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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 -
Proceedings of the National Academy of... Jan 2017The spectrum of genetic mutations differs among cancers in different organs, implying a cellular context-dependent effect for genetic aberrations. However, the extent to...
The spectrum of genetic mutations differs among cancers in different organs, implying a cellular context-dependent effect for genetic aberrations. However, the extent to which the cellular context affects the consequences of oncogenic mutations remains to be fully elucidated. We reprogrammed colon tumor cells in an Apc (adenomatous polyposis coli) mouse model, in which the loss of the Apc gene plays a critical role in tumor development and subsequently, established reprogrammed tumor cells (RTCs) that exhibit pluripotent stem cell (PSC)-like signatures of gene expression. We show that the majority of the genes in RTCs that were affected by Apc mutations did not overlap with the genes affected in the intestine. RTCs lacked pluripotency but exhibited an increased expression of Cdx2 and a differentiation propensity that was biased toward the trophectoderm cell lineage. Genetic rescue of the mutated Apc allele conferred pluripotency on RTCs and enabled their differentiation into various cell types in vivo. The redisruption of Apc in RTC-derived differentiated cells resulted in neoplastic growth that was exclusive to the intestine, but the majority of the intestinal lesions remained as pretumoral microadenomas. These results highlight the significant influence of cellular context on gene regulation, cellular plasticity, and cellular behavior in response to the loss of the Apc function. Our results also imply that the transition from microadenomas to macroscopic tumors is reprogrammable, which underscores the importance of epigenetic regulation on tumor promotion.
Topics: Adenomatous Polyposis Coli; Alleles; Animals; Cell Lineage; Cell Plasticity; Colonic Neoplasms; Epigenesis, Genetic; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Genes, APC; Intestinal Mucosa; Mice; Mutation; Pluripotent Stem Cells
PubMed: 28057861
DOI: 10.1073/pnas.1614197114 -
Cancer Science Jan 2007Colon cancer arises through different histological stages representing different genetic and epigenetic alterations. The Apc(Min/+) mouse has a point mutation at the Apc... (Review)
Review
Colon cancer arises through different histological stages representing different genetic and epigenetic alterations. The Apc(Min/+) mouse has a point mutation at the Apc gene, and it is considered to be a model for human familial adenomatous polyposis. Our previous studies have revealed the presence of a number of intramucosal microadenomas in the colons of Apc(Min/+) mice, in which only a few macroscopic tumors were recognized. These observations suggest that there are two distinct stages for colon carcinogenesis in Apc(Min/+) mouse, and the Apc(Min/+) mouse is regarded as a good model to study multistage colon carcinogenesis. A number of genes that modify intestinal tumorigenesis have been identified using Apc mutant mice combined with other mutant mice. It has become apparent that epigenetic modification strongly affects intestinal tumorigenesis in Apc(Min/+) mice. We herein describe the different stages of colon tumorigenesis and their modifiers, and discuss the possible application of Apc mutant mice in order to better understand the molecular mechanisms of multistage carcinogenesis in the large bowel of humans.
Topics: Animals; Colonic Neoplasms; Disease Models, Animal; Disease Progression; Epigenesis, Genetic; Genes, APC; Humans; Mice; Mice, Mutant Strains; Models, Biological; Mutation; Precancerous Conditions
PubMed: 17052257
DOI: 10.1111/j.1349-7006.2006.00348.x -
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 -
Pharmacology & Therapeutics Dec 2015The genetic and epigenetic alterations occurring during the course of multistage colorectal carcinogenesis have been extensively studied in the last few decades. One of... (Review)
Review
The genetic and epigenetic alterations occurring during the course of multistage colorectal carcinogenesis have been extensively studied in the last few decades. One of the most notable findings is that the great majority of colorectal cancers (>80%) have mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Loss of functional APC protein results in activation of canonical Wnt/β-catanin signaling and initiates intestinal carcinogenesis. Mutational inactivation of APC is the first genetic event, but colorectal cancer cells retain their dependency on constitutive Wnt signal activation even after accumulation of other genetic events. Accordingly, pharmacological blocking of Wnt signaling has been considered an attractive therapeutic approach for colorectal cancer. Several therapeutics targeting various molecular components of the Wnt signaling pathway, including porcupine, frizzled receptors and co-receptor, tankyrases, and cAMP response element binding protein (CREB)-binding protein (CBP), have been developed, and some of those are currently being evaluated in early-phase clinical trials. Traf2- and Nck-interacting protein kinase (TNIK) has been identified as a regulatory component of the T-cell factor-4 and β-catenin transcriptional complex independently by two research groups. TNIK regulates Wnt signaling in the most downstream part of the pathway, and its inhibition is expected to block the signal even in colorectal cancer cells with APC gene mutation. Here we discuss some of the TNIK inhibitors under preclinical development.
