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Familial Cancer Apr 2021Germline variants in the APC and MUTYH genes contribute to colorectal cancer (CRC) and adenoma risk, though may occur with varying frequencies in individuals of...
Germline variants in the APC and MUTYH genes contribute to colorectal cancer (CRC) and adenoma risk, though may occur with varying frequencies in individuals of different ancestries. The aim of this study was to evaluate the prevalence of APC, monoallelic MUTYH and biallelic MUTYH germline variants in Ashkenazi Jewish (AJ) and Other Ancestry (OA) individuals with colorectal adenomas. We studied 7225 individuals with colorectal adenomas who had germline APC and MUTYH testing at a commercial laboratory. Cross-sectional medical history data were extracted from provider-completed test requisition forms. We performed bivariate analysis to compare the frequency of APC and MUTYH variants between AJ and OA, and examined APC p.I1307K and monoallelic MUTYH carrier phenotypes using logistic regression. Pathogenic APC variants occurred in 38/285 AJ (13%) and 1342/6940 OA (19%; P = 0.09); biallelic MUTYH variants in 2/285 (1%) AJ and 399/6940 (6%) OA (P < 0.0001); APC p.I1307K in 35/285 (12%) AJ and 29/6940 (1%) OA (P < 0.0001); and monoallelic MUTYH in 2/285 (1%) AJ and 133/6940 (2%) OA (P = 0.06). Monoallelic MUTYH variants were significantly associated with having a personal history of CRC, regardless of ancestry (OR 1.78; 95% CI 1.21-2.49; P < 0.01), but no significant association was found between APC p.I1307K variants and personal history of CRC (OR 1.38; 95% CI 0.79-2.44; P = 0.26). Ashkenazim with colorectal adenomas rarely have monoallelic or biallelic MUTYH variants, suggesting different genetic etiologies for polyposis in AJ compared to OA individuals. AJ ancestry assessment may be important in clinical evaluation for polyposis.
Topics: Adenoma; Cohort Studies; Colorectal Neoplasms; DNA Glycosylases; Female; Gene Frequency; Genes, APC; Genetic Testing; Germ-Line Mutation; Humans; Jews; Male; Middle Aged; Odds Ratio; Phenotype
PubMed: 32743790
DOI: 10.1007/s10689-020-00198-x -
British Journal of Cancer Feb 2021Most cancer cells employ the Warburg effect to support anabolic growth and tumorigenesis. Here, we discovered a key link between Warburg effect and aberrantly activated...
BACKGROUND
Most cancer cells employ the Warburg effect to support anabolic growth and tumorigenesis. Here, we discovered a key link between Warburg effect and aberrantly activated Wnt/β-catenin signalling, especially by pathologically significant APC loss, in CRC.
METHODS
Proteomic analyses were performed to evaluate the global effects of KYA1797K, Wnt/β-catenin signalling inhibitor, on cellular proteins in CRC. The effects of APC-loss or Wnt ligand on the identified enzymes, PKM2 and LDHA, as well as Warburg effects were investigated. A linkage between activation of Wnt/β-catenin signalling and cancer metabolism was analysed in tumour of Apc mice and CRC patients. The roles of PKM2 in cancer metabolism, which depends on Wnt/β-catenin signalling, were assessed in xenograft-tumours.
RESULTS
By proteomic analysis, PKM2 and LDHA were identified as key molecules regulated by Wnt/β-catenin signalling. APC-loss caused the increased expression of metabolic genes including PKM2 and LDHA, and increased glucose consumption and lactate secretion. Pathological significance of this linkage was indicated by increased expression of glycolytic genes with Wnt target genes in tumour of Apc mice and CRC patients. Warburg effect and growth of xenografted tumours-induced by APC-mutated-CRC cells were suppressed by PKM2-depletion.
CONCLUSIONS
The β-catenin-PKM2 regulatory axis induced by APC loss activates the Warburg effect in CRC.
Topics: Animals; Carrier Proteins; Colorectal Neoplasms; Genes, APC; Heterografts; Humans; L-Lactate Dehydrogenase; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondrial Proton-Translocating ATPases; Neoplasm Proteins; Proteomics; Thiazolidines; Thyroid Hormones; Tissue Array Analysis; Warburg Effect, Oncologic; Wnt Signaling Pathway; beta Catenin; Thyroid Hormone-Binding Proteins
PubMed: 33071283
DOI: 10.1038/s41416-020-01118-7 -
Journal of Industrial Microbiology &... Jan 2020The impact of the global secondary metabolite regulators LaeA and VeA on echinocandin B production and morphological development was evaluated in the industrial...
