POLE/POLD1 mutation and tumor immunotherapy

Ma, Xiaoting; Lin, Dong; Liu, Xiu; Ou, Kai; Yang, Lin

doi:10.1186/s13046-022-02422-1

Cited by 55 publications

(42 citation statements)

References 70 publications

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“…Te SBS10a, only present in the highrisk group, may be generated by POLE exonuclease domain mutations. Te exonuclease domain of POLE recognizes and removes wrong bases generated during replication [92]. Te mutations in the exonuclease of POLE, referred to as hypermutators, cause a 10-to-100fold increase in the mutation rate during replication [92], which is in accordance with the interesting fnding that CC patients with several hypermutators had the most kataegis in the high-risk group.…”

Section: Discussionsupporting

confidence: 58%

Prognosis and Characterization of Microenvironment in Cervical Cancer Influenced by Fatty Acid Metabolism-Related Genes

Zhou

Zhu

et al. 2023

Journal of Oncology

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Increasing evidence suggests that diverse activation patterns of metabolic signalling pathways may lead to molecular diversity of cervical cancer (CC). But rare research focuses on the alternation of fatty acid metabolism (FAM) in CC. Therefore, we constructed and compared models based on the expression of FAM-related genes from the Cancer Genome Atlas by different machine learning algorithms. The most reliable model was built with 14 significant genes by LASSO-Cox regression, and the CC cohort was divided into low-/high-risk groups by the median of risk score. Then, a feasible nomogram was established and validated by C-index, calibration curve, net benefit, and decision curve analysis. Furthermore, the hub genes among differential expression genes were identified and the post-transcriptional and translational regulation networks were characterized. Moreover, the somatic mutation and copy number variation landscapes were depicted. Importantly, the specific mutation drivers and signatures of the FAM phenotypes were excavated. As a result, the high-risk samples were featured by activated de novo fatty acid synthesis, epithelial to mesenchymal transition, angiogenesis, and chronic inflammation response, which might be caused by mutations of oncogenic driver genes in RTK/RAS, PI3K, and NOTCH signalling pathways. Besides the hyperactivity of cytidine deaminase and deficiency of mismatch repair, the mutations of POLE might be partially responsible for the mutations in the high-risk group. Next, the antigenome including the neoantigen and cancer germline antigens was estimated. The decreasing expression of a series of cancer germline antigens was identified to be related to reduction of CD8 T cell infiltration in the high-risk group. Then, the comprehensive evaluation of connotations between the tumour microenvironment and FAM phenotypes demonstrated that the increasing risk score was related to the suppressive immune microenvironment. Finally, the prediction of therapy targets revealed that the patients with high risk might be sensitive to the RAF inhibitor AZ628. Our findings provide a novel insight for personalized treatment in CC.

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Section: Discussionsupporting

confidence: 58%

Prognosis and Characterization of Microenvironment in Cervical Cancer Influenced by Fatty Acid Metabolism-Related Genes

Zhou

Zhu

et al. 2023

Journal of Oncology

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“…On the other hand, some studies also reported that the responsiveness or tolerance to immunotherapy was significantly related with tumor mutations ( 43 , 44 ). Thus, we analyzed the mutation profiles and found that the TMB between C1 and C2 was similar.…”

