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PloS One 2022Adenomatous polyposis coli (APC) is the most commonly mutated gene in colon cancer and can cause familial adenomatous polyposis (FAP). Hypermethylation of the APC...
Adenomatous polyposis coli (APC) is the most commonly mutated gene in colon cancer and can cause familial adenomatous polyposis (FAP). Hypermethylation of the APC promoter can also promote the development of breast cancer, indicating that APC is not limited to association with colorectal neoplasms. However, no pan-cancer analysis has been conducted. We studied the location and structure of APC and the expression and potential role of APC in a variety of tumors by using The Cancer Genome Atlas and Gene Expression Omnibus databases and online bioinformatics analysis tools. The APC is located at 5q22.2, and its protein structure is conserved among H. sapiens, M. musculus with C. elaphus hippelaphus. The APC identity similarity between homo sapiens and mus musculus reaches 90.1%. Moreover, APC is highly specifically expressed in brain tissues and bipolar cells but has low expression in most cancers. APC is mainly expressed on the cell membrane and is not detected in plasma by mass spectrometry. APC is low expressed in most tumor tissues, and there is a significant correlation between the expressed level of APC and the main pathological stages as well as the survival and prognosis of tumor patients. In most tumors, APC gene has mutation and methylation and an enhanced phosphorylation level of some phosphorylation sites, such as T1438 and S2260. The expressed level of APC is also involved in the level of CD8+ T-cell infiltration, Tregs infiltration, and cancer-associated fibroblast infiltration. We conducted a gene correlation study, but the findings seemed to contradict the previous analysis results of the low expression of the APC gene in most cancers. Our research provides a comparative wholesale understanding of the carcinogenic effects of APC in various cancers, which will help anti-cancer research.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; DNA Methylation; Genes, APC; Humans; Mice; Promoter Regions, Genetic
PubMed: 35303016
DOI: 10.1371/journal.pone.0265655 -
World Journal of Gastrointestinal... Oct 2023mRNA vaccines have been investigated in multiple tumors, but limited studies have been conducted on their use for hepatocellular carcinoma (HCC).
BACKGROUND
mRNA vaccines have been investigated in multiple tumors, but limited studies have been conducted on their use for hepatocellular carcinoma (HCC).
AIM
To identify candidate mRNA vaccine antigens for HCC and suitable subpopulations for mRNA vaccination.
METHODS
Gene expression profiles and clinical information of HCC datasets were obtained from International Cancer Genome Consortium and The Cancer Genome Atlas. Genes with somatic mutations and copy number variations were identified by cBioPortal analysis. The differentially expressed genes with significant prognostic value were identified by Gene Expression Profiling Interactive Analysis 2 website analysis. The Tumor Immune Estimation Resource database was used to assess the correlation between candidate antigens and the abundance of antigen-presenting cells (APCs). Tumor-associated antigens were overexpressed in tumors and associated with prognosis, genomic alterations, and APC infiltration. A consensus cluster analysis was performed with the Consensus Cluster Plus package to identify the immune subtypes. The weighted gene coexpression network analysis (WGCNA) was used to determine the candidate biomarker molecules for appropriate populations for mRNA vaccines.
RESULTS
, and were identified as candidate HCC antigens for mRNA vaccine development. Four immune subtypes (IS1-IS4) and five immune gene modules of HCC were identified that were consistent in both patient cohorts. The immune subtypes showed distinct cellular and clinical characteristics. The IS1 and IS3 immune subtypes were immunologically "cold". The IS2 and IS4 immune subtypes were immunologically "hot", and the immune checkpoint genes and immunogenic cell death genes were upregulated in these subtypes. IS1-related modules were identified with the WGCNA algorithm. Ultimately, five hub genes ( and ) were identified, and they might be potential biomarkers for mRNA vaccines.
CONCLUSION
, and have been identified as candidate HCC antigens for mRNA vaccine development. The IS1 and IS3 immune subtypes are suitable populations for mRNA vaccination. and are potential biomarkers for mRNA vaccines.
PubMed: 37969406
DOI: 10.4251/wjgo.v15.i10.1717 -
Proceedings of the National Academy of... Aug 2020Quantifying evolutionary dynamics of cancer initiation and progression can provide insights into more effective strategies of early detection and treatment. Here we...
