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Medicina (Kaunas, Lithuania) Sep 2019Familial adenomatous polyposis is one of the -associated polyposis conditions described as genetically predetermined colorectal polyposis syndrome with a variety of...
Familial adenomatous polyposis is one of the -associated polyposis conditions described as genetically predetermined colorectal polyposis syndrome with a variety of symptoms. The purpose of this study was to determine sequence variants of the gene in patients with familial adenomatous polyposis (FAP) phenotype and positive or negative family history. Eight families with defined criteria of adenomatous polyposis underwent molecular genetic testing. Coding regions and flanking intron regions of the gene were analyzed by Sanger sequencing. Eight allelic variants of the gene coding sequence were detected. All allelic variants of the gene were predicted to be pathogenic based on criteria according to the "Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology" (2015), four of them c.1586_1587insAT, c.2336delT, c.3066_3067insGA, and c.4303_4304insC, were considered novel. The timely molecular genetic analysis of germline variants and standardized interpretation of the pathogenicity of novel allelic variants has a high impact on choice for treatment, cancer prevention, and family genetic counseling.
Topics: Adenomatous Polyposis Coli; Adult; Female; Genes, APC; Genetic Variation; Germ-Line Mutation; Humans; Latvia; Male; Middle Aged; Pedigree; Sequence Analysis, DNA
PubMed: 31547110
DOI: 10.3390/medicina55100612 -
PloS One 2020Computational algorithms are often used to assess pathogenicity of Variants of Uncertain Significance (VUS) that are found in disease-associated genes. Most...
Computational algorithms are often used to assess pathogenicity of Variants of Uncertain Significance (VUS) that are found in disease-associated genes. Most computational methods include analysis of protein multiple sequence alignments (PMSA), assessing interspecies variation. Careful validation of PMSA-based methods has been done for relatively few genes, partially because creation of curated PMSAs is labor-intensive. We assessed how PMSA-based computational tools predict the effects of the missense changes in the APC gene, in which pathogenic variants cause Familial Adenomatous Polyposis. Most Pathogenic or Likely Pathogenic APC variants are protein-truncating changes. However, public databases now contain thousands of variants reported as missense. We created a curated APC PMSA that contained >3 substitutions/site, which is large enough for statistically robust in silico analysis. The creation of the PMSA was not easily automated, requiring significant querying and computational analysis of protein and genome sequences. Of 1924 missense APC variants in the NCBI ClinVar database, 1800 (93.5%) are reported as VUS. All but two missense variants listed as P/LP occur at canonical splice or Exonic Splice Enhancer sites. Pathogenicity predictions by five computational tools (Align-GVGD, SIFT, PolyPhen2, MAPP, REVEL) differed widely in their predictions of Pathogenic/Likely Pathogenic (range 17.5-75.0%) and Benign/Likely Benign (range 25.0-82.5%) for APC missense variants in ClinVar. When applied to 21 missense variants reported in ClinVar and securely classified as Benign, the five methods ranged in accuracy from 76.2-100%. Computational PMSA-based methods can be an excellent classifier for variants of some hereditary cancer genes. However, there may be characteristics of the APC gene and protein that confound the results of in silico algorithms. A systematic study of these features could greatly improve the automation of alignment-based techniques and the use of predictive algorithms in hereditary cancer genes.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Algorithms; Amino Acid Sequence; Computational Biology; Computer Simulation; Databases, Protein; Enhancer Elements, Genetic; Evolution, Molecular; Exons; Genes, APC; Genetic Variation; Humans; Mutation, Missense; Phylogeny; Protein Isoforms; RNA Splice Sites; Sequence Alignment
PubMed: 32750050
DOI: 10.1371/journal.pone.0233673 -
Philosophical Transactions of the Royal... Jun 1998The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regulate the transition between... (Review)
Review
The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regulate the transition between normal and neoplastic growth. A gene of central importance in mediating these alternative patterns of growth is Apc, the mouse homologue of the human adenomatous polyposis coli (APC) gene. When adenomas form in the Min mouse, both copies of the Apc gene must be inactivated. One copy is mutated by the nonsense Apc allele carried in heterozygous form in this strain. The other copy can be silenced by any of several mechanisms. These range from loss of the homologue bearing the wild-type Apc allele; to interstitial deletions surrounding the wild-type allele; to intragenic mutation, including nonsense alleles; and finally, to a reduction in expression of the locus, perhaps owing to mutation in a regulatory locus. Each of these proposed mechanisms may constitute a two-hit genetic process as initially posited by Knudson; however, apparently the two hits could involve either a single locus or two