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Advances in Experimental Medicine and... 2009Colon cancer closely follows the paradigm of a single "gatekeeper gene." Mutations inactivating the APC (adenomatous polyposis coli) gene are found in approximately 80%... (Review)
Review
Colon cancer closely follows the paradigm of a single "gatekeeper gene." Mutations inactivating the APC (adenomatous polyposis coli) gene are found in approximately 80% of all human colon tumors and heterozygosity for such mutations produces an autosomal dominant colon cancer predisposition in humans and in murine models. However, this tight association between a single genotype and phenotype belies a complex association of genetic and epigenetic factors that together generate the broad phenotypic spectrum ofboth familial and sporadic colon cancers. In this Chapter, we give a general overview of the structure, function and outstanding issues concerning the role of Apc in human and experimental colon cancer. The availability of increasingly close models for human colon cancer in genetically tractable animal species enables the discovery and eventual molecular identification of genetic modifiers of the Apc-mutant phenotypes, connecting the central role of Apc in colon carcinogenesis to the myriad factors that ultimately determine the course of the disease.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Colorectal Neoplasms; Genes, APC; Humans; Mutation
PubMed: 19928355
DOI: 10.1007/978-1-4419-1145-2_8 -
Frontiers in Immunology 2023Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of large number of colorectal adenomas with high risk of evolving into...
Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of large number of colorectal adenomas with high risk of evolving into colorectal tumors. Mutations of the gene is often at the origin of this disease, as well as of a high percentage of spontaneous colorectal tumors. is therefore considered a tumor suppressor gene. While the role of in intestinal epithelium homeostasis is well characterized, its importance in immune responses remains ill defined. Our recent work indicates that the APC protein is involved in various phases of both CD4 and CD8 T cells responses. This prompted us to investigate an array of immune cell features in FAP subjects carrying mutations. A group of 12 FAP subjects and age and sex-matched healthy controls were studied. We characterized the immune cell repertoire in peripheral blood and the capacity of immune cells to respond to different stimuli either in whole blood or in purified T cells. A variety of experimental approaches were used, including, pultiparamater flow cytometry, NanosString gene expression profiling, Multiplex and regular ELISA, confocal microscopy and computer-based image analyis methods. We found that the percentage of several T and natural killer (NK) cell populations, the expression of several genes induced upon innate or adaptive immune stimulation and the production of several cytokines and chemokines was different. Moreover, the capacity of T cells to migrate in response to chemokine was consistently altered. Finally, immunological synapses between FAP cytotoxic T cells and tumor target cells were more poorly structured. Our findings of this pilot study suggest that mild but multiple immune cell dysfunctions, together with intestinal epithelial dysplasia in FAP subjects, may facilitate the long-term polyposis and colorectal tumor development. Although at an initial discovery phase due to the limited sample size of this rare disease cohort, our findings open new perspectives to consider immune cell abnormalities into polyposis pathology.
Topics: Humans; Adenomatous Polyposis Coli; Cell Movement; Colorectal Neoplasms; Genes, APC; Mutation; Pilot Projects; T-Lymphocytes
PubMed: 37533857
DOI: 10.3389/fimmu.2023.1163466 -
Medicine Apr 2020The methylation status of the adenomatous polyposis coli (APC) promoter has been shown to be associated with the occurrence of gastric cancer, but this finding remains... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The methylation status of the adenomatous polyposis coli (APC) promoter has been shown to be associated with the occurrence of gastric cancer, but this finding remains controversial. The aim of this study was to investigate the relationship between methylation of the APC gene promoter and gastric cancer.
METHODS
We searched the Web of Science, EMBASE, Medline, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from the date of creation until August 1, 2019. According to the inclusion criteria, the relationship between the methylation status of the APC gene promoter and gastric cancer was investigated. The incidence of APC promoter methylation in the tissues or blood of patients with and without gastric cancer was compared. The results are expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed effects model or a random effects model to generate forest plots. We further validated the results using the MethHC database.
RESULTS
Eight studies (985 samples) were included. Our meta-analysis showed that the incidence of APC promoter methylation in patients with gastric cancer was higher than that of patients without gastric cancer (OR = 3.86, 95% CI 1.71-8.74, P = .001). Methylation of the APC promoter is associated with the incidence of gastric cancer, and it increases the risk of gastric cancer.
CONCLUSION
This study provides a new strategic direction for research on gastric cancer. Methylation of the APC promoter may be a potential biomarker for the diagnosis of gastric cancer, but the results of this work require further confirmation.