Quantifying evolutionary dynamics of cancer initiation and progression can provide insights into more effective strategies of early detection and treatment. Here we develop a mathematical model of colorectal cancer initiation through inactivation of two tumor suppressor genes and activation of one oncogene, accounting for the well-known path to colorectal cancer through loss of tumor suppressors and and gain of the oncogene. In the model, we allow mutations to occur in any order, leading to a complex network of premalignant mutational genotypes on the way to colorectal cancer. We parameterize the model using experimentally measured parameter values, many of them only recently available, and compare its predictions to epidemiological data on colorectal cancer incidence. We find that the reported lifetime risk of colorectal cancer can be recovered using a mathematical model of colorectal cancer initiation together with experimentally measured mutation rates in colorectal tissues and proliferation rates of premalignant lesions. We demonstrate that the order of driver events in colorectal cancer is determined primarily by the fitness effects that they provide, rather than their mutation rates. Our results imply that there may not be significant immune suppression of untreated benign and malignant colorectal lesions.
Topics: Carcinogenesis; Colonic Neoplasms; Colorectal Neoplasms; Disease Progression; Genes, APC; Genes, p53; Genes, ras; Humans; Models, Theoretical; Mutation; Mutation Rate; Oncogenes; Proto-Oncogene Proteins p21(ras); Tumor Suppressor Protein p53
PubMed: 32788368
DOI: 10.1073/pnas.2003771117 -
Molecular Biology of the Cell Jan 2021The adenomatous polyposis coli (APC) tumor suppressor protein is associated with the regulation of Wnt signaling; however, APC also controls other cellular processes...
The adenomatous polyposis coli (APC) tumor suppressor protein is associated with the regulation of Wnt signaling; however, APC also controls other cellular processes including the regulation of cell adhesion and migration. The expression of full-length APC in SW480 colorectal cancer cells (SW480+APC) not only reduces Wnt signaling, but increases membrane E-cadherin and restores cell-cell adhesion. This report describes the effects of full-length, wild-type APC (fl-APC) on cell-cell adhesion genes and p120-catenin isoform switching in SW480 colon cancer cells: fl-APC increased the expression of genes implicated in cell-cell adhesion, whereas the expression of negative regulators of E-cadherin was decreased. Analysis of cell-cell adhesion-related proteins in SW480+APC cells revealed an increase in p120-catenin isoform 3A; similarly, depletion of APC altered the p120-catenin protein isoform profile. Expression of ESRP1 (epithelial splice regulatory protein 1) is increased in SW480+APC cells, and its depletion results in reversion to the p120-catenin isoform 1A phenotype and reduced cell-cell adhesion. The ESRP1 transcript is reduced in primary colorectal cancer, and its expression correlates with the level of APC. Pyrvinium pamoate, which inhibits Wnt signaling, promotes ESRP1 expression. We conclude that re-expression of APC restores the cell-cell adhesion gene and posttranscriptional regulatory programs leading to p120-catenin isoform switching and associated changes in cell-cell adhesion.
Topics: Adenomatous Polyposis Coli Protein; Catenins; Cell Adhesion; Cell Line, Tumor; Colorectal Neoplasms; Epithelial Cells; Gene Expression Regulation, Neoplastic; Humans; Models, Biological; Protein Isoforms; RNA, Messenger; RNA-Binding Proteins; Subcellular Fractions; Wnt Signaling Pathway; Delta Catenin
PubMed: 33237836
DOI: 10.1091/mbc.E20-05-0321 -
BMC Medical Genomics Feb 2023Currently, endometrial adenocarcinoma lacks an effective prognostic indicator. This study was to develop and validate a gene biomarker and a nomogram to predict the...
OBJECTIVES
Currently, endometrial adenocarcinoma lacks an effective prognostic indicator. This study was to develop and validate a gene biomarker and a nomogram to predict the survival of endometrial adenocarcinoma, explore potential mechanisms and select sensitive drugs.
METHODS
425 endometrial adenocarcinoma cases with RNA sequencing data from TCGA were used to identify the most immune-related module by WGCNA. As an external test set, 103 cases from GSE17025 were used. Immune-related genes were downloaded from Innate DB. The three sets of data were used to identify the prognostic genes. Based on 397 cases with complete clinical data from TCGA, randomly divided into the training set (n = 199) and test set (n = 198), we identified CXCR3 as the prognostic gene biomarker. Age, grade, FIGO stage, and risk were used to develop and validate a predictive nomogram. AUC, C-index, calibration curve and K-M estimate evaluated the model's predictive performance. KEGG enrichment analysis, immune functions, TMB, the effectiveness of immunotherapy, and drug sensitivity between the high-risk and low-risk groups.