The impact of the global secondary metabolite regulators LaeA and VeA on echinocandin B production and morphological development was evaluated in the industrial production strain Aspergillus pachycristatus NRRL 11440. Other representative secondary metabolites were examined as well to determine if the velvet complex functions as in A. nidulans and other species of fungi. Genetic methods used for gene manipulations in A. nidulans were applied to A. pachycristatus. Separate deletions of genes Apc.laeA and Apc.veA resulted in similar yet differing phenotypes in strain NRRL 11440. Disruption of Apc.laeA and Apc.veA significantly reduced, but did not eliminate, the production of echinocandin B. Similar to what has been observed in A. nidulans, the production of sterigmatocystin was nearly eliminated in both mutants. Quantitative reverse transcription PCR analyses confirmed that selected genes of both the echinocandin B and sterigmatocystin gene clusters were down-regulated in both mutant types. The two mutants differed with respect to growth of aerial hyphae, pigmentation, development of conidiophores, conidial germination rate, and ascospore maturation. Further functional annotation of key regulatory genes in A. pachycristatus and related Aspergillus species will improve our understanding of regulation of echinocandin production and co-produced metabolites.
Topics: Aspergillus; Echinocandins; Fungal Proteins; Gene Expression Regulation, Fungal; Genome, Fungal; Multigene Family; Secondary Metabolism; Spores, Fungal
PubMed: 31758414
DOI: 10.1007/s10295-019-02250-x -
Plant Physiology Jan 2022SAMBA has been identified as a plant-specific regulator of the anaphase-promoting complex/cyclosome (APC/C) that controls unidirectional cell cycle progression in... (Comparative Study)
Comparative Study
SAMBA has been identified as a plant-specific regulator of the anaphase-promoting complex/cyclosome (APC/C) that controls unidirectional cell cycle progression in Arabidopsis (Arabidopsis thaliana), but so far its role has not been studied in monocots. Here, we show the association of SAMBA with the APC/C is conserved in maize (Zea mays). Two samba genome edited mutants showed growth defects, such as reduced internode length, shortened upper leaves with erect leaf architecture, and reduced leaf size due to an altered cell division rate and cell expansion, which aggravated with plant age. The two mutants differed in the severity and developmental onset of the phenotypes, because samba-1 represented a knockout allele, while translation re-initiation in samba-3 resulted in a truncated protein that was still able to interact with the APC/C and regulate its function, albeit with altered APC/C activity and efficiency. Our data are consistent with a dosage-dependent role for SAMBA to control developmental processes for which a change in growth rate is pivotal.
Topics: Cell Cycle Proteins; Cell Division; Crops, Agricultural; Gene Expression Regulation, Plant; Genes, Plant; Genetic Variation; Genotype; Phenotype; Zea mays
PubMed: 34791456
DOI: 10.1093/plphys/kiab514 -
PeerJ 2023The sequencing panel composed of 61 target genes was used to explore the related mutation genes of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF)...
OBJECTIVE
The sequencing panel composed of 61 target genes was used to explore the related mutation genes of oral squamous cell carcinoma (OSCC) and oral submucous fibrosis (OSF) cancerization, so as to provide a theoretical basis for the early diagnosis of oral submucous fibrosis cancerization, find the most important mutations in OSF cancerization, and more targeted prevention of OSF cancerization.
METHODS
A total of 74 clinically diagnosed samples were included, including 36 cases of OSCC and 38 cases of OSF cancer patients. DNA was extracted, and targeted gene panel sequencing technology was used to analyze the gene frequency of pathogenic mutation sites in clinical samples.
RESULTS
Gene panel sequencing analysis showed that there were 69 mutations in 18 genes in OSCC and OSF cancerous specimens. The results of gene panel sequencing were screened, and 18 mutant genes were finally screened out and their mutation frequencies in the samples were analyzed. According to the frequency of gene mutations from high to low, they were TP53, FLT4, PIK3CA, CDKN2A, FGFR4, HRAS, BRCA1, PTPN11, NF1, KMT2A, RB1, PTEN, MSH2, MLH1, KMT2D, FLCN, BRCA2, APC. The mutation frequency of FLT4 gene was significantly higher than that of OSCC group ( < 0.05).
CONCLUSION
FLT4 gene may be related to OSF cancerization and is expected to be an early diagnostic biomarker for OSF cancerization.
