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

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.

The Genomic Signatures of Linitis Plastica Signal the Entrance into a New Era: Novel Approaches for Diagnosis and Treatment

“…The etiology of LP is not solely rooted in mutations within cancerous cells, it also hinges on the interactions between stromal and cancerous cells. Huang et al assert that these mutations result from spontaneous deaminations or defects in DNA mismatch repair mechanisms, mostly occurring after failures in repairing DNA double-strand breaks [9]. LP stands out as one of the most heterogeneous cancers in terms of mutated genes, but in each distinct case, it exhibits the same mutations across all its regions, with a prevalence ranging from 68-95% [9].…”

“…Huang et al assert that these mutations result from spontaneous deaminations or defects in DNA mismatch repair mechanisms, mostly occurring after failures in repairing DNA double-strand breaks [9]. LP stands out as one of the most heterogeneous cancers in terms of mutated genes, but in each distinct case, it exhibits the same mutations across all its regions, with a prevalence ranging from 68-95% [9]. The invasive nature of LP is attributed to mutations in genes and proteins associated with tight junctions.…”

“…The PI3KT-AKT pathway is up-regulated in LP, while the AMPK pathway is down-regulated, both contributing to cell growth due to their "oncogene-like functioning" [3]. Huang et al, in their cohort, report that the most frequently traced mutations among LP patients were RELN, CDH1 and ARID1A, with occurrence rates of 76%, 65% and 40%, respectively [9]. On the other hand, Liu et al demonstrate that the most common mutations affect the TTN gene, followed by TP53, MUC16, CDH1, LRP1B, CYNE1 and ARID1A.…”

“…LP originates from the fundic gland cells and infiltrates the entire stomach with a desmoplastic growth pattern, unlike the development of a solid tumor. Tumor cells are dispersed within the thickened fibrous tissue, extending into the submucosal and serous layer [5,7,[9][10][11]. In 91.1% of cases, LP presents as a poorly differentiated adenocarcinoma, and in 77.7% of cases, it is often histologically linked with signet ring cells [8].…”

“…LP predominantly affects women and younger individuals, distinguishing it from other types of GC [8,11]. Its aggressive behavior, stemming from its unique features, places the 5-year overall survival (OS) at 5%, while non-LP GC patients have a median 5-year OS of 36%, respectively [8,9,12,13]. Only a small percentage of LP patients are diagnosed at an early stage and are consequently candidates for R0 resection.…”