Background Although TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported. Methods An integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway. Findings The TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy. Interpretation Our study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs. Funding The study was supported by Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU)

The development of non-invasive, inexpensive, and effective early diagnosis tests for gastric and small-bowel lesions is an urgent requirement. The introduction of magnetically guided capsule endoscopy (MGCE) has aided examination of the small bowel for diagnoses. However, the distribution of the fecal microbiome in abnormal erosions of the stomach and small bowel remains unclear. Herein, alternations in the fecal microbiome in three groups [normal, small-bowel inflammation, and chronic gastritis (CG)] were analyzed by metagenomics and our well-developed method [individual-specific edge-network analysis (iENA)]. In addition to the dominant microbiota identified by the conventional differential analysis, iENA could recognize novel network biomarkers of microbiome communities, such as the genus Bacteroide in CG and small-bowel inflammation. Combined with differential network analysis, the network-hub microbiota within rewired microbiota networks revealed high-ranked iENA microbiota markers, which were disease specific and had particular pathogenic functions. Our findings illuminate the components of the fecal microbiome and the importance of specific bacteria in CG and small-bowel erosions, and could be employed to develop preventive and non-invasive therapeutic strategies.

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