Three Major Signaling Pathways Involved in PMP Pathogenesis: A Comprehensive Analysis of Mutation Profiles and Prognosis

Based on the mutation profile and prognosis analysis, we have identified three major signaling pathways that may be involved in PMP: the TGF-beta signaling pathway, the Rap1 signaling pathway, and the p53 signaling pathway. The TGF-beta signaling pathway and the p53 signaling pathway were found to be more involved in HG-PMP. Specifically, most of the mutated SMAD4 and ATM genes were detected in HG-PMP or HG-PMP with signet ring cells. Therefore, the activation of these pathways may contribute to the pathogenesis of HG-PMP. TGF-β ligands activate cell membrane-associated TGF-β type II and type I Ser/Thr kinase receptors (TβRI and TβRII, respectively). These receptors then phosphorylate SMAD2 and SMAD3, leading to the formation of a hetero-oligomer with SMAD4. This complex subsequently activates transcription. The TGFβ signaling pathway regulates diverse physiological processes in cells, including angiogenesis, wound healing, immune suppression, and epithelial-to-mesenchymal transition (EMT). Activation of this signaling pathway can result in CD8+ T cell exhaustion and immunosuppression. Therapeutic co-administration of TGFβ-blocking agents and immune checkpoint blockers (ICB) could facilitate the production of tumor infiltrating lymphocytes (TILs), provoking vigorous anti-tumor immunity and achieving tumor regression. This therapy may be effective in treating PMP if mutations associated with the TGF-beta signaling pathway are detected. 11. ATM, as a DNA damage response factor, encodes damage sensor proteins that phosphorylate p53 (encoded by TP53) at several residues, including Serine 15 (Ser15), which stabilizes p53. Subsequently, p53 proteins mediate apoptotic cell death or DNA repair. Univariate and multivariate Cox proportional hazards models in our study have shown that TP53 is an independent prognostic factor in overall survival. The signaling cascade between TP53 and ATM implies a complex molecular pathway regulation in the pathogenesis of PMP. Therefore, considering the combined influence of ATM and TP53 mutations can provide a more accurate assessment of the prognostic value and potential treatment strategies for individuals affected by these genetic alterations. It is possible that the activation of the p53 signaling pathway could predict a worse prognosis for patients with PMP. 12. GNAS is a hub gene enriched in the Rap1 signaling pathway. Rap1, as a small GTPase, is highly similar to the RAS sequence. The wild-type RAS family gene retains hydrolytic activity of GTP and cooperates with the Rap1 signaling pathway to initiate and sustain ERK signaling, which is activated in various types of cancer. Although Rap1 was not detected in our cohort, the frequency of FLG gene mutations is relatively low, occurring across three histopathologies. FLG can induce the phosphorylation of Rap1. Additionally, in our cohort, the incidence of GNAS, KRAS, and FLG mutations was universal among the three histopathologies. It is possible that the Rap1 signaling pathway is a universal mechanism of PMP pathogenesis. The downstream of the Rap1 signaling pathway, the ERK signaling pathway, should be inhibited using targeted therapy.