loci. The kinetic order for the transition to adenoma may be still higher than two, if polyclonal adenomas require stronger interactions than passive fusion. The severity of the intestinal neoplastic phenotype of the Min mouse is strongly dependent upon loci other than Apc. One of these, Mom1, has now been rigorously identified at the molecular level as encoding an active resistance conferred by a secretory phospholipase. Mom1 acts locally within a crypt lineage, not systemically. Within the crypt lineage, however, its action seems to be non-autonomous: when tumours arise in Mom1 heterozygotes, the active resistance allele is maintained in the tumour (MOH or maintenance of heterozygosity). Indeed, the secretory phospholipase is synthesized by post-mitotic Paneth cells, not by the proliferative cells that presumably generate the tumour. An analysis of autonomy of modifier gene action in chimeric mice deserves detailed attention both to the number of genetic factors for which an animal is chimeric and to the clonal structure of the tissue in question. Beyond Mom1, other loci can strongly modify the severity of the Min phenotype. An emergent challenge is to find ways to identify the full set of genes that interact with the intestinal cancer predisposition of the Min mouse strain. With such a set, one can then work, using contemporary mouse genetics, to identify the molecular, cellular and organismal strategies that integrate their functions. Finally, with appropriately phenotyped human families, one can investigate by a candidate approach which modifying factors influence the epidemiology of human colon cancer. Even if a candidate modifier does not explain any of the genetic epidemiology of colon cancer in human populations, modifier activities discovered by mouse genetics provide candidates for chemopreventive and/or therapeutic modalities in the human.
Topics: Adenoma; Adenomatous Polyposis Coli; Animals; Chromosome Deletion; Genes, APC; Genes, Regulator; Humans; Intestinal Mucosa; Intestinal Neoplasms; Mice
PubMed: 9684289
DOI: 10.1098/rstb.1998.0256 -
Mutation Research Nov 2010With improvements to DNA sequencing technologies, including the advent of massively parallel sequencing to perform "deep sequencing" of tissue samples, the ability to... (Review)
Review
With improvements to DNA sequencing technologies, including the advent of massively parallel sequencing to perform "deep sequencing" of tissue samples, the ability to determine all of the nucleotide variations in a tumor becomes a possibility. This information will allow us to more fully understand the heterogeneity within each tumor, as well as to identify novel genes involved in cancer development. However, the new challenge that arises will be to interpret the pathogenic significance of each genetic variant. The enormity and complexity of this challenge can be demonstrated by focusing on just the genes involved in the hereditary colon cancer syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis coli (HNPCC). The genes responsible for each disease were identified almost two decades ago -APC for FAP and the MMR genes for HNPCC - and a large number of germline variations have been identified in these genes in hereditary cancer patients. However, relating the effect of an individual genotype to phenotype is not always straightforward. This review focuses on the roles of the APC and MMR genes in tumor development and the work that has been done to relate different variants in each gene to functional aberrations and ultimately tumorigenesis. By considering the work that has already been done on two well-defined diseases with clear genetic associations, one can begin to understand the challenges that lie ahead as new genes and gene mutations are discovered through tumor sequencing.
Topics: Adenomatous Polyposis Coli; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Genes, APC; Genetic Variation; Genotype; Humans; Mutation; Phenotype
PubMed: 19766128
DOI: 10.1016/j.mrfmmm.2009.09.004 -
The Journal of Biological Chemistry 2021Hyperactivation of Wnt/β-catenin (canonical) signaling in colorectal cancers (CRCs) was identified in the 1990s. Most CRC patients have mutations in genes that encode... (Review)
Review
Hyperactivation of Wnt/β-catenin (canonical) signaling in colorectal cancers (CRCs) was identified in the 1990s. Most CRC patients have mutations in genes that encode components of the Wnt pathway. Inactivating mutations in the adenomatous polyposis coli (APC) gene, which encodes a protein necessary for β-catenin degradation, are by far the most prevalent. Other Wnt signaling components are mutated in a smaller proportion of CRCs; these include a FZD-specific ubiquitin E3 ligase known as ring finger protein 43 that removes FZDs from the cell membrane. Our understanding of the genetic and epigenetic landscape of CRC has grown exponentially because of contributions from high-throughput sequencing projects such as The Cancer Genome Atlas. Despite this, no Wnt modulators have been successfully developed for CRC-targeted therapies. In this review, we will focus on the Wnt receptor complex, and speculate on recent discoveries about ring finger protein 43regulating Wnt receptors in CRCs. We then review the current debate on a new APC-Wnt receptor interaction model with therapeutic implications.
