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

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.

Prognostic factors in patients with diffuse type gastric cancer (linitis plastica) after operative treatment.

OBJECTIVE: Treatment options for patients with diffuse type gastric cancer (linitis plastica) are discussed controversial. It is sometimes discussed that these patients should be treated primarily in palliative intention conservative without resection. METHODS: In a single-center analysis, we investigated 120 patients with diffuse type gastric cancer. All patients underwent a total gastrectomy, 45 patients even a multivisceral resection because of infiltrating growth, or metastases. Serum tumor marker CEA, CA 72-4, and CA 19-9 were recorded in all patients before surgery. An immunocytochemical detection of free peritoneal tumor cells (FPTC) using Ber-EP4 antibody was correlated with tumor stage and survival. Median follow-up time was 38 months. RESULTS: Complete resection rate was 31% (n = 37). 61% (n = 73) of all patients had already distant metastases at the time of surgery, 80% of them peritoneal carcinomatosis. Median survival for the whole group was 8 months, after complete resection 17 months. Lavage cytology, distant metastases, resection rate, and CA19-9 levels had significant influence on survival. CONCLUSION: A significant survival advantage for patients with diffuse type gastric cancer can only be achived after complete resection. We could define a subset of patients with an extremely poor prognosis even after surgical resection. Meticulous preoperative staging, including a diagnostic laparoscopy to exclude peritoneal carcinomatosis and free peritoneal tumor cells before resection should be mandatory in these patients.