DataSheet_1_Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers.docx

BackgroundFBXW7 is recognized as a critical tumor suppressor gene and a component of the ubiquitin-proteasome system, mediating the degradation of multiple oncogenic proteins, including c-MYC, Cyclin E, c-Jun, Notch, p53. Around 16% of colorectal cancer (CRC) patients carried FBXW7 somatic mutations, while a comprehensive characterization of FBXW7 somatic mutations in CRC is still lacking.MethodsColorectal cancer patients with tumor samples and matching white blood cell samples in the past five years were screened and DNA sequenced. DNA sequencing data of MSK MetTropism cohort and RNA sequencing data of TCGA COAD cohort were analyzed.ResultsWe discovered that the FBXW7 mutations were associated with higher tumor mutation burden (TMB), higher microsatellite instability (MSI) score, and lower chromosomal instability (CIN) score. Patients with FBXW7 mutations showed better overall survival (HR: 0.67; 95%CI: 0.55-0.80, P < 0.001). However, patients with FBXW7 R465C mutation displayed worse overall survival in multi-variate cox analysis when compared with patients carrying other FBXW7 mutations (HR: 1.6; 95%CI: 1.13-3.1, P = 0.015), and with all other patients (HR: 1.87; 95%CI: 0.99-2.5, P = 0.053). Moreover, in MSI patients, the FBXW7 mutated group showed higher M1 macrophage, CD8+ T cell, and regulatory T cell (Tregs) infiltration rates, and significant enrichment of multiple immune-related gene sets, including interferon-gamma response, interferon-alpha response, IL6 JAK STAT3 signaling, p53 pathway.ConclusionThis analysis comprehensively identified FBXW7 alterations in colorectal cancer patients and uncovered the molecular, clinicopathological, and immune-related patterns of FBXW7-altered CRC patients.

背景：FBXW7基因被视为一种关键的肿瘤抑制基因，同时也是泛素-蛋白酶体系统的一部分，参与介导多种癌基因蛋白的降解，包括c-MYC、Cyclin E、c-Jun、Notch和p53。约16%的结直肠癌（CRC）患者携带FBXW7体细胞突变，然而，对CRC患者中FBXW7体细胞突变进行全面表征的研究仍显不足。方法：筛选过去五年内具有肿瘤样本及匹配的血液白细胞样本的结直肠癌患者，对其DNA进行测序。分析MSK MetTropism队列的DNA测序数据和TCGA COAD队列的RNA测序数据。结果：研究发现，FBXW7突变与更高的肿瘤突变负荷（TMB）、更高的微卫星不稳定性（MSI）评分以及更低的染色体不稳定性（CIN）评分相关。携带FBXW7突变的患者的总生存期（HR：0.67；95%CI：0.55-0.80，P < 0.001）较好。然而，在多变量Cox分析中，与携带其他FBXW7突变的患者相比，携带FBXW7 R465C突变的患者表现出较差的总生存期（HR：1.6；95%CI：1.13-3.1，P = 0.015），与所有其他患者相比，其总生存期也较差（HR：1.87；95%CI：0.99-2.5，P = 0.053）。此外，在MSI患者中，FBXW7突变组的M1巨噬细胞、CD8+ T细胞和调节性T细胞（Tregs）浸润率较高，且多个免疫相关基因集显著富集，包括干扰素-γ反应、干扰素-α反应、IL6 JAK STAT3信号通路和p53通路。结论：本研究全面鉴定了结直肠癌患者中的FBXW7变异，并揭示了FBXW7变异结直肠癌患者的分子、临床病理和免疫相关模式。