Publisher: Baylor College of Medicine, Houston, Texas, etc.
Endometrial carcinoma is a malignant tumor originating from endometrium. On February 3, 2020, Cell magazine published a large-scale multi-group research report on endometrial cancer, describing the characteristics of 95 cases of endometrial cancer, including 83 cases of endometrioid tumors and 12 cases of serous tumors, and 49 cases of normal tissues. The researchers sequenced the whole exon, genome, transcriptome and miRNA of each tumor and normal sample, and analyzed DNA methylation to quantify the relative levels of protein and PTM sites in the sample.
Tumors are divided into four genome subtypes: POLE, a rare hypermutant subtype with endometrial histology and good prognosis; Microsatellite instability (MSI), a hypermutant endometrioid subtype; Low copy number (CNV), including most other cases of endometriosis; High CNV includes all serous and most invasive endometrioid tumors. The cohort included 7 poles, 25 MSI, 43 low CNV tumors and 20 high CNV tumors. The levels of protein and PTM vary with genome subtypes.
The research team reported that about 6 1% of all somatic mutations were found in seven polar tumors, and MSI tumors carried 88% of all InDel in this cohort. In addition, they also identified INPPL 1, KMT2B and JAK 1 as putative significant mutant genes (SMG) of MSI subtype. In another analysis, the team examined TP53 mutations and found them in 23 tumors in the cohort, including all serous cancers. Instead of grouping all TP53 mutant tumors together and looking for a single molecular phenotype, they were separated by mutation type and location, and some characteristics of protein omics and phosphorylated protein omics were identified.
The team also compared the changes of protein and transcriptome between cancer subtypes. They scored each sample according to the phosphoprotein labeled by DNA damage response (DDR), and found that the samples with high DDR content were rich in serous tumors, so they were rich in high subtypes of CNV. Endometrioid tumors come from high CNV, POLE and MSI genome subgroups. This shows that the signal transduction of active DNA damage is largely independent of genome subtypes.
The authors emphasize that the comprehensive quantitative measurement of protein, phosphorylation and acetylation combined with genome and transcriptome measurement not only provides novel insights into the basic biological processes related to carcinogenesis, but also provides interesting clues for the potential treatment of endometrial cancer.
95 cases of endometrial carcinoma have the characteristics of protein histology, including 83 cases of endometrioid carcinoma and 12 cases of serous tumor. The analysis revealed the possible new results of p53 and Wnt /β-catenin pathway disorder, identified the potential role of circRNA in epithelial-mesenchymal transition, and provided new information about protein histochemical markers of clinical and genomic tumor subsets, including known drug-related pathways. Extensive genome-wide acetylation research has produced profound insights into the regulatory mechanism of Wnt signal and histone acetylation. The study also characterized all aspects of tumor immune status, including immunogenicity changes, new antigens, common cancer/testis antigens and immune microenvironment, which can provide basis for immunotherapy decision-making.
Protein genomics provides a new perspective for signal transduction of endometrial carcinoma.
The study of total acetylation group and phosphoprotein group found a new regulatory mechanism;
QKI, circRNA and miRNA form a potential feedback loop to promote EMT;;
Defect of antigen presentation can block MSI tumor resistance barrier.
Among 95 cases of endometrial carcinoma (83 cases of endometrioid tumor and 2 cases of serous tumor/kloc-0), 7 cases were extremely carcinoma, 25 cases were MSI, 43 cases were low CNV and 20 cases were high CNV. The levels of protein and PTM are different among genome subtypes. The relative phosphorylation level of cyclins in low CNV subtypes is low, and phosphorylation is related to the increase of cell transport and metabolic proteins. High CNV subtype enhanced phosphorylation of proteins involved in ATM signal transduction. Pole, MSI and high CNV subtypes usually inhibit mismatch repair. Serous samples have the highest up-regulated ribosome biosynthesis, which is related to the poor prognosis of cancer.
About 6 1% of all somatic mutations occur in 7-pole tumors. MSI tumor carried 88% of all INDELs in the cohort. Microsatellite INDELs analysis showed that the mutation rate of significant mutant gene (SMG) of this subtype was high. All JAK 1 frameshift mutations are in MSI samples, and they come from microsatellite insertion deletion, which is related to high tumor grade in MSI samples and promotes immune escape.
In the first part, all the sample characteristics are summarized through the overall correlation of multi-omics. In the following, more emphasis is placed on the local correlation of 2-3 omics, and some detailed features are explained at a specific molecular or pathway level.
