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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. [ABSTRACT FROM AUTHOR]

In total patients, low bTMB (bTMB-L, optimal cutoff = 4) showed significantly longer OS ( I p i = .019) compared with high bTMB (bTMB-H) (Figure 1A and B), and bTMB was significantly associated with disease control rate (DCR) (Figure 1C and D), but not objective response rate (ORR) (Supplementary Figure S4A). Patients with bMSAF-H and bTMB-H (n = 11) are indicated in red, patients with bMSAF-L and bTMB-H (n = 21) are indicated in blue, and those with bMSAF-L and bTMB-L (n = 10) are indicated in green. BMSAF is a prognostic predictor for advanced hepatocellular carcinoma patients treated with immune checkpoint inhibitor camrelizumab and anti-angiogenic agent apatinib combination therapy. [Extracted from the article]

Background: Cervical cancer (CC) is the second leading cause of cancer death among women worldwide. Epigenetic regulation of gene expression through DNA methylation and hydroxymethylation plays a pivotal role during tumorigenesis. In this study, to analyze the epigenomic landscape and identify potential biomarkers for CCs, we selected a series of samples from normal to cervical intra‐epithelial neoplasia (CINs) to CCs and performed an integrative analysis of whole‐genome bisulfite sequencing (WGBS‐seq), oxidative WGBS, RNA‐seq, and external histone modifications profiling data. Results: In the development and progression of CC, there were genome‐wide hypo‐methylation and hypo‐hydroxymethylation, accompanied by local hyper‐methylation and hyper‐hydroxymethylation. Hydroxymethylation prefers to distribute in the CpG islands and CpG shores, as displayed a trend of gradual decline from health to CIN2, while a trend of increase from CIN3 to CC. The differentially methylated and hydroxymethylated region‐associated genes both enriched in Hippo and other cancer‐related signaling pathways that drive cervical carcinogenesis. Furthermore, we identified eight novel differentially methylated/hydroxymethylated‐associated genes (DES, MAL, MTIF2, PIP5K1A, RPS6KA6, ANGEL2, MPP, and PAPSS2) significantly correlated with the overall survival of CC. In addition, no any correlation was observed between methylation or hydroxymethylation levels and somatic copy number variations in CINs and CCs. Conclusion: Our current study systematically delineates the map of methylome and hydroxymethylome from CINs to CC, and some differentially methylated/hydroxymethylated‐associated genes can be used as the potential epigenetic biomarkers in CC prognosis. [ABSTRACT FROM AUTHOR]