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Asian Pacific Journal of Cancer... May 2022Familial adenomatous polyposis (FAP) is a hereditary disorder primarily caused by germline mutations in the APC gene. The most common type of mutation in the APC gene is...
BACKGROUND
Familial adenomatous polyposis (FAP) is a hereditary disorder primarily caused by germline mutations in the APC gene. The most common type of mutation in the APC gene is point mutation, while deletion mutation is much less frequent. The current study was conducted to investigate the mutation spectrum of the APC gene in Vietnamese FAP patients.
METHODS
Patients with the clinical diagnosis of FAP on colorectal endoscopy were screened for mutations in the APC gene using Sanger sequencing. Those who exhibited no point mutation subsequently underwent MLPA assay to detect deletion and duplication mutations. Besides, the relatives of patients with mutated APC genes were recruited for detecting carrier status.
RESULTS
Sixty-three patients with clinical colorectal polyposis were recruited. Mutations in the APC gene were detected in 26/63 patients (41.3%). Genetic analysis of 105 asymptomatic relatives of these 26 patients found mutations in the APC gene in 55 individuals (52.4%).
CONCLUSION
We successfully established the APC gene mutation spectrum in Vietnamese FAP patients for the first time. Of importance, we discovered two novel point mutations in the APC gene. The high prevalence of carrier status in asymptomatic family members of patients with mutation emphasizes the crucial role of appropriate genetic screening for early diagnosis, surveillance, and preventive measurements.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Asian People; Genes, APC; Humans; Mutation; Point Mutation; Vietnam
PubMed: 35633533
DOI: 10.31557/APJCP.2022.23.5.1517 -
Oncology Reviews Feb 2021Inactivating mutations of the () gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC),...
Inactivating mutations of the () gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests mutations are also found in gastric, breast and other cancers. The gene, located on chromosome 5q, is responsible for negatively regulating the b-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3b, and CK1. In the event of an mutation, b-catenin accumulates, translocates to the cell nucleus and increases the transcription of Wnt target genes that have carcinogenic consequences in gastrointestinal epithelial stem cells. A literature review was conducted to highlight carcinogenesis related to mutations, as well as preclinical and clinical studies for potential therapies that target steps in inflammatory pathways, including IL-6 transduction, and Wnt pathway signaling regulation. Although a range of molecular targets have been explored in murine models, relatively few pharmacological agents have led to substantial increases in survival for patients with colorectal cancer clinically. This article reviews a range of molecular targets that may be efficacious targets for tumors with mutations.
PubMed: 34267890
DOI: 10.4081/oncol.2021.534 -
Gastroenterology Jan 2022Inactivation of the Apc gene is a critical early event in the development of sporadic colorectal cancer (CRC). Expression of serine-threonine kinase receptor-associated...
BACKGROUND & AIMS
Inactivation of the Apc gene is a critical early event in the development of sporadic colorectal cancer (CRC). Expression of serine-threonine kinase receptor-associated protein (STRAP) is elevated in CRCs and is associated with poor outcomes. We investigated the role of STRAP in Apc mutation-induced intestinal tumor initiation and progression.
METHODS
We generated Strap intestinal epithelial knockout mice (Strap) by crossing mice containing floxed alleles of Strap (Strap) with Villin-Cre mice. Then we generated Apc;Strap;Vill-Cre (Apc;Strap) mice for RNA-sequencing analyses to determine the mechanism of function of STRAP. We used human colon cancer cell lines (DLD1, SW480, and HT29) and human and mouse colon tumor-derived organoids for STRAP knockdown and knockout and overexpression experiments.
