Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China.
Front Immunol. 2022 Dec 9;13:1013828. doi: 10.3389/fimmu.2022.1013828. eCollection 2022.
This study aimed to identified the key genes and sequencing metrics for predicting prognosis and efficacy of neoadjuvant chemotherapy (nCT) in rectal cancer (RC) based on genomic DNA sequencing in samples with different origin and multi-omics association database.
We collected 16 RC patients and obtained DNA sequencing data from cancer tissues and plasma cell-free DNA before and after nCT. Various gene variations were analyzed, including single nucleotide variants (SNV), copy number variation (CNV), tumor mutation burden (TMB), copy number instability (CNI) and mutant-allele tumor heterogeneity (MATH). We also identified genes by which CNV level can differentiate the response to nCT. The Cancer Genome Atlas database and the Clinical Proteomic Tumor Analysis Consortium database were used to further evaluate the specific role of therapeutic relevant genes and screen out the key genes in multi-omics levels. After the intersection of the screened genes from differential expression analysis, survival analysis and principal components analysis dimensionality reduction cluster analysis, the key genes were finally identified.
The genes CNV level of principal component genes in baseline blood and cancer tissues could significantly distinguish the two groups of patients. The CNV of HSP90AA1, EGFR, SRC, MTOR, etc. were relatively gained in the better group compared with the poor group in baseline blood. The CNI and TMB was significantly different between the two groups. The increased expression of HSP90AA1, EGFR, and SRC was associated with increased sensitivity to multiple chemotherapeutic drugs. The nCT predictive score obtained by therapeutic relevant genes could be a potential prognostic indicator, and the combination with TMB could further refine prognostic prediction for patients. After a series of analysis in multi-omics association database, EGFR and HSP90AA1 with significant differences in multiple aspects were identified as the key predictive genes related to prognosis and the sensitivity of nCT.
This work revealed that effective combined application and analysis in multi-omics data are critical to search for predictive biomarkers. The key genes EGFR and HSP90AA1 could serve as an effective biomarker to predict prognose and neoadjuvant chemosensitivity.
本研究旨在基于基因组 DNA 测序，从不同来源的样本和多组学关联数据库中，鉴定关键基因和测序指标，以预测直肠癌（RC）新辅助化疗（nCT）的预后和疗效。
我们收集了 16 例 RC 患者，获得了 nCT 前后癌组织和血浆无细胞 DNA 的 DNA 测序数据。分析了各种基因变异，包括单核苷酸变异（SNV）、拷贝数变异（CNV）、肿瘤突变负荷（TMB）、拷贝数不稳定性（CNI）和突变等位基因肿瘤异质性（MATH）。我们还鉴定了能够区分 nCT 反应的 CNV 水平的基因。使用癌症基因组图谱数据库和临床蛋白质组肿瘤分析联盟数据库进一步评估治疗相关基因的特定作用，并筛选出多组学水平的关键基因。对差异表达分析、生存分析和主成分分析降维聚类分析筛选出的基因进行交集后，最终确定了关键基因。
基线血液和癌组织中主成分基因的 CNV 水平可显著区分两组患者。与基线血液中较差组相比，较好组中 HSP90AA1、EGFR、SRC、MTOR 等基因的 CNV 相对增加。两组之间 CNI 和 TMB 有显著差异。HSP90AA1、EGFR 和 SRC 的表达增加与对多种化疗药物的敏感性增加有关。通过治疗相关基因获得的 nCT 预测评分可能是一个潜在的预后指标，与 TMB 结合可进一步细化对患者的预后预测。在多组学关联数据库的一系列分析后，发现 EGFR 和 HSP90AA1 在多个方面差异显著，被鉴定为与 nCT 预后和敏感性相关的关键预测基因。
本研究表明，对多组学数据的有效联合应用和分析对于寻找预测生物标志物至关重要。关键基因 EGFR 和 HSP90AA1 可作为预测预后和新辅助化疗敏感性的有效生物标志物。
