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Abstract：
The conventional treatment strategies for patients with metastatic colorectal cancer (mCRC) are predominantly guided by the status of RAS and BRAF mutations. Although patients may exhibit analogous pathological characteristics and undergo similar treatment regimens, notable disparities in their prognostic outcomes can be observed. Therefore, tissue and plasma samples from 40 mCRC patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Genomic variations and canonical oncogenic pathways were investigated for their prognostic effects in association with progression-free survival (PFS) of these patients. We found that patients with BRCA2 and KMT2A mutations exhibited worse prognostic outcomes after chemotherapy-based treatment (univariate, P < 0.01). Further pathway analysis indicated that alterations in the homologous recombination pathway and in the KMT2A signaling network were also significantly associated with shortened PFS (univariate, P < 0.01). Additionally, mutation signature analysis showed that patients with higher proportions of defective mismatch repair (dMMR)-related mutational signatures. Had a worse prognosis (univariate, P = 0.02). KMT2A mutations (hazard ratio [HR], 4.47; 95% confidence interval [CI], 1-19.93; P =0.050) and dMMR signature proportions (HR, 3.57; 95% CI, 1.42-8.96; P = 0.007) remained independently associated with PFS after multivariate analysis and the results were further externally validated. These findings may enhance our understanding of this disease and may potentially facilitate the optimization of its treatment approaches.
摘要：
转移性结直肠癌（mCRC）患者的常规治疗策略主要由RAS和BRAF突变状态指导。尽管患者可能表现出类似的病理特征并接受类似的治疗方案，在预后结局方面可以观察到显著差异.因此,40例mCRC患者的组织和血浆样本接受了针对425个癌症相关基因的新一代测序.研究了基因组变异和典型致癌途径与这些患者的无进展生存期（PFS）相关的预后效果。我们发现，BRCA2和KMT2A突变的患者在化疗后表现出更差的预后结果（单变量，P<0.01)。进一步的途径分析表明，同源重组途径和KMT2A信号网络的改变也与缩短的PFS显着相关（单变量，P<0.01)。此外,突变特征分析显示,错配修复缺陷(dMMR)相关突变特征比例较高的患者.预后较差(单变量，P=0.02)。KMT2A突变（危险比[HR]，4.47；95%置信区间[CI]，1-19.93；P=0.050）和dMMR签名比例（HR，3.57；95%CI，1.42-8.96；P=0.007）在多变量分析后仍然与PFS独立相关，结果得到了进一步的外部验证。这些发现可能会增强我们对这种疾病的理解，并可能促进其治疗方法的优化。
