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通过多区域外显子组和 T 细胞受体测序分析皮革胃中的肿瘤基因组和免疫异质性。

Analysis of genomic and immune intratumor heterogeneity in linitis plastica via multiregional exome and T-cell receptor sequencing.

机构信息

The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Department of Oncology, Xiangya HospitalXiangya Hospital, Central South University, Changsha, China.

出版信息

Mol Oncol. 2023 Aug;17(8):1531-1544. doi: 10.1002/1878-0261.13381. Epub 2023 Mar 7.

Abstract

The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole-exome sequencing (WES) and T-cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunological levels in LP tumors were compared with multiple cancers that have previously been reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6339 non-silent mutations from multi-samples, with a median tumor mutation burden (TMB) of 3.30 mutations per Mb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas (TCGA) cohort (P = 0.53). An extremely high level of genomic ITH was observed, with only 12.42%, 5.37%, 5.35%, and 30.67% of mutations detectable across 10 regions within the same tumors of each patient, respectively. TCR sequencing revealed that TCR clonality was substantially lower in LP than in multi-cancers. IHC using antibodies against CD4, CD8, and PD-L1 demonstrated scant T-cell infiltration in the four LP tumors. Furthermore, profound TCR ITH was observed in all LP tumors, with no T-cell clones shared across tumor regions in any of the patients, while over 94% of T-cell clones were restricted to individual tumor regions. The Morisita overlap index (MOI) ranged from 0.21 to 0.66 among multi-regions within the same tumors, significantly lower than that of lung cancer (P = 0.002). Our results show that LP harbored extremely high genomic and TCR ITH and suppressed T-cell infiltration, suggesting a potential contribution to the frequent recurrence and poor therapeutic response of this adenocarcinoma.

摘要

胃弥漫型大B 细胞淋巴瘤(LP)的分子特征和肿瘤内异质性(ITH)结构尚不清楚。我们对 4 名 LP 患者的 40 个肿瘤区域进行了全外显子组测序(WES)和 T 细胞受体(TCR)测序。比较了 LP 肿瘤在基因组和免疫水平上的特征与先前报道的多种癌症。通过免疫组织化学(IHC)进一步评估了 LP 肿瘤中的淋巴细胞浸润。总共从多份样本中鉴定出 6339 个非沉默突变,中位肿瘤突变负荷(TMB)为 3.30 个突变/Mb,与癌症基因组图谱(TCGA)队列中的胃腺癌相当(P=0.53)。观察到极高水平的基因组 ITH,在每个患者的同一肿瘤的 10 个区域内,只有 12.42%、5.37%、5.35%和 30.67%的突变是可检测的。TCR 测序显示 LP 中的 TCR 克隆性明显低于多种癌症。使用针对 CD4、CD8 和 PD-L1 的抗体进行 IHC 显示,4 个 LP 肿瘤中的 T 细胞浸润极少。此外,在所有 LP 肿瘤中都观察到了深刻的 TCR ITH,在任何患者的肿瘤区域之间都没有共享的 T 细胞克隆,而超过 94%的 T 细胞克隆局限于单个肿瘤区域。Morisita 重叠指数(MOI)在同一肿瘤的多个区域之间的范围为 0.21 至 0.66,明显低于肺癌(P=0.002)。我们的结果表明,LP 具有极高的基因组和 TCR ITH,并抑制了 T 细胞浸润,这可能是导致这种腺癌频繁复发和治疗反应不佳的原因之一。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/976a/10399711/464afd682046/MOL2-17-1531-g002.jpg

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