RESULTS
Strap deficiency extended the average survival of Apc mice by 80 days and decreased the formation of intestinal adenomas. Expression profiling revealed that the intestinal stem cell signature, the Wnt/β-catenin signaling, and the MEK/ERK pathway are down-regulated in Strap-deficient adenomas and intestinal organoids. Correlation studies suggest that these STRAP-associated oncogenic signatures are conserved across murine and human colon cancer. STRAP associates with MEK1/2, promotes binding between MEK1/2 and ERK1/2, and subsequently induces the phosphorylation of ERK1/2. STRAP activated Wnt/β-catenin signaling through MEK/ERK-induced phosphorylation of LRP6. STRAP was identified as a target of mutated Apc and Wnt/β-catenin signaling as chromatin immunoprecipitation and luciferase assays revealed putative binding sites of the β-catenin/TCF4 complex on the Strap promoter.
CONCLUSIONS
STRAP is a target of, and is required in, Apc mutation/deletion-induced intestinal tumorigenesis through a novel feed-forward STRAP/MEK-ERK/Wnt-β-catenin/STRAP regulatory axis.
Topics: Animals; Cell Proliferation; Cell Transformation, Neoplastic; Colorectal Neoplasms; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Genes, APC; HT29 Cells; Humans; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase Kinases; Mutation; RNA-Binding Proteins; Tumor Cells, Cultured; Wnt Signaling Pathway; Mice
PubMed: 34520730
DOI: 10.1053/j.gastro.2021.09.010 -
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 -
Oncotarget 2022Tumors are composed of the tumor cells and the surrounding microenvironment. Both are closely interwoven and interact by a complex and multifaceted cross-talk which...
Tumors are composed of the tumor cells and the surrounding microenvironment. Both are closely interwoven and interact by a complex and multifaceted cross-talk which plays an integral part in tumor initiation, growth, and progression. has been shown to be a potent suppressor of colorectal cancer and ubiquitous inactivation of strongly promoted colorectal carcinogenesis in mice and in a chemically-induced colorectal cancer model. The aim of the present study was to investigate whether 's tumor suppressive function is tumor-cell-autonomous. Expression of in cancer cells had no effect on both colon tumor development in mice and formation of xenograft tumors. In contrast, DRO1/CCDC80 loss in the microenvironment strongly increased tumor growth in xenograft models, inhibited cancer cell apoptosis, and promoted intestinal epithelial cell migration. Moreover, stromal inactivation facilitated formation of intestinal epithelial organoids. Expression analyses showed to be significantly down-regulated in murine gastric cancer associated fibroblasts, in colon tumor primary stromal cells and in microdissected stroma from human colorectal cancer compared to normal, non-tumor stroma. Our results demonstrate epithelial derived DRO1/CCDC80 to be dispensable for intestinal tissue homeostasis and identify Dro1/Ccdc80 as tumor suppressor in the tumor microenvironment.
Topics: Animals; Apoptosis; Carcinogenesis; Colonic Neoplasms; Extracellular Matrix Proteins; Genes, Tumor Suppressor; Humans; Mice; Tumor Microenvironment
PubMed: 35422964
DOI: 10.18632/oncotarget.28084 -
BMC Gastroenterology Mar 2023APC (adenomatous polyposis coli) gene mutation is a central initialization in colon cancer tumorigenesis. However, the connection between APC gene mutation and...
OBJECTIVE
APC (adenomatous polyposis coli) gene mutation is a central initialization in colon cancer tumorigenesis. However, the connection between APC gene mutation and immunotherapy efficacy for colon cancer remains unknown. This study aimed to explore the impact of APC mutation on immunotherapy efficacy for colon cancer.
METHODS
Colon cancer data from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC) were used for the combined analysis. Survival analysis was performed to evaluate the association between APC mutation and immunotherapy efficacy in colon cancer patients. The expressions of immune check point molecules, tumor mutation burden (TMB), CpG methylation level, tumor purity (TP), microsatellite instability (MSI) status and tumor-infiltrating lymphocyte (TIL) in the two APC status were compared to evaluate the associations between APC mutation and immunotherapy efficacy indicators. Gene set enrichment analysis (GSEA) was performed to identify signaling pathways related to APC mutation.
