Genomic and Immune Intratumor Heterogeneity in Gastric Linitis Plastica.

e16518 Background: Gastric linitis plastica (LP) is a rare and aggressive type of gastric cancer (GC) for which the genomic landscape and architecture have gone largely undescribed. Methods: 4 LP patients were enrolled. 10 region tumor samples of each LP patient and matched peripheral blood were collected. Matched blood cells of each patient were also collected for removing germline background Whole-exome sequencing(WES), TCR sequencing, TCGA gastric cancer and several WES articles data were used to investigate intra and inter patient genomic and immune heterogeneity. Results: All 4 LP patients were female and were in stage III. LP biopsies were sequenced with median 290.6x effective depth. A total of 11,504 somatic mutations including 6,339 non-silent mutations were identified. The median non-silent tumor mutation burden (TMB) of biopsy samples was 3.23 mutations/Mb (range from 1.36 to 4.88), which was comparable to gastric adenocarcinoma(p = 0.3). Phylogenetic trees of 4 LP patients demonstrated clear evidence of branched evolution, and the phylogenetic trees varied extensively across the four cases. The percentages of trunk mutations of 4 LP were 12.8%, 5.4%, 5.4% and 30.7%, respectively, while the proportions of trunk neoantigens were 6.2%, 2.2%, 12% and 12.4, respectivelyWhen comparing LP to other multiregion WES studies, e.g., lung adenocarcinoma, renal cell carcinoma, and esophageal squamous cell carcinoma, LP was one of the most heterogeneous tumor types. The top mutational signatures in this cohort associated with spontaneous deamination, DNA mismatch repair (MMR), and small indels at repeats etc. Furthermore, profound TCR ITH was observed in all 4 LP patients. None of the T cell clones were shared among all tumor regions and 94.23-94.41% T cells were restricted to individual tumor regions. To quantify the TCR ITH, we utilized the Morisita overlap index (MOI), which ranged from 0.34 to 0.56 across different regions within the same tumors suggesting marked inter-individual TCR repertoire heterogeneity and profound intratumor TCR heterogeneity. Conclusions: Based on whole-exome sequencing and TCR sequencing, we demonstrate that LP is highly heterogeneous for mutations, neoantigens and T cells, which contributes to its poor prognosis.