS）系统-提供了根据mCRC患者独特的生物学和分子特征对其进行分类的潜力。已经定义了四个不同的CMS类别：免疫(CMS1)，规范(CMS2)，代谢（CMS3），和间充质（CMS4）。然而，目前尚无将患者准确分类为CMS类别的标准化方案.为了应对这一挑战，逆转录聚合酶链反应(RT-qPCR)和下一代基因组测序(NGS)技术有望将mCRC患者精确分类为CMS.
目的：研究mCRC患者是否可以使用标准化的分子生物学工作流程分为CMS类别。
方法：这项观察性研究在智利大学临床医院进行，纳入了接受化疗和/或靶向治疗的不可切除的mCRC患者。采用分子生物学技术来分析来自这些患者的原发性肿瘤样品。RT-qPCR用于评估与纤维化（TGF-β和β-catenin）和细胞生长途径（c-MYC）相关的基因的表达。使用25个基因组(TumorSec)进行NGS以鉴定特定的基因组突变。然后根据肿瘤委员会的临床共识将患者分为四个CMS类别之一。在参与本研究之前，所有患者均已获得知情同意。所有技术均在智利大学进行。
结果：对26名患者进行了研究，然后由肿瘤委员会进行评估以确定特定的CMS。其中,23%(n=6)，19%(n=5)，31%(n=8)，19％（n=5）分别被分类为CMS1，CMS2，CMS3和CMS4。此外,8%的患者(n=2)不能被分为四个CMS类别中的任何一个。总样本的中位总生存期为28个月，CMS1、CMS2、CMS3和CMS4分别为11、20、30和45个月，组间差异无统计学意义。
结论：分子生物学工作流程和临床共识分析可用于对mCRC患者进行准确分类。这个分类过程，将患者分为四个CMS类别，在改进针对mCRC特定特征的研究策略和靶向治疗方面具有重要潜力。
目的：研究mCRC患者是否可以使用标准化的分子生物学工作流程分为CMS类别。
方法：这项观察性研究在智利大学临床医院进行，纳入了接受化疗和/或靶向治疗的不可切除的mCRC患者。采用分子生物学技术来分析来自这些患者的原发性肿瘤样品。RT-qPCR用于评估与纤维化（TGF-β和β-catenin）和细胞生长途径（c-MYC）相关的基因的表达。使用25个基因组(TumorSec)进行NGS以鉴定特定的基因组突变。然后根据肿瘤委员会的临床共识将患者分为四个CMS类别之一。在参与本研究之前，所有患者均已获得知情同意。所有技术均在智利大学进行。
结果：对26名患者进行了研究，然后由肿瘤委员会进行评估以确定特定的CMS。其中,23%(n=6)，19%(n=5)，31%(n=8)，19％（n=5）分别被分类为CMS1，CMS2，CMS3和CMS4。此外,8%的患者(n=2)不能被分为四个CMS类别中的任何一个。总样本的中位总生存期为28个月，CMS1、CMS2、CMS3和CMS4分别为11、20、30和45个月，组间差异无统计学意义。
结论：分子生物学工作流程和临床共识分析可用于对mCRC患者进行准确分类。这个分类过程，将患者分为四个CMS类别，在改进针对mCRC特定特征的研究策略和靶向治疗方面具有重要潜力。