Topics: Adenomatous Polyposis Coli; Biomarkers, Tumor; Computational Biology; DNA Methylation; Genes, APC; Genetic Predisposition to Disease; Humans; Incidence; Promoter Regions, Genetic; Risk Factors; Stomach Neoplasms
PubMed: 32312003
DOI: 10.1097/MD.0000000000019828 -
Genes & Development Jun 2006The Wnt signaling pathway controls cell proliferation and body patterning throughout development. A surprising number of cytoplasmic Wnt regulators (e.g., beta-catenin,... (Review)
Review
The Wnt signaling pathway controls cell proliferation and body patterning throughout development. A surprising number of cytoplasmic Wnt regulators (e.g., beta-catenin, Bcl-9/Lgs, APC, Axin) also appear, often transiently, in the nucleus. beta-Catenin is an integral component of E-cadherin complexes at intercellular adherens junctions, but also recruits chromatin remodeling complexes to activate transcription in the nucleus. The APC tumor suppressor is a part of the cytoplasmic beta-catenin destruction complex, yet also counteracts beta-catenin transactivation and histone H3K4 methylation at Wnt target genes. Furthermore, APC coordinates the cyclic exchange of Wnt coregulator complexes at the DNA. These opposing roles of APC and beta-catenin enable a rapid coordination of gene expression and cytoskeletal organization throughout the cell in response to signaling.
Topics: Animals; Cell Nucleus; Genes, APC; Neoplasms; Signal Transduction; Stem Cells; Wnt Proteins; beta Catenin
PubMed: 16751178
DOI: 10.1101/gad.1424006 -
The International Journal of Biological... 2012Germline nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene are found in approximately 90% of individuals affected by familial adenomatous...
PURPOSE
Germline nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene are found in approximately 90% of individuals affected by familial adenomatous polyposis (FAP) and a genotype-phenotype relationship has been observed. Missense mutations have also been found in a few cases, even if their role in FAP is still unknown. An association between a missense mutation, APC I1307K, and the risk of sporadic colorectal cancer (CRC) has been reported. In order to improve the knowledge about the genetic effect of APC I1307K on the phenotype, we tried a new approach using matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS).
EXPERIMENTAL DESIGN
An APC mutation (I1307K) was found in an index case of a non-Jewish woman and her son with attenuated familial adenomatous polyposis (A-FAP) and no family history of cancer. In order to evaluate whether the presence and abundance of the ionic species are related to the presence of cancer or the presence of mutation, comparative analyses of 11 healthy clean-colon subjects, 59 patients with CRC (stage II n=19, stage III n=23, stage IV n=17) without polyps, and 9 FAP patients, carriers of a nonsense mutation in the APC gene, were evaluated.
RESULTS
Comparative analysis of serum protein profiles of the index patient and her healthy son, FAP and sporadic CRC patients, and subjects with preneoplastic lesions showed a characteristic abundance of ionic species at m/z 905, which was not present in healthy controls. Two peptides were identified from MALDI/MS/MS spectra of m/z 905 belonging to the kininogen-1 precursor and the human forkhead box protein 01A (FOXO1A). FOXO1A was present in only two subjects carrying I1307K, but not in other patients.
CONCLUSIONS
Our findings seem to suggest a relationship between m/z 905, FOXO1A and the development and growth of colorectal cancer. FOXO1A fragment determination in serum with MALDI/MS might be a promising approach for early detection of colon carcinoma or for the development of targeted therapies.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Adolescent; Adult; Codon, Nonsense; Colorectal Neoplasms; Female; Forkhead Box Protein O1; Forkhead Transcription Factors; Genes, APC; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Mutation, Missense; Sequence Analysis, DNA; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Young Adult
PubMed: 22180177
DOI: 10.5301/JBM.2011.8908 -
Molecular Cancer Aug 2011Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene strongly predispose to development of gastro-intestinal tumors. Central to the tumorigenic events... (Review)
Review
Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene strongly predispose to development of gastro-intestinal tumors. Central to the tumorigenic events in APC mutant cells is the uncontrolled stabilization and transcriptional activation of the protein β-catenin. Many questions remain as to how APC controls β-catenin degradation. Remarkably, the large C-terminal region of APC, which spans over 2000 amino acids and includes critical regions in downregulating β-catenin, is predicted to be natively unfolded. Here we discuss how this uncommonly large disordered region may help to coordinate the multiple cellular functions of APC. Recently, a significant number of germline and somatic missense mutations in the central region of APC were linked to tumorigenesis in the colon as well as extra-intestinal tissues. We classify and localize all currently known missense mutations in the APC structure. The molecular basis by which these mutations interfere with the function of APC remains unresolved. We propose several mechanisms by which cancer-related missense mutations in the large disordered domain of APC may interfere with tumor suppressor activity. Insight in the underlying molecular events will be invaluable in the development of novel strategies to counter dysregulated Wnt signaling by APC mutations in cancer.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Cell Transformation, Neoplastic; Genes, APC; Genes, Tumor Suppressor; Humans; Models, Biological; Mutation, Missense; Neoplasms; Protein Folding; Protein Structure, Tertiary
PubMed: 21859464
DOI: 10.1186/1476-4598-10-101 -
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 -
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 -
World Journal of Gastroenterology Jun 2001To study the genetic alteration in ACF and to define the possibility that ACF may be a very early morphological lesion with molecular changes,and to explore the...
