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Cellular Signalling Dec 2022Molecular alterations in oncogenes and tumor suppressors in various signaling pathways are basis for personalized therapy in cancer. Periampullary carcinoma behaves... (Review)
Review
Molecular alterations in oncogenes and tumor suppressors in various signaling pathways are basis for personalized therapy in cancer. Periampullary carcinoma behaves differently from pancreatic carcinoma both in prognosis and outcome, therefore it needs special attention. Pancreatic cancer have higher incidence of nodal spread and perineural &lymphovascular invasion suggesting it biologically more aggressive tumor compared to periampullary cancer. Since PAC tumors consist of heterogenous tissue of origin, they might contain different mutations in tumor associated genes and other changes in tissue composition among different subgroups clubbed together. Significant progress has been made in understanding the molecular nature of PAC in the previous two decades, and a large number of mutations and other genetic changes have been identified as being responsible for the disease. This review article targets to collate and discuss the molecular evolution of PAC and their implication in its outcome. As per literature, mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and Wnt signaling are the most common pathways involved in PAC. Mutations in KRAS, TP53, CTNNB1, SMAD4 and APC genes were the most frequently reported. I-subtype resembles colorectal cancer while the morphology of PB-type shows close resemblance to pancreatic tumors. The frequency of driver gene mutations is higher in I-type compared to PB-type of PAC indicating I-type to be genetically more unstable. The genetic landscape of PAC obtained from WES data highlighted PI3/AKT pathway to be a primary target in I-type and RAS/RAF in PB-type.
PubMed: 36096460
DOI: 10.1016/j.cellsig.2022.110461 -
Molecular Genetics and Genomics : MGG Sep 2023Speckle-Type Poz Protein (SPOP) involved in the regulation of proteasome-mediated degradation of several oncoproteins, resulting in cancer initiation and progression....
Speckle-Type Poz Protein (SPOP) involved in the regulation of proteasome-mediated degradation of several oncoproteins, resulting in cancer initiation and progression. Mutations in Adenomatous Polyposis Coli (APC) gene is reported in most sporadic and hereditary colorectal cancer (CRC). Identifying the cellular changes involved in carcinogenesis when APC is mutated is an important issue that needs attention. The tumor suppressive function of SPOP and APC has long been a major focus in the research field of colorectal cancer. However, the clinical significance of SPOP and APC gene alteration in CRC has not been established to date. Mutational analysis was performed by single-strand conformational polymorphism followed by Sanger sequencing, methylation status by methylation-specific PCR, and protein expression by immunohistochemistry on 142 tumor tissues along with their adjacent non-cancerous specimens. The overall survival (OS) and recurrence free survival (RFS) were estimated by Kaplan-Meier Curve. Mutation rates of APC and SPOP gene were 2.8% and 11.9% while that of promoter hypermethylation were 37% and 47%, respectively. The grade of differentiation and Lymph node metastasis were significantly correlated with APC methylation pattern (p ≤ 0.05). The down regulation of APC was more often seen in colonic cancer compared to rectal cancer (p = 0.07) and more commonly in T3-4 depth of invasion (p = 0.07) and in patients without lymphovascular and perineural invasion (p = 0.007, p = 0.08 respectively). The median overall survival and recurrence free survival (RFS) was 67 & 36 months while 3-yr and 5-yr OS and RFS were 61.1% & 56.4% and 49.2% & 44.8%, respectively. APC promoter methylation had a better overall survival (p = 0.035) while loss of SPOP expression had a worse survival (p = 0.09). Our findings reveal high percentage of SPOP gene mutations in CRC. A significant link is found between promoter hyper methylation and protein expression in all mutant cases of APC and SPOP, suggesting that both genes may be associated in the development of colorectal cancer in people of Indian decent. Hypermethylation of APC gene and loss of SPOP expression have shown an association with disease prognosis and could be further studied looking at its potential role in planning adjuvant treatment in CRC patients.