Topics: ATP-Binding Cassette Transporters; Colorectal Neoplasms; Genes, APC; Humans; Intracellular Signaling Peptides and Proteins; Protein Serine-Threonine Kinases; TNF Receptor-Associated Factor 2; Wnt Proteins; Wnt Signaling Pathway; beta Catenin
PubMed: 26542362
DOI: 10.1016/j.pharmthera.2015.10.009 -
Familial Cancer Jan 2022In addition to classic germline APC gene variants, APC mosaicism and deep intronic germline APC variants have also been reported to be causes of adenomatous polyposis....
In addition to classic germline APC gene variants, APC mosaicism and deep intronic germline APC variants have also been reported to be causes of adenomatous polyposis. In this study, we investigated 80 unexplained colorectal polyposis patients without germline pathogenic variants in known polyposis predisposing genes to detect mosaic and deep intronic APC variants. All patients developed more than 50 colorectal polyps, with adenomas being predominantly observed. To detect APC mosaicism, we performed next-generation sequencing (NGS) in leukocyte DNA. Furthermore, using Sanger sequencing, the cohort was screened for the following previously reported deep intronic pathogenic germline APC variants: c.1408 + 731C > T, p.(Gly471Serfs*55), c.1408 + 735A > T, p.(Gly471Serfs*55), c.1408 + 729A > G, p.(Gly471Serfs*55) and c.532-941G > A, p.(Phe178Argfs*22). We did not detect mosaic or intronic APC variants in the screened unexplained colorectal polyposis patients. The results of this study indicate that the deep intronic APC variants investigated in this study are not a cause of colorectal polyposis in this Dutch population. In addition, NGS did not detect any further mosaic variants in our cohort.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Colorectal Neoplasms; Genes, APC; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Mutation
PubMed: 33683519
DOI: 10.1007/s10689-021-00236-2 -
Proceedings of the National Academy of... Apr 1993The APC gene has been found to be mutated during the development of sporadic colorectal tumors as well as in the germ line of familial adenomatous polyposis patients. To...
The APC gene has been found to be mutated during the development of sporadic colorectal tumors as well as in the germ line of familial adenomatous polyposis patients. To facilitate the characterization of both normal and mutant APC protein, a series of monoclonal and polyclonal antibodies specific for the APC protein was produced. When lymphoblastoid cell lines derived from seven familial adenomatous polyposis patients with known mutations were analyzed by Western blot, an approximately 300-kDa protein corresponding to the predicted size of full-length APC was detected in all 7 cell lines. In addition, truncated APC proteins corresponding to the product of the known mutated alleles could be detected in 4 of the 7 lines. Similar analysis of 23 colon carcinoma and 9 adenoma cell lines revealed truncated proteins in 24 (75%) of the cell lines. Moreover, 26 (81%) of the colon tumor lines were totally devoid of the normal, full-length protein. In contrast, Western blot analysis of 40 cell lines derived from sporadic tumors of other organs detected only full-length APC. Immunohistochemical analysis of APC in normal colonic mucosa revealed cytoplasmic staining with more intense staining in the basolateral margins of the epithelial cell. This staining was markedly increased in the upper portions of the crypts, suggesting an increased level of expression with maturation. These studies provide some initial clues to the function of the cytoplasmic protein APC and demonstrate the feasibility of identifying APC mutations by direct analysis of the APC protein.