AIM
To study the genetic alteration in ACF and to define the possibility that ACF may be a very early morphological lesion with molecular changes,and to explore the relationship between ACF and colorectal adenoma even carcinoma.
METHODS
DNA from 35 CRC, 15 adenomas, 34 ACF and 10 normal mucus was isolated by means of microdissection. Direct gene sequencing of K-ras gene including codon 12, 13 and 61 as well as the mutation cluster region (MCR) of APC gene was performed.
RESULTS
K-ras gene mutation frequency in ACF, adenoma and carcinoma was 17.6% (6/34), 13.3% (2/15), and 14.3% (5/35) respectively, showing no difference (P > 0.05) in K-ras gene mutation among three pathologic procedures. The K-ras gene mutation in adenoma, carcinoma and 4 ACF restricted in codon 12 (GGT GAT), but the other 2 mutations from ACF located in codon 13 (GGC GAC). K-ras gene mutation was found more frequently in older patients and patients with polypoid cancer. No mutation in codon 61 was found in the three tissue types. Mutation rate of APC gene in adenoma and carcinoma was 22.9% (8/35) and 26.7% (4/15), which was higher than ACF (2.9%) (P <0.05). APC gene mutation in carcinoma was not correlated with age of patients, location, size and differentiation of tumor.
CONCLUSION
ACF might be a very early morphological lesion in the tumorogenesis of colorectal tumor. The morphological feature and gene mutation status was different in ACF and adenoma. ACF is possibly putative microadenoma that might be the precursor of adenoma. In addition, the development of a subgroup of colorectal carcinomas might undergo a way of normal epithelium ACF carcinomas .
Topics: Adenoma; Colorectal Neoplasms; DNA Mutational Analysis; Gene Frequency; Genes, APC; Genes, ras; Humans; Point Mutation
PubMed: 11819789
DOI: 10.3748/wjg.v7.i3.352 -
Gut Dec 1996Hepatoblastoma is a rare, rapidly progressive, usually fatal childhood malignancy, which if confined to the liver can be cured by radical surgical resection. An...
BACKGROUND
Hepatoblastoma is a rare, rapidly progressive, usually fatal childhood malignancy, which if confined to the liver can be cured by radical surgical resection. An association between hepatoblastoma and familial adenomatous polyposis (FAP), which is due to germline mutation of the APC (adenomatous polyposis coli) gene, has been confirmed, but correlation with site of APC mutation has not been studied.
AIM
To analyse the APC mutational spectrum in FAP families with hepatoblastoma as a possible basis to select kindreds for surveillance.
PATIENTS
Eight patients with hepatoblastoma in seven FAP kindreds were compared with 97 families with identified APC gene mutation in a large Registry.
METHODS
APC gene mutation was evaluated by RNase protection assay or in vitro synthesis protein assay. The chi 2 test and correlation were used for data analysis.
RESULTS
APC gene mutation was identified in all seven FAP kindreds in which an at risk member developed hepatoblastoma. A male predominance was noted (six of eight), similar to literature cases (18 of 25, p < 0.01. Mutations were restricted to codons 141 to 1230, but no significant difference in site of mutation between pedigrees with and without hepatoblastoma was identified.
CONCLUSIONS
Hepatoblastoma occurs primarily in boys in FAP kindreds and is associated with germline APC mutation in the 5' end of the gene. However, the site of APC mutation cannot be used to predict occurrence of this extracolonic cancer in FAP pedigrees.
Topics: Adenomatous Polyposis Coli; Adolescent; Child; Child, Preschool; DNA Mutational Analysis; Female; Genes, APC; Germ-Line Mutation; Hepatoblastoma; Humans; Infant; Liver Neoplasms; Male; Sex Factors
PubMed: 9038672
DOI: 10.1136/gut.39.6.867