RESULTS
APC was the most frequently mutated gene in colon cancer. The survival analysis demonstrated that APC mutation was correlated with a worse immunotherapy outcome. APC mutation was associated with lower TMB, lower expression of immune check point molecules (PD-1/PD-L1/PD-L2), higher TP, lower MSI-High proportion and less CD8 + T cells and follicular helper T cells infiltration. GSEA indicated that APC mutation up-regulated mismatch repair pathway, which may play a negative role in evoking an antitumor immune response.
CONCLUSION
APC mutation is associated with worse immunotherapy outcome and inhibition of antitumor immunity. It can be used as a negative biomarker to predict immunotherapy response.
Topics: Humans; Adenomatous Polyposis Coli; Biomarkers, Tumor; Colonic Neoplasms; Immunotherapy; Microsatellite Instability; Mutation
PubMed: 36977982
DOI: 10.1186/s12876-023-02725-3 -
Middle East Journal of Digestive... Jul 2022: With a global prevalence of about 10%, gastric cancer is among the most prevalent cancers. Currently, there has been an ongoing trend toward investigating genetic... (Review)
Review
: With a global prevalence of about 10%, gastric cancer is among the most prevalent cancers. Currently, there has been an ongoing trend toward investigating genetic disruptions in different cancers because they can be used as a target-specific therapy. We aimed to systemically review some gene expression patterns in gastric cancer. : The current systematic review was designed and executed in 2020. Scopus, PubMed, Cochrane Library, Google Scholar, web of knowledge, and Science Direct were searched for relevant studies. A manual search of articles (hand searching), reference exploring, checking for grey literature, and seeking expert opinion were also done. : In this review, 65 studies were included, and the expression pattern of HER2/ ERBB2, ER1/Erb1/EGFR, PIK3CA, APC, KRAS, ARID1A, TP53, FGFR2 and MET was investigated. TP53, APC, KRAS, and PIK3CA mutation cumulative frequency were 24.8 (I=95.05, Q value=525.53, df=26, <0.001), 7.2 (I=89.79, Q value=48.99, df=5, <0.001), 7.8 (I=93.60, Q value=140.71, df=9, =0.001) and 8.6 (I=80.78, Q value=525.53, df=9, <0.001) percent, respectively. Overexpression was investigated for HER1/ Erb1/EGFR, PIK3CA, APC, KRAS, ARID1A, TP53, CCND1, FGFR2, MET and MYC. The frequency of TP53 and HER2/ERBB2 were 43.1 (I=84.06, Q value=58.09, df=9, <0.001) and 20.8 (I=93.61, Q value=234.89, df=15, <0.001) percent, respectively. : More research is encouraged to investigate the genes for which we could not perform a meta-analysis.
PubMed: 36619267
DOI: 10.34172/mejdd.2022.292 -
Cancer Research and Treatment Oct 2023Loss-of-function mutations in the adenomatous polyposis coli (APC) gene are common in metastatic colorectal cancer (mCRC). However, the characteristic of APC specific...
PURPOSE
Loss-of-function mutations in the adenomatous polyposis coli (APC) gene are common in metastatic colorectal cancer (mCRC). However, the characteristic of APC specific mutations in mCRC is poorly understood. Here, we explored the clinical and molecular characteristics of N-terminal and C-terminal side APC mutations in Chinese patients with mCRC.
MATERIALS AND METHODS
Hybrid capture-based next-generation sequencing was performed on tumor tissues from 275 mCRC pati-ents to detect mutations in 639 tumor-associated genes. The prognostic value and gene-pathway difference between APC specific mutations in mCRC patients were analyzed.
RESULTS
APC mutations were highly clustered, accounting for 73% of all mCRC patients, and most of them were truncating mutations. The tumor mutation burden of the N-terminal side APC mutations group (n=76) was significantly lower than that of the C-terminal side group (n=123) (p < 0.001), further confirmed by the public database. Survival analysis showed that mCRC patients with N-terminus side APC mutations had longer overall survival than C-terminus side. Tumor gene pathway analysis showed that gene mutations in the RTK/RAS, Wnt and transforming growth factor β signaling pathways of the C-terminal group were significantly higher than those of the N-terminal group (p < 0.05). Additionally, KRAS, AMER1, TGFBR2, and ARID1A driver mutations were more common in patients with C-terminal side APC mutations.