Topics: Humans; Oral Submucous Fibrosis; Carcinoma, Squamous Cell; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Mutation
PubMed: 38050610
DOI: 10.7717/peerj.16392 -
Frontiers in Cell and Developmental... 2021Cancers of unknown primary (CUPs) comprise a heterogeneous group of rare metastatic tumors whose primary site cannot be identified after extensive clinical-pathological...
Cancers of unknown primary (CUPs) comprise a heterogeneous group of rare metastatic tumors whose primary site cannot be identified after extensive clinical-pathological investigations. CUP patients are generally treated with empirical chemotherapy and have dismal prognosis. As recently reported, CUP genome presents potentially druggable alterations for which targeted therapies could be proposed. The paucity of tumor tissue, as well as the difficult DNA testing and the lack of dedicated panels for target gene sequencing are further relevant limitations. Here, we propose that circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) could be used to identify actionable mutations in CUP patients. Blood was longitudinally collected from two CUP patients. CTCs were isolated with CELLSEARCH and DEPArray NxT and Parsortix systems, immunophenotypically characterized and used for single-cell genomic characterization with 1 kits. Circulating cell-free DNA (ccfDNA), purified from plasma at different time points, was tested for tumor mutations with a CUP-dedicated, 92-gene custom panel using SureSelect Target Enrichment technology. In parallel, FFPE tumor tissue was analyzed with three different assays: FoundationOne CDx assay, DEPArray LibPrep and OncoSeek Panel, and the SureSelect custom panel. These approaches identified the same mutations, when the gene was covered by the panel, with the exception of an insertion in gene. which was detected by OncoSeek and SureSelect panels but not FoundationOne. and gene amplifications were detected in single CTCs, tumor tissue, and ccfDNAs in one patient. A somatic variant in gene (p.R1276) was detected in the tumor tissue and ccfDNAs. The alterations were validated by Droplet Digital PCR in all ccfDNA samples collected during tumor evolution. CTCs from a second patient presented a pattern of recurrent amplifications in and genes and loss of . The 92-gene custom panel identified 16 non-synonymous somatic alterations in ccfDNA, including a deletion (I1485Rfs19) and a somatic mutation (p. A1487V) in gene and a point mutation in gene (p.G384R). Our results support the feasibility of non-invasive liquid biopsy testing in CUP cases, either using ctDNA or CTCs, to identify CUP genetic alterations with broad NGS panels covering the most frequently mutated genes.
PubMed: 34178989
DOI: 10.3389/fcell.2021.666156 -
Journal of the American Heart... Feb 2020Background Animal and in vitro experiments implicate the Wnt pathway in cardiac development, fibrosis, vascular calcification, and atherosclerosis, but research in...
Background Animal and in vitro experiments implicate the Wnt pathway in cardiac development, fibrosis, vascular calcification, and atherosclerosis, but research in humans is lacking. We examined peripheral blood Wnt pathway gene expression and arterial stiffness in 369 healthy African ancestry men (mean age, 64 years). Methods and Results Gene expression was assessed using a custom Nanostring nCounter gene expression panel (N=43 genes) and normalized to housekeeping genes and background signal. Arterial stiffness was assessed via brachial-ankle pulse-wave velocity. Fourteen Wnt genes showed detectable expression and were tested individually as predictors of pulse-wave velocity using linear regression, adjusting for age, height, weight, blood pressure, medication use, resting heart rate, current smoking, alcohol intake, and sedentary lifestyle. Adenomatous polyposis coli regulator of Wnt signaling pathway (), glycogen synthase kinase 3β (), and transcription factor 4 () were significantly associated with arterial stiffness (<0.05 for all). When entered into a single model, and expression remained independently associated with arterial stiffness (=0.04 and 0.003, respectively), and each explained ≈3% of the variance in pulse-wave velocity. Conclusions The current study establishes a novel association between in vivo expression of the Wnt pathway genes, and , with arterial stiffness in African ancestry men, a population at high risk of hypertensive vascular disease.
Topics: Adenomatous Polyposis Coli Protein; Aged; Aged, 80 and over; Ankle Brachial Index; Black People; Gene Expression Profiling; Humans; Male; Middle Aged; Prospective Studies; Pulse Wave Analysis; Transcription Factor 4; Transcriptome; Trinidad and Tobago; Vascular Stiffness; Wnt Signaling Pathway
PubMed: 32013702
DOI: 10.1161/JAHA.119.014170 -
Asian Pacific Journal of Cancer... Dec 2021It is known that many genes are associated with colon cancer. We aimed to investigate the effect of gene mutations on metastasis and overall survival in metastatic and...
