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

Sep 24, 2026

Genomic and immunological intratumor heterogeneity in gastric linitis plastica (LP) remains poorly characterized. Whole-exome sequencing and T-cell receptor sequencing were performed on 40 tumor regions from four LP patients, comparing the resulting genomic landscape and ITH across multiple previously reported cancers. Lymphocyte infiltration was evaluated by immunohistochemistry. The study identified 6339 non-silent mutations with low-to-moderate tumor mutation burden, very high genomic ITH, reduced TCR clonality, scant CD4/CD8/PD-L1–related T-cell infiltration, and profound TCR ITH without shared clones.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Study design and sequencing strategy

Genomic landscape and tumor mutation burden

Genomic intratumor heterogeneity

TCR clonality and TCR intratumor heterogeneity

Immunohistochemistry assessment of T-cell infiltration

Summary of key findings and implications

Analysis of genomic and immune intratumor heterogeneity in linitis plastica via multiregional exomeand T-cell receptor sequencing Jin Huang 1,2,3,4,5, Guofeng Zhao6,7, Qiu Peng8, Xin Yi6,7, Liyan Ji6,7, Jing Li6,7, Pansong Li6,7 , Yanfang Guan6,7, Jie Ge3, Ling Chen3, Runzhe Chen9,10 , Xin Hu9,10, Won-Chul Lee9, Alexandre Reuben9, P. Andrew Futreal 10, Xuefeng Xia7, Jian Ma 1,5,8, Jianjun Zhang9,10 and Zihua Chen 1,3,4,5 1 The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, Central South University, Changsha, Hunan, China 2 Department of Oncology, Xiangya HospitalXiangya Hospital, Central South University, Changsha, China 3 Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China 4 International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Changsha, China 5 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China 6 Geneplus-Beijing Institute, Beijing, China 7 Geneplus-Beijing, Beijing, China 8 Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China 9 Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 10 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Keywords gastric linitis plastica; intratumor heterogeneity; multiregional whole-exome sequencing; T-cell receptor repertoires Correspondence J. Ma, Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha 410008, Hunan, China E-mail: maj[ian@csu.edu.cn](ian@csu.edu.cn) J. Zhang, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Houston, TX, 77030, USA E-mail: [jzhang20@mdanderson.org](jzhang20@mdanderson.org) and Z. Chen, The Hunan Provincial Key Lab of Precision Diagnosis and Treatment for Gastrointestinal Tumor, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China E-mail: [402899@csu.edu.cn](402899@csu.edu.cn) 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 multiregions within the same tumors, signiﬁcantly lower than that of lung cancer (P = 0.002) . Our results show that LP harbored extremely high genomic Abbreviations BRCA, breast invasive carcinoma; CRC, colorectal cancer; DFS, disease-free survival; GC, gastric carcinoma; H&E, hematoxylin and eosin; ITH, intratumor heterogeneity; LP, linitis plastica; LUAD, lung adenocarcin

FAQs

What sequencing approaches were used to study linitis plastica heterogeneity?

Whole-exome sequencing and T-cell receptor sequencing were performed across 40 tumor regions from four LP patients. The work also included immunohistochemistry to assess lymphocyte infiltration.

How was genomic intratumor heterogeneity characterized in this study?

The study detected 6339 non-silent mutations across multi-samples and reported low-to-moderate tumor mutation burden. It also found extremely high genomic ITH, with only small fractions of mutations shared across 10 regions within the same tumors.

What did the T-cell receptor and immunohistochemistry results indicate about immune infiltration?

TCR sequencing showed substantially lower clonality in LP than in multi-cancers, and no T-cell clones were shared across tumor regions within any patient. Immunohistochemistry using CD4, CD8, and PD-L1 antibodies demonstrated scant T-cell infiltration in the four LP tumors.

Sep 24, 2026

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