Topics: Humans; Genes, APC; Clinical Relevance; Colorectal Neoplasms; Adenomatous Polyposis Coli; Transcription Factors; DNA Methylation
PubMed: 37289229
DOI: 10.1007/s00438-023-02029-x -
Frontiers in Genetics 2023Colorectal cancer is a complex disease resulting from the interaction of genetics, epigenetics, and environmental factors. DNA methylation is frequently found in tumor... (Review)
Review
Colorectal cancer is a complex disease resulting from the interaction of genetics, epigenetics, and environmental factors. DNA methylation is frequently found in tumor suppressor genes to promote cancer development. Several factors are associated with changes in the DNA methylation pattern, and recently, the gastrointestinal microbiota could be associated with this epigenetic change. The predominant phyla in gut microbiota are Firmicutes and Bacteroidetes; however, an enrichment of , , and , among others, has been reported in colorectal cancer, although the composition could be influenced by several factors, including diet, age, sex, and cancer stage, a gram-negative anaerobic bacillus, is mainly associated with colorectal cancer patients positive for the CpG island methylator phenotype, although hypermethylation in genes such as , , , , , , and has also been described. Moreover, , a gram-positive, rod-shaped bacterium, is related to hypermethylation in , , , , , , , and genes. The underlying epigenetic mechanism is unclear, although it could be implicated in the regulation of DNA methyltransferases, enzymes that catalyze the transfer of a methyl group on cytosine of CpG sites. Since DNA methylation is a reversible event, changes in gut microbiota could modulate the gene expression through DNA methylation and improve the colorectal cancer prognosis.
PubMed: 37614819
DOI: 10.3389/fgene.2023.1037406 -
International Journal of Molecular... Mar 2023Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic... (Review)
Review
Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP.
Topics: Humans; Adenomatous Polyposis Coli Protein; Quality of Life; Adenomatous Polyposis Coli; Colorectal Neoplasms; Genes, APC; Adenoma; Carcinogenesis; Tumor Microenvironment
PubMed: 36982759
DOI: 10.3390/ijms24065687 -
Biomedica : Revista Del Instituto... May 2022Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability,...
Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability, and epigenetics are involved in its development. Objective: To perform molecular characterization in 44 individuals with sporadic colorectal cancer. Materials and methods: We conducted mutation analyses of the APC, KRAS, TP53 y BRAF genes using Sanger sequencing techniques; microsatellite instability was determined by capillary electrophoresis with five STR genetic markers while the methylation status of the MHL1 promotor gene was analyzed using methylation-specific PCR. Results: APC, KRAS, and TP53 genes mutation frequency was 18.1%, 25%, and 4.5%, respectively; the somatic mutations detected were located more frequently in the right colon. The frequency of microsatellite instability was 27.2% and 73.1% of the tumors had the MHL1 gene methylated while 91.6% of microsatellite instability-positive tumors had the methylated MLH1 gene. The mutation profile of microsatellite stability tumors APC, KRAS, and TP53 genes was more frequent than in the microsatellite instability-positive tumors. The methylation of the MLH1 gene was the most predominant molecular alteration. Conclusions: We identified molecular alterations in different genetic pathways of the colorectal cancer patients evaluated, which are common in the carcinogenesis of this cancer. These patients showed a different mutational profile compared to other populations. Our findings confirm the molecular heterogeneity described in the development of colorectal cancer.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability; Proto-Oncogene Proteins p21(ras); Retrospective Studies
PubMed: 35866738
DOI: 10.7705/biomedica.5957 -
Annals of Clinical Biochemistry Nov 2015A small minority of colorectal cancers (CRCs) (≤5%) are caused by a single, inherited faulty gene. These diseases, the Mendelian colorectal cancer (CRC) syndromes,... (Review)
Review
A small minority of colorectal cancers (CRCs) (≤5%) are caused by a single, inherited faulty gene. These diseases, the Mendelian colorectal cancer (CRC) syndromes, have been central to our understanding of colorectal carcinogenesis in general. Most of the approximately 13 high-penetrance genes that predispose to CRC primarily predispose to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1). Lynch syndrome (MSH2, MLH1, MSH6, PMS2), by contrast, is associated primarily with cancer risk. Major functional pathways are consistently inactivated in the Mendelian CRC syndromes: certain types of DNA repair (proofreading of DNA replication errors, mismatch repair and base excision repair) and signalling (bone morphogenetic protein (BMP), Wnt signalling and mTOR). The inheritance of the CRC syndromes also varies: most are dominant but some of the DNA repair deficiencies are recessive. Some of the Mendelian CRC genes are especially important because they play a role through somatic inactivation in sporadic CRC (APC, MLH1, SMAD4, POLE). Additional Mendelian CRC genes may remain to be discovered and searches for these genes are ongoing, especially in patients with multiple adenomas and hyperplastic polyps.