RESULTS
CXCR3 was identified as a prognostic biomarker. We calculated the risk score and divided the cases into the high-risk and low-risk groups by the median value of the risk score. The OS of the high-risk group was better than the low-risk group. The risk was the prognostic indicator independent of age, grade, and FIGO stage. We constructed the nomogram including age, grade, FIGO stage, and risk to predict the prognosis of endometrial adenocarcinoma. The top five KEGG pathways enriched by the DEGs between the high- and low-risk groups were viral protein interaction with cytokine and cytokine receptors, cytokine-cytokine receptor interaction, chemokine signaling pathway, natural killer cell-mediated cytotoxicity, and cell adhesion molecules. We analyzed the difference in immune cells and found that CD8+ T cells, activated CD4+ T cells, T helper cells, monocytes, and M1 macrophages were infiltrated more in the low-risk group. However, M0 macrophages and activated dendritic cells were more in the high-risk group. The immune function including APC coinhibition, APC costimulation, CCR, checkpoint, cytolytic activity, HLA, inflammation-promoting, MHC-I, parainflammation, T cell coinhibition, T cell costimulation, type I-IFN-response, and type II-IFN-response were better in the low-risk group. TMB and TIDE scores were both better in the low-risk group. By 'the pRRophetic' package, we found 56 sensitive drugs for different risk groups.
CONCLUSION
We identified CXCR3 as the prognostic biomarker. We also developed and validated a predictive nomogram model combining CXCR3, age, histological grade, and FIGO stage for endometrial adenocarcinoma, which could help explore the precise treatment.
Topics: Humans; Prognosis; Risk Factors; Cytokines; Adenocarcinoma; Biomarkers; Receptors, CXCR3
PubMed: 36750966
DOI: 10.1186/s12920-023-01451-9 -
Journal of Visceral Surgery Apr 2020Nearly 5% of colorectal cancers are hereditary colorectal cancers, including adenomatous polyposis. The aim of this review was to highlight the current management of... (Review)
Review
Nearly 5% of colorectal cancers are hereditary colorectal cancers, including adenomatous polyposis. The aim of this review was to highlight the current management of adenomatous polyposis. The two main genetic conditions responsible for adenomatous polyposis are familial adenomatous polyposis (FAP) (caused by an autosomal dominant mutation of the APC gene) and MUTYH-associated polyposis (MAP) (caused by bi-allelic recessive mutations of the MUTYH (MutY human homolog) gene). FAP is characterized by the presence of >1000 polyps and a young age at diagnosis (mean age of 10). In the absence of screening, the risk of colorectal cancer at age 40 is 100%. It is recommended to start screening at the age of 10-12 years. For patients with FAP and MAP, it is also recommended to screen the upper gastrointestinal tract (stomach and duodenum). In FAP, prophylactic surgery aims to reduce the risk of death without impairment of patient quality of life. The best age for prophylactic surgery is not well-defined; in Europe, prophylactic surgery is usually performed at age 20 as the risk of cancer increases sharply during the third decade. There are three main surgical procedures employed: total colectomy with an ileorectal anastomosis, restorative coloproctectomy with a J pouch anastomosis and coloproctectomy with a stoma. Restorative coloproctectomy with J pouch anastomosis is the reference procedure; however, disease can vary in severity from one patient to another and this must be taken into account to decide which procedure should be performed. In conclusion, the management of adenomatous polyposis is complex but is well-defined by guidelines, particularly in France.
Topics: Adenomatous Polyposis Coli; Age Factors; Anastomosis, Surgical; Colectomy; DNA Glycosylases; Endoscopy, Gastrointestinal; Genes, APC; Genetic Markers; Humans; Laparoscopy; Mutation; Quality of Life
PubMed: 32113818
DOI: 10.1016/j.jviscsurg.2019.12.003 -
World Journal of Gastrointestinal... Dec 2019Adenomatous polyposis (AP) is classified according to cumulative adenoma number in classical AP (CAP) and attenuated AP (AAP). Genetic susceptibility is the major risk... (Review)
Review
Adenomatous polyposis (AP) is classified according to cumulative adenoma number in classical AP (CAP) and attenuated AP (AAP). Genetic susceptibility is the major risk factor in CAP due to mutations in the known high predisposition genes and . However, the contribution of genetic susceptibility to AAP is lower and less understood. New predisposition genes have been recently proposed, and some of them have been validated, but their scarcity hinders accurate risk estimations and prevalence calculations. AAP is a heterogeneous condition in terms of severity, clinical features and heritability. Therefore, clinicians do not have strong discriminating criteria for the recommendation of the genetic study of known predisposition genes, and the detection rate is low. Elucidation and knowledge of new AAP high predisposition genes are of great importance to offer accurate genetic counseling to the patient and family members. This review aims to update the genetic knowledge of AAP, and to expound the difficulties involved in the genetic analysis of a highly heterogeneous condition such as AAP.
PubMed: 31908716
DOI: 10.4251/wjgo.v11.i12.1101 -
Scientific Reports Sep 2022Small bowel adenocarcinoma (SBA) is a gastrointestinal malignancy with low incidence but poor prognosis, and its pathogenesis is still unclear. This study aimed to...