Section: Discussionmentioning

confidence: 99%

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

et al. 2022

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Copper (Cu) is an essential element of organisms, which can affect the survival of cells. However, the role of copper metabolism and cuproptosis on hepatic carcinoma is still unclear. In this study, the TCGA database was used as the test set, and the ICGC database and self-built database were used as the validation set. We screened out a class of copper metabolism and cuproptosis-related genes (CMCRGs) that could influence hepatic carcinoma prognosis by survival analysis and differential comparison. Based on CMCRGs, patients were divided into two subtypes by cluster analysis. The C2 subtype was defined as the high copper related subtype, while the C1 subtype was defied as the low copper related subtype. At the clinical level, compared with the C1 subtype, the C2 subtype had higher grade pathological features, risk scores, and worse survival. In addition, the immune response and metabolic status also differed between C1 and C2. Specifically, C2 subtype had a higher proportion of immune cell composition and highly expressed immune checkpoint genes. C2 subtype had a higher TIDE score with a higher proportion of tumor immune dysfunction and exclusion. At the molecular level, the C2 subtype had a higher frequency of driver gene mutations (TP53 and OBSCN). Mechanistically, the single nucleotide polymorphisms of C2 subtype had a very strong transcriptional strand bias for C>A mutations. Copy number variations in the C2 subtype were characterized by LOXL3 CNV gain, which also showed high association with PDCD1/CTLA4. Finally, drug sensitivity responsiveness was assessed in both subtypes. C2 subtype had lower IC50 values for targeted and chemotherapeutic agents (sorafenib, imatinib and methotrexate, etc.). Thus, CMCRGs related subtypes showed poor response to immunotherapy and better responsiveness to targeted agents, and the results might provide a reference for precision treatment of hepatic carcinoma.

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“…Accordingly, the POLE gene confers to Polε both replicative and 3 to 5 repair capabilities for the new strand. Previous studies have suggested that different Polε gene members are associated with different stages of several different cancers, for example, Ma et al [13] pointed out in their study that mutations in POLE are associated with the development of various tumors; Zhu et al [14] found that people with POLE mutations are more prone to gastrointestinal tumors. However, the study of Raffone A et al [15]pointed out that patients with POLE mutations have increased numbers of tumor-in ltrating lymphocytes in endometrial cancer, suggesting a better prognosis, this seems to contradict the previous studies to some extent.…”

Section: Discussionmentioning

confidence: 99%

“…Available studies have shown that four Polε genes are associated with the prognosis of gastrointestinal tumors [11], endometrioid carcinoma [12], lung cancer, and bladder cancer [13]. However, its role in hepatocellular carcinoma still lacks relevant studies and exploration.…”

Section: Introductionmentioning

confidence: 99%

Multi-omics integration of DNA polymerase epsilon protein family reveals clinical outcomes and functional signatures in hepatocellular carcinoma

Zhang

Liu

et al. 2022

Preprint

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BACKGROUND Numerous genetic sequencing projects have demonstrated that alterations in Polε (DNA polymerase epsilon ) due to various causes are associated with the development of multiple human cancers. However, the biological functions of its four core genes, POLE1/2/3/4/, in the occurrence, progression, and prognosis of hepatocellular carcinoma(HCC) remain poorly understood to date. METHODS Multi-omics, multi-level deep mining of HCC data from TCGA and other publicly available databases by using online analysis tools from GEPIA2, TIMER2.0, DAVID, Kaplan-Meier plotter, cBioPortal and MethSurv databases, as well as the R package to assess Polε family members in HCC for their potential biological functions. RESULTS We found that the four target genes were significantly upregulated in HCC (P < 0.001), their high expression was associated with a lower survival rate (P < 0.05), and both diagnostic ROC curves and disease-specific survival time-dependent ROC curves suggested that POLE2/3 showed better disease predictive efficacy, and the four genes were significantly associated with immune infiltration, and drug sensitivity analysis suggested that the high expression groups showed higher drug sensitivity in some chemotherapeutic drugs(P < 0.001). CONCLUSIONS The POLE1/2/3 are potential prognostic predictive molecules for HCC and correlate with immune infiltration, and high expression of POLE may serve as a potential predictor of the effect of targeted therapies. POLE2/3 may be the potential diagnostic biomarkers for HCC, and the expression level of POLE3 may be a biological predictor of HCC chemotherapy sensitivity.

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POLE/POLD1 mutation and tumor immunotherapy

Cited by 55 publications

References 70 publications

Prognosis and Characterization of Microenvironment in Cervical Cancer Influenced by Fatty Acid Metabolism-Related Genes

Prognosis and Characterization of Microenvironment in Cervical Cancer Influenced by Fatty Acid Metabolism-Related Genes

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma

Multi-omics integration of DNA polymerase epsilon protein family reveals clinical outcomes and functional signatures in hepatocellular carcinoma

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