Topics: Adenoma; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Antibodies; Antibodies, Monoclonal; Base Sequence; Blotting, Western; Colon; Colonic Neoplasms; Colorectal Neoplasms; Female; Genes, APC; Humans; Immunohistochemistry; Intestinal Mucosa; Mice; Mice, Inbred Strains; Molecular Sequence Data; Mutation; Neoplasm Proteins; Oligodeoxyribonucleotides; Polymerase Chain Reaction; Tumor Cells, Cultured
PubMed: 8385345
DOI: 10.1073/pnas.90.7.2846 -
Genes Feb 2022Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary...
Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of and genes, showedmutation in , and genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of mutations with one case of double mutation in gene. In FAP family, we found a pathogenic mutation in gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband's mutation. Although correlative by its nature, the presence of a mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; BRCA1 Protein; BRCA2 Protein; Carcinoma, Pancreatic Ductal; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Genes, APC; Germ Cells; Hereditary Breast and Ovarian Cancer Syndrome; Humans; MutL Protein Homolog 1; Mutation; Pancreatic Neoplasms; Phenotype
PubMed: 35205366
DOI: 10.3390/genes13020321 -
The Journal of International Medical... Aug 2022Primitive neuroectodermal tumor (PNET) of the lung is rare in adults, and treatment options vary. We herein describe the disease course and follow-up of PNET in an... (Review)
Review
Primitive neuroectodermal tumor (PNET) of the lung is rare in adults, and treatment options vary. We herein describe the disease course and follow-up of PNET in an adult. A 27-year-old man was admitted to our hospital because of cough and headache, and whole-exome sequencing revealed positive expression of the fusion gene and amplification of the gene. Although the patient received multidisciplinary treatment including chemotherapy regimens of etoposide plus cisplatin; focal radiotherapy focusing on the cerebrum, lung, and kidneys; and a subsequent palliative gastrointestinal operation, he eventually died of multiple organ functional failure. His overall survival period was 18 months, and his progression-free survival period was 4 months. During the treatment, the patient showed remarkable sensitivity to radiotherapy. In conclusion, PNET of the lung in adult patients is extremely rare, and the prognosis is very poor. Involvement of a multidisciplinary team in the development of personalized therapeutic strategies is essential. This patient with gene amplification showed excellent sensitivity to radiotherapy for intrapulmonary and intracranial lesions, suggesting that gene amplification may be related to radiotherapy sensitivity. However, further clinical research is needed.
Topics: Adult; Disease Progression; Gene Amplification; Genes, APC; Humans; Male; Neuroectodermal Tumors, Primitive; Prognosis
PubMed: 35983861
DOI: 10.1177/03000605221118704 -
Biochimica Et Biophysica Acta Feb 2000The wnt signal transduction pathway is involved in many differentiation events during embryonic development and can lead to tumor formation after aberrant activation of... (Review)
Review
The wnt signal transduction pathway is involved in many differentiation events during embryonic development and can lead to tumor formation after aberrant activation of its components. The cytoplasmic component beta-catenin is central to the transmission of wnt signals to the nucleus: in the absence of wnts beta-catenin is constitutively degraded in proteasomes, whereas in the presence of wnts beta-catenin is stabilized and associates with HMG box transcription factors of the LEF/TCF family. In tumors, beta-catenin degradation is blocked by mutations of the tumor suppressor gene APC (adenomatous polyposis coli), or of beta-catenin itself. As a consequence, constitutive TCF/beta-catenin complexes are formed and activate oncogenic target genes. This review discusses the mechanisms that silence the pathway in cells that do not receive a wnt signal and goes on to describe the regulatory steps involved in the activation of the pathway.
Topics: Adaptor Proteins, Signal Transducing; Animals; Arabidopsis Proteins; Axin Protein; Cytoskeletal Proteins; Dishevelled Proteins; Genes, APC; Humans; Mice; Mice, Mutant Strains; Phosphoproteins; Protein Kinases; Proteins; Proto-Oncogene Proteins; Repressor Proteins; Signal Transduction; Trans-Activators; Transcriptional Activation; Tumor Cells, Cultured; Wnt Proteins; Zebrafish Proteins; beta Catenin
PubMed: 10656974
DOI: 10.1016/s0167-4889(99)00158-5