OBJECTIVE
It is known that many genes are associated with colon cancer. We aimed to investigate the effect of gene mutations on metastasis and overall survival in metastatic and non metastatic colon cancers.
METHODS
A total of 50 patients with metastatic (n=25) and non metastatic (n=25) diagnosed with colon cancer between 2010 and 2018 were included in the study. APC, MUTYH, RAD50, MEN1, ATM, PALB2, NSH2, BRCA1, BRCA2, MLH1, BRIP1, TP53, PTEN, BARD1, MSH6, PMS2, NBN, and FAM175A gene mutations were evaluated using the next generation sequencing method. The effect of gene mutations on metastasis and overall survival were evaluated.
RESULTS
The mean age of patients with colon cancer without distant metastasis was 48.64±14.72 years and for patients with distance metases was 56.68±11.65. The mean survival time of colon cancer patients with distant organ metastasis after the metastasis date was 104.36±58.59 weeks. The presence of APC, MUTYH, and TP53 genetic mutations was observed with a higher rate in metastatic colon cancer (p<0.05).
CONCLUSION
We showed that APC, MUTYH, and TP53 mutations are associated with distant organ metastasis.
Topics: Adolescent; Adult; Aged; Case-Control Studies; Colonic Neoplasms; DNA Glycosylases; Female; Genes, APC; Genes, p53; Genetic Predisposition to Disease; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Retrospective Studies; Survival Analysis; Young Adult
PubMed: 34967562
DOI: 10.31557/APJCP.2021.22.12.3839 -
International Journal of Clinical... Sep 2021Familial adenomatous polyposis (FAP), an autosomal dominant disorder characterized by multiple colonic polyps, is caused by a germline pathogenic variant of the APC...
BACKGROUND
Familial adenomatous polyposis (FAP), an autosomal dominant disorder characterized by multiple colonic polyps, is caused by a germline pathogenic variant of the APC gene. However, this variant is not detected in up to 30% of patients with the adenomatous polyposis phenotype.
METHODS
We performed next-generation sequencing (NGS) to identify the causative genes in FAP patients with 10 or more polyps. For patients in whom the APC germline variant was not able to be identified, we screened for APC mosaicism using high-coverage NGS of APC with DNA from leucocytes and/or frozen tissue.
RESULTS
The pathogenic APC germline variant was found in 93.3%, 71.6%, and 17.1% of patients with profuse-type polyposis, sparse-type polyposis, and oligo-polyposis, respectively. The APC germline variant detection rate in patients with FAP-related diseases was 69.7% for fundic gland polyposis, 79.7% for duodenal adenoma, 94.7% for desmoid tumor, and 71.4% for thyroid cancer, with increasing numbers of extracolonic lesions associated with an increasing APC germline variant detection rate. A mosaic test detected nine patients with APC mosaicism. A comparison of APC-associated polyposis with APC mosaicism showed that patients with APC mosaicism had a low frequency of duodenal adenoma and a family history of colonic polyposis.
CONCLUSIONS
We determined the detection rate of the APC germline variant by phenotype and identified APC mosaicism. Genetic testing of FAP patients is important because it can help with surgical decision-making, monitoring, and genetic counseling. Furthermore, genetic testing by NGS proved to be an effective method of detecting APC germline variants.
PubMed: 34106356
DOI: 10.1007/s10147-021-01946-4 -
European Journal of Human Genetics :... Jan 2020Familial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of colorectal adenomas and results from inherited or somatic mosaic...
Familial adenomatous polyposis (FAP) is characterised by the development of hundreds to thousands of colorectal adenomas and results from inherited or somatic mosaic variants in the APC gene. Index patients with suspected FAP are usually investigated by APC coding region sequence and dosage analysis in a clinical diagnostic setting. The identification of an APC variant which is predicted to alter protein function enables predictive genetic testing to guide the management of family members. This report describes a 4-generation family with a phenotype consistent with FAP, but in which an APC variant had not been identified, despite testing. To explore this further, quantitative PCR (qPCR) was employed to assess APC transcription, demonstrating reduced levels of APC RNA. Next generation sequencing (NGS) identified the APC 5'UTR/ Exon 1 variant, c.-190 G>A, that had been reported previously in an another FAP family with APC allelic imbalance. Quantitative RNA studies and DNA sequencing of the APC promoters/ Exon 1 may be useful diagnostically for patients with suspected FAP when coding region variants cannot be identified.
Topics: 5' Untranslated Regions; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Humans; Mutation; Pedigree; Promoter Regions, Genetic; RNA, Messenger
PubMed: 31383941
DOI: 10.1038/s41431-019-0486-2