Topics: Colorectal Neoplasms; Humans; Inheritance Patterns
PubMed: 26169059
DOI: 10.1177/0004563215597944 -
The Journal of Pathology Jan 2016Murine models of intestinal cancer are powerful tools to recapitulate human intestinal cancer, understand its biology and test therapies. With recent developments... (Review)
Review
Murine models of intestinal cancer are powerful tools to recapitulate human intestinal cancer, understand its biology and test therapies. With recent developments identifying the importance of the tumour microenvironment and the potential for immunotherapy, autochthonous genetically engineered mouse models (GEMMs) will remain an important part of preclinical studies for the foreseeable future. This review will provide an overview of the current mouse models of intestinal cancer, from the Apc(Min/+) mouse, which has been used for over 25 years, to the latest 'state-of-the-art' organoid models. We discuss here how these models have been used to define fundamental processes involved in tumour initiation and the attempts to generate metastatic models, which is the ultimate cause of cancer mortality. Together these models will provide key insights to understand this complex disease and hopefully will lead to the discovery of new therapeutic strategies.
Topics: Adenocarcinoma; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Animals; Carcinogenesis; Colorectal Neoplasms; Disease Models, Animal; Forecasting; Genes, APC; Humans; Mice; Mice, Transgenic; Mutation; Neoplasm Metastasis; Neoplasm Transplantation
PubMed: 26414675
DOI: 10.1002/path.4645 -
Modern Pathology : An Official Journal... Apr 2022Osteoma is a benign bone forming tumor predominantly arising on the surface of craniofacial bones. While the vast majority of osteomas develops sporadically, a small...
Osteoma is a benign bone forming tumor predominantly arising on the surface of craniofacial bones. While the vast majority of osteomas develops sporadically, a small subset of cases is associated with Gardner syndrome, a phenotypic variant of familial adenomatous polyposis caused by mutations in the APC gene resulting in aberrant activation of WNT/β-catenin signaling. In a sequencing analysis on a cohort of sporadic, non-syndromal osteomas, we identified hotspot mutations in the CTNNB1 gene (encoding β-catenin) in 22 of 36 cases (61.1%), harbouring allelic frequencies ranging from 0.04 to 0.53, with the known S45P variant representing the most frequent alteration. Based on NanoString multiplex expression profiling performed in a subset of cases, CTNNB1-mutated osteomas segregated in a defined "WNT-cluster", substantiating functionality of CTNNB1 mutations which are associated with β-catenin stabilization. Our findings for the first time convincingly show that osteomas represent genetically-driven neoplasms and provide evidence that aberrant WNT/β-catenin signaling plays a fundamental role in their pathogenesis, in line with the well-known function of WNT/β-catenin in osteogenesis. Our study contributes to a better understanding of the molecular pathogenesis underlying osteoma development and establishes a helpful diagnostic molecular marker for morphologically challenging cases.