CONCLUSION
APC specific mutations have potential function as mCRC prognostic biomarkers. There are obvious differences in the gene mutation patterns between the C-terminus and N-terminus APC mutations group, which may have certain guiding significance for the subsequent precise treatment of mCRC.
Topics: Humans; Prognosis; Colorectal Neoplasms; Adenomatous Polyposis Coli; Mutation; Colonic Neoplasms; Rectal Neoplasms
PubMed: 37114476
DOI: 10.4143/crt.2023.415 -
Cancer Science Dec 2023Familial adenomatous polyposis (FAP) patients develop various life-threatening extracolonic comorbidities that appear individually or within a family. This diversity can...
Familial adenomatous polyposis (FAP) patients develop various life-threatening extracolonic comorbidities that appear individually or within a family. This diversity can be explained by the localization of the adenomatous polyposis coli (APC) variant, but few reports provide definitive findings about genotype-phenotype correlations. Therefore, we investigated FAP patients and the association between the severe phenotypes and APC variants. Of 247 FAP patients, 126 patients from 85 families identified to have APC germline variant sites were extracted. These sites were divided into six groups (Regions A to F), and the frequency of severe comorbidities was compared among the patient phenotypes. Of the 126 patients, the proportions of patients with desmoid tumor stage ≥III, number of FGPs ≥1000, multiple gastric neoplasms, gastric neoplasm with high-grade dysplasia, and Spigelman stage ≥III were 3%, 16%, 21%, 12%, and 41%, respectively, while the corresponding rates were 30%, 50%, 70%, 50%, and 80% in patients with Region E (codons 1398-1580) variants. These latter rates were significantly higher than those for patients with variants in other regions. Moreover, the proportion of patients with all three indicators (desmoid tumor stage ≥III, number of FGPs ≥1000, and Spigelman stage ≥III) was 20% for those with variants in Region E and 0% for those with variants in other regions. Variants in Region E indicate aggressive phenotypes, and more intensive management is required.
Topics: Humans; Genes, APC; Fibromatosis, Aggressive; Genotype; Adenomatous Polyposis Coli; Phenotype; Stomach Neoplasms; Genetic Association Studies; Mutation
PubMed: 37798255
DOI: 10.1111/cas.15945 -
International Journal of Biological... Dec 2022The anaphase promoting complex/cyclosome (APC/C) is a large multi-subunit complex, regulating plant development and cell cycle. In plants, the APC/C gene family has been...
The anaphase promoting complex/cyclosome (APC/C) is a large multi-subunit complex, regulating plant development and cell cycle. In plants, the APC/C gene family has been identified in Arabidopsis, rice, and maize. The APC/Cs in rose has not yet been reported. In this study, a total of 19 APC/C genes were identified in rose. Furthermore, we also investigated phylogenetic relationships, chromosomal distribution, gene structure, motif analysis, promoter sequence analysis and expression pattern of RhAPC/C genes. Synteny analysis indicated that AtAPC/Cs and RhAPC/Cs show a high degree of conservation. RhAPC/C promoters contains numerous cis-elements involved in plant morphogenesis, hormone response and stress response. Based on the transcription of RhAPC/Cs in different tissues and developmental stages, it appears that RhAPC/Cs may play a variety of roles in rose growth and development. RhAPC/Cs have limitations in the time and space during which they respond to hormones and abiotic stress. RhAPC5, RhAPC11d, RhAPC13a and RhAPC13c may play a role in rose responding to abiotic stress. The expression of RhAPC10 was altered by infection with fungal pathogen. Our study will serve as a basis for determining the functional role of APC/C genes in roses and help future research on woody plants.
Topics: Anaphase-Promoting Complex-Cyclosome; Phylogeny; Rosa; Arabidopsis; Cell Cycle; Plants
PubMed: 36372105
DOI: 10.1016/j.ijbiomac.2022.11.085