Starting with the significant mutation gene (SMG), the effects on protein group (focusing on the relationship between mutation and protein expression) and phosphorylated protein group (focusing on the relationship between mutation and protein activity) were discussed. Increased levels of p53 itself and other proteins in p53 pathway (such as CDK 1 and CHEK 1) were observed in tumors with TP53 mutation. The levels of cis-phosphorylated ARID 1A, MAP3K4, KMT2D and INPPL 1 decreased, but the levels of phosphorylated β-catenin and p53 increased. The truncated mutation caused the protein levels of ARID 1A, INPPL 1, JAK 1, PTEN and RBM27 to decrease. The effect of mutation in the population on protein level is usually related to phosphoprotein level, and no difference in combined RNA level indicates strong regulation related to translation and protein stability.
The characteristics of acetylase in patients' cancer tissues are limited, and it is observed that the enrichment of acetylated protein in endometrial cancer involves splicing, RNA transport, protein synthesis and degradation and metabolic pathways. Histone acetylation pattern is heterogeneous to a great extent, but it has no strong correlation with discrete genome subtypes or clinical characteristics. The level of BRD3 protein is positively correlated with several N- terminal acetylation sites of H2B, which indicates that BRD3 may bind to N- terminal acetyl residues of H2B to prevent deacetylation. The negative correlation between IRT 1 and SIRT3 and H3 acetylation indicates that these histone deacetylases can regulate the acetylation level of H3K27 and K36.
In order to evaluate how mutation affects histone acetylation, the importance of acetylation driving mechanism in Wnt signal transduction is emphasized. The protein levels of BRD3 and SIRT 1 in CTNNB 1 heat mutant increased, and the gene expression of several Wnt pathway genes in samples with high acetylation level of H2B was up-regulated.
Deacetylation of FOXA2-K274 will reduce the stability of FOXA2. The increase of acetylation degree of FOXA2 in low CNV subtype may indicate that the stability and activity of the protein are improved, which may promote the proliferation of low CNV endometrial cancer.
This part is the local correlation analysis between acetylation and genome variation. This result emphasizes the heterogeneity of acetyl in endometrial carcinoma and the potential influence of significant mutation gene (SMG) on histone acetylation level, which may have a comprehensive impact on tumor biology through the interaction with Wnt signaling pathway, BRD protein and methylated protein. The tumor-specific up-regulation of translation elongation factor and the up-regulation of acetylation level in methyltransferase protein, as well as the potential role of FOXA2 in more aggressive CNV subtypes were also determined.
DNA methylation analysis showed that the methylation of CpG island in MSI tumor increased, which led to the inhibition of DNA repair pathway. The comprehensive analysis of somatic copy number change (SCNA) based on the data of transcriptomics and protein omics showed that the SCNA with the strongest trans-action was concentrated on chromosomes 1q, 3q, 4q and 20q in tumors with high CNV. The amplification of 1q is related to the inhibition of p53 pathway, the proteins positively related to 3q amplification include DNA replication and cyclin, and the pathways most affected by 4q deletion include cytoskeleton and ciliary assembly. Combined with DNA methylation modification, the apparent silence of DNA repair pathway is expounded. The combination of copy number variation and expression profile analysis explains the imbalance between deletion or amplification and expression.
A small part of circRNA is also discussed according to ceRNA mechanism. The protein level of circRNA regulator QKI is up-regulated during EMT, which can promote EMT by regulating hundreds of alternative splicing targets. Because circRNA can act as a miRNA sponge to regulate the activity of miRNA, the author predicted the miRNA binding sites related to the level of QKI in circRNA, and found that the activity of these mirnas may be blocked by QKI, suggesting the mechanism of promoting EMT in DNA repair.
The ultimate goal of large-scale omics data set is to find the key molecules that clearly distinguish disease subtypes. In order to promote early diagnosis and determine possible therapeutic targets, it is very important to identify molecular subtype markers. The authors searched for markers by combining genomic variation, transcription, protein and epigenetic modification levels. Considering that drug targeting is mainly protein interaction, protein phosphorylation modification is the key. Because the prognosis of patients with high CNV tumor is particularly poor regardless of histology, we focus on finding overactive proteins to develop new chemotherapy drugs. According to the kinase activity inferred from protein data, several kinases activated in endometrioid tumors with high CNV can be targeted by many FDA-approved drugs.
Combining the comprehensive quantitative measurement of protein, phosphorylation and acetylation with the measurement of genome and transcriptome not only provides new insights into the basic biological process related to carcinogenesis, but also provides fascinating clues for the new treatment of endometrial cancer. In this study, the molecular system of endometrial carcinoma was comprehensively introduced from the levels of genome, transcriptome and protein omics. It confirmed the protein level expression of predicted events previously described at genome and transcriptome level, and proved that different subtypes of endometrial carcinoma can be reliably distinguished by their protein levels and subsequent post-translational modification patterns. Although the results provided in this paper are mainly observational, they provide the basis for several hypotheses of clinical relevance, which can be further explored by the scientific community.
Is the memory method of mind mapping effective?
Does mind mapping have any effect?
Recently, I heard friends in the group say something about mind mapping mem