Topics: Animals; Colonic Neoplasms; Genes, APC; Humans; Low Density Lipoprotein Receptor-Related Protein-6; Mutation; Receptors, Wnt; Signal Transduction; beta Catenin
PubMed: 34000297
DOI: 10.1016/j.jbc.2021.100782 -
Modern Pathology : An Official Journal... Mar 2018Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway...
Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear β-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of β-catenin and truncating APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear β-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P=0.0001). However, unlike the conventional pathway, truncating APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations common in conventional adenomas.
Topics: Adenoma; Carcinogenesis; Carcinoma; Colonic Polyps; Colorectal Neoplasms; Genes, APC; Humans; Microsatellite Instability; Mutation; Wnt Signaling Pathway
PubMed: 29148535
DOI: 10.1038/modpathol.2017.150 -
Cell Mar 1998
Review
Topics: Animals; Colonic Neoplasms; Disease Progression; Genes, APC; Genes, DCC; Genes, Tumor Suppressor; Humans; Mice; Signal Transduction; Transforming Growth Factor beta
PubMed: 9506511
DOI: 10.1016/s0092-8674(00)81124-1 -
Genes Dec 2022Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by a germline mutation in the adenomatous polyposis coli () gene. Patients with FAP develop... (Review)
Review
Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by a germline mutation in the adenomatous polyposis coli () gene. Patients with FAP develop up to thousands of colorectal adenomas as well as lesions in the upper GI tract. In FAP, the upper digestive lesions include gastric fundic gland polyps (FGPs), antrum adenomas, duodenal or small intestinal adenomas, and carcinoma. Patients, after colectomy, are still at significant risk for extracolonic malignancies. Advances in endoscope resolution and optical enhancement technologies allow endoscopists to provide assessments of benign and malignant polyps. For this reason, in the past decades, endoscopic resection techniques have become the first line of treatment in patients with polyps in the upper GI, whereby polyps and even early cancers can be successfully cured. In FAP patients, endoscopic ampullectomy appears to be a safe and effective way of treating patients with ampullary tumors. According to current indications, endoscopic retrograde cholangiopancreatography (ERCP) and stenting of the main pancreatic duct follow ampullectomy.
Topics: Humans; Adenomatous Polyposis Coli; Polyps; Genes, APC; Adenoma; Upper Gastrointestinal Tract
PubMed: 36553595
DOI: 10.3390/genes13122329 -
Journal of Medical Genetics Nov 2023While constitutional pathogenic variants in the gene cause familial adenomatous polyposis, c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate... (Meta-Analysis)
Meta-Analysis
While constitutional pathogenic variants in the gene cause familial adenomatous polyposis, c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on the I1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of the I1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals.
Topics: Humans; Genetic Predisposition to Disease; Adenomatous Polyposis Coli; Colorectal Neoplasms; Genes, APC; Risk Factors; Jews
PubMed: 37076288
DOI: 10.1136/jmg-2022-108984 -
Scientific Reports Dec 2021The tumor suppressor gene adenomatous polyposis coli (APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance...
The tumor suppressor gene adenomatous polyposis coli (APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance of aberrant regulation of intracellular WNT signaling in CRC development. Recent studies have found that early-onset CRC exhibits an increased proportion of tumors lacking an APC mutation. We set out to identify mechanisms underlying APC mutation-negative (APC) CRCs. We analyzed data from The Cancer Genome Atlas to compare clinical phenotypes, somatic mutations, copy number variations, gene fusions, RNA expression, and DNA methylation profiles between APC and APC mutation-positive (APC) microsatellite stable CRCs. Transcriptionally, APC CRCs clustered into two approximately equal groups. Cluster One was associated with enhanced mitochondrial activation. Cluster Two was strikingly associated with genetic inactivation or decreased RNA expression of the WNT antagonist RNF43, increased expression of the WNT agonist RSPO3, activating mutation of BRAF, or increased methylation and decreased expression of AXIN2. APC CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and RSPO3. APC CRCs comprise two groups of tumors characterized by enhanced mitochondrial activation or increased sensitivity to extracellular WNT, suggesting that they could be respectively susceptible to inhibition of these pathways.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Colorectal Neoplasms; DNA Copy Number Variations; DNA Methylation; Disease Progression; Genes, APC; Humans; Microsatellite Instability; Microsatellite Repeats; Mutation; Neoplastic Processes; Phenotype; Promoter Regions, Genetic; Wnt Signaling Pathway
PubMed: 34873211
DOI: 10.1038/s41598-021-02806-x