Topics: Adenomatous Polyposis Coli Protein; Genes, APC; Humans; Mutation; Osteoma; beta Catenin
PubMed: 34725446
DOI: 10.1038/s41379-021-00956-x -
Oncology Letters Nov 2020Negative growth regulatory tumor suppressor genes and positive growth regulatory oncogenes serve important roles in initiation/progression of colon cancer. Germline... (Review)
Review
Negative growth regulatory tumor suppressor genes and positive growth regulatory oncogenes serve important roles in initiation/progression of colon cancer. Germline mutation in the adenomatous polyposis coli (APC) tumor suppressor gene represents a primary genetic defect for familial adenomatous polyposis (FAP) syndrome, a predisposing factor for clinical colon cancer. Somatic mutations in the APC gene are common in sporadic colon cancer. Preclinical and clinical efficacy is documented for targeted therapy with non-steroidal anti-inflammatory drugs, selective cyclo-oxygenase-2 inhibitors for prostaglandin biosynthesis and selective inhibitor of ornithine decarboxylase for polyamine biosynthesis. However, these therapeutic options lead to systemic toxicity, acquired tumor resistance and emergence of therapy resistant cancer stem cells. By contrast, non-toxic natural products are unlikely to exhibit drug resistance and may represent testable alternatives for therapy resistant colon cancer. Tumorigenic Apc [-/-] colonic epithelial cell lines derived from preclinical FAP models provide novel cellular models for drug resistant cancer stem cells. Apc [-/-] Sulindac resistant (SUL-R) cells exhibit upregulated expression levels of cancer stem cell markers. Natural products, such as naturally occurring vitamin A derivative all-trans retinoic acid (ATRA) and the anti-cancer agent from Turmeric root curcumin (CUR), represent testable alternatives. Relative to the non-tumorigenic Apc [+/+] C57 COL colonic epithelial cells, the tumorigenic Apc [-/-] 1638N COL and Apc [-/-] 850 COL cells exhibit aneuploid cell hyper-proliferation and upregulated expression of Apc target genes β-catenin, cyclin D1, c-myc and COX-2. The SUL-R phenotypes exhibit enhanced tumor spheroid formation and upregulated expression levels of stem cell markers CD44, CD133 and c-Myc. Treatment of the SUL-R stem cells with ATRA and CUR inhibits tumor spheroid formation and reduces the expression of stem cell markers. Stem cell models developed for FAP syndrome provide a novel experimental approach to identify mechanistic leads for efficacious natural products as testable alternatives for therapy-resistant, genetically predisposed colon cancer.
PubMed: 32934706
DOI: 10.3892/ol.2020.11998 -
Mutation Research. Genetic Toxicology... Feb 2017The origins of human cancers remain unclear except for a limited number of potent environmental mutagens, such as tobacco and UV light, and in rare cases, familial germ... (Review)
Review
The origins of human cancers remain unclear except for a limited number of potent environmental mutagens, such as tobacco and UV light, and in rare cases, familial germ line mutations that affect tumor suppressor genes or oncogenes. A significant component of cancer etiology has been deemed stochastic and correlated with the number of stem cells in a tissue, the number of times the stem cells divide and a low incidence of random DNA polymerase errors that occur during each cell division. While somatic mutations occur during each round of DNA replication, mutations in cancer driver genes are not stochastic. Out of a total of 2843 codons, 1031 can be changed to stop codons by a single base substitution in the tumor suppressor APC gene, which is mutated in 76% of colorectal cancers (CRC). However, the nonsense mutations, which comprise 65% of all the APC driver mutations in CRC, are not random: 43% occur at Arg CGA codons, although they represent <3% of the codons. In TP53, CGA codons comprise <3% of the total 393 codons but they account for 72% and 39% of the mutations in CRC and ovarian cancer OVC, respectively. This mutation pattern is consistent with the kinetically slow, but not stochastic, hydrolytic deamination of 5-methylcytosine residues at specific methylated CpG sites to afford T·G mismatches that lead to C→T transitions and stop codons at CGA. Analysis of nonsense mutations in CRC, OVC and a number of other cancers indicates the need to expand the predictable risk factors for cancer to include, in addition to random polymerase errors, the methylation status of gene body CGA codons in tumor suppressor genes.
Topics: CpG Islands; Deamination; Humans; Mutation; Neoplasms; Stochastic Processes
PubMed: 28137366
DOI: 10.1016/j.mrgentox.2016.12.006