RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
基因组与表达数据综合分析鉴定预测结直肠癌（CRC）预后与免疫反应的潜在标志物
英文原题：Comprehensive Analysis of Genomic and Expression Data Identified Potential Markers for Predicting Prognosis and Immune Response in CRC.
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Comprehensive Analysis of Genomic and Expression Data Identified Potential Markers for Predicting Prognosis and Immune Response in CRC.
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中文摘要
结直肠癌（CRC）是胃肠道最常见的恶性肿瘤。本研究描绘CRC患者的基因组改变图谱。基于全外显子组测序（WES），鉴定出31个显著突变基因，其中TP53、KRAS、APC、PIK3CA和BRAF等已被既往研究报道为显著突变基因。
本研究中最常突变的是编码肿瘤抑制蛋白p53的TP53，约影响60%的CRC患者。研究进一步比较正常组和肿瘤组中显著突变基因的表达谱，鉴定出20个差异表达基因（DEG）；其中CSMD3、DCHS2、LRP2、RYR2和ZFHX4与无进展生存期（PFS）显著负相关。研究还根据显著体细胞突变基因的表达进行共识聚类，将CRC分为3个亚型：簇1（n=453）、簇2（n=158）和簇3（n=9）。临床病理分析显示，C1亚型PFS最长，中位数8.2年；C2和C3分别为4.1年和2.7年。
此外，3个亚型与肿瘤浸润深度、淋巴结转移及远处转移相关。免疫浸润分析显示，三组间初始B细胞、CD8阳性T细胞、活化记忆CD4阳性T细胞、γδ T细胞、静息NK细胞、M0和M2巨噬细胞、活化髓系树突状细胞、活化及静息肥大细胞等浸润水平显著不同，表明依据22个显著体细胞突变基因表达划分的亚型能够有效区分不同免疫状态，有助于预测CRC患者免疫治疗应答。研究结果或可为CRC预后预测提供新的潜在指标，并为CRC免疫治疗提供靶点。
展开英文摘要原文
Colorectal cancer (CRC) is the most prevalent type of malignant tumor of the gastrointestinal tract. In the current study, we characterized the landscape of genomic alterations in CRC patients. Based on the results of whole-exome sequencing (WES), we identified 31 significantly mutated genes.
Among them, several genes including TP53, KRAS, APC, PI3KCA, and BRAF were reported as significantly mutated genes in previous studies. In the current study, the most frequently mutated gene was TP53, which encodes tumor suppressor p53, affecting approximately 60% of CRC patients.
In addition, we performed the expression profiles of significantly mutated genes between the normal group and tumor groups and identified 20 differentially expressed genes (DEGs); among them, CSMD3, DCHS2, LRP2, RYR2, and ZFHX4 were significantly negatively correlated with PFS.
Moreover, consensus clustering analysis for CRC based on the expression of significantly somatic mutated genes was performed. In total, three subtypes of CRC were identified in CRC, including cluster1 ( n = 453), cluster2 ( n = 158), and cluster 3 ( n = 9), based on expression level of significantly somatic mutated genes. Clinicopathological features analysis showed subtype C1 had the longest progression-free survival (PFS) with median time of 8. 2 years, while subtypes C2 and C3 had 4. 1 and 2. 7 years of PFS, respectively.
Moreover, we found three subtypes related to tumor infiltration depth, lymph node metastasis, and distant metastasis.
Immune infiltration analysis showed the tumor infiltration levels of B cell native, T cell CD8+, T cell CD4+ memory activated, T cell gamma delta, NK cell resting, macrophage M0, macrophage M2, myeloid dendritic cell activated, mast cell activated, and mast cell resting significantly changed among the three groups, demonstrating the three subgroups classified by 22 somatically significantly mutated genes had a high capacity to differentiate patients with different immune statuses, which is helpful for the prediction of immunotherapy response of CRC patients.
Our findings could provide novel potential predictive indicators for CRC prognosis and therapy targets for CRC immunotherapy.
论文信息
- 作者
- He Y、Dai X、Chen Y、Huang S
- 单位
- Department of Colorectal Surgery, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China.China
- 期刊
- Genetics research2022
- 原文标识
- PubMed 35975176 · DOI 10.1155/2022/1831211
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