Small bowel adenocarcinoma (SBA) is a gastrointestinal malignancy with low incidence but poor prognosis, and its pathogenesis is still unclear. This study aimed to explore potential disease-causing biomarkers of SBA. The gene expression datasets of SBA and normal samples were downloaded from the Gene Expression Omnibus database. First, differential gene expression analysis and weighted gene coexpression network analysis (WGCNA) were performed. Common genes (CGs) were obtained by intersection of differentially expressed genes (DEGs) and optimal modal genes of WGCNA. Subsequently, a protein‒protein interaction network was established to screen hub genes, and target genes were obtained by Lasso regression analysis of hub genes. An SBA risk prediction model was established based on target genes. The prediction accuracy of the model was evaluated by the area under the receiver operating characteristic curve (AUC). The levels of immune cell infiltration and activation of immune pathways were compared between SBA and normal samples using the "ggpubr" and "reshape2" packages. A total of 1058 DEGs were identified. WGCNA showed that the signature gene in the brown module was significantly associated with SBA (p = 7E-17), and 469 CGs were obtained. Four target genes (APOA4, APOB, COL1A2, FN1) were identified and showed excellent prediction of SBA risk (AUC = 0.965). In addition, active dendritic cells and macrophages showed higher infiltration levels in SBA. Meanwhile, the APC_co_stimulation pathway and parainflammation pathway were strongly active in SBA. Four target genes (APOA4, APOB, COL1A2, FN1) may be involved in the pathogenesis of small bowel adenocarcinoma.
Topics: Adenocarcinoma; Apolipoproteins B; Biomarkers; Biomarkers, Tumor; Computational Biology; Duodenal Neoplasms; Gene Expression Profiling; Gene Regulatory Networks; Humans; Prognosis
PubMed: 36171259
DOI: 10.1038/s41598-022-20599-5 -
Scientific Reports Mar 2021Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound...
Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Adult; Cell Line, Tumor; Cell Transformation, Neoplastic; Colorectal Neoplasms; Female; Genetic Predisposition to Disease; Genotype; Germ-Line Mutation; Heterozygote; Human Embryonic Stem Cells; Humans; Male; Middle Aged; Pedigree
PubMed: 33664379
DOI: 10.1038/s41598-021-84564-4 -
Gastroenterology Jan 2021Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that...
BACKGROUND & AIMS
Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify Wnt signaling in intestinal stem cells. Alterations in RSPO genes have been identified in human colorectal tumors. We studied the effects of RSPO1 overexpression in Apc mutant mice.
METHODS
An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into Apcmice. Their intestinal crypts were isolated and cultured as organoids. which were incubated with or without RSPO1-Fc and an inhibitor of transforming growth factor beta receptor (TGFBR). Livers were collected from mice and analyzed by immunohistochemistry. Organoids and adenomas were analyzed by quantitative reverse-transcription PCR, single cell RNA sequencing, and immunohistochemistry.
RESULTS
Intestines from Apc mice injected with the vector encoding RSPO1-Fc had significantly deeper crypts, longer villi, with increased EdU labeling, indicating increased proliferation of epithelial cells, in comparison to mice given control vector. AAV-RSPO1-Fc-transduced Apc mice also developed fewer and smaller intestinal tumors and had significantly longer survival times. Adenomas of Apc mice injected with the RSPO1-Fc vector showed a rapid increase in apoptosis and in the expression of Wnt target genes, followed by reduced expression of messenger RNAs and proteins regulated by the Wnt pathway, reduced cell proliferation, and less crypt branching than adenomas of mice given the control vector. Addition of RSPO1 reduced the number of adenoma organoids derived from Apc mice and suppressed expression of Wnt target genes but increased phosphorylation of SMAD2 and transcription of genes regulated by SMAD. Inhibition of TGFBR signaling in organoids stimulated with RSPO1-Fc restored organoid formation and expression of genes regulated by Wnt. The TGFBR inhibitor restored apoptosis in adenomas from Apc mice expressing RSPO1-Fc back to the same level as in the adenomas from mice given the control vector.
CONCLUSIONS
Expression of RSPO1 in Apc mice increases apoptosis and reduces proliferation and Wnt signaling in adenoma cells, resulting in development of fewer and smaller intestinal tumors and longer mouse survival. Addition of RSPO1 to organoids derived from adenomas inhibits their growth and promotes proliferation of intestinal stem cells that retain the APC protein; these effects are reversed by TGFB inhibitor. Strategies to increase the expression of RSPO1 might be developed for the treatment of intestinal adenomas.
Topics: Adenoma; Animals; Disease Models, Animal; Intestinal Neoplasms; Mice; Organoids; Thrombospondins; Transforming Growth Factor beta; Wnt Signaling Pathway
PubMed: 32941878
DOI: 10.1053/j.gastro.2020.09.011