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Japanese Journal of Cancer Research :... Oct 1999The status of genetic alterations in ulcerative colitis (UC)-associated neoplasia (UCAN) was investigated focusing on microsatellite instability (MSI) which is seen in a...
The status of genetic alterations in ulcerative colitis (UC)-associated neoplasia (UCAN) was investigated focusing on microsatellite instability (MSI) which is seen in a certain fraction of colorectal carcinomas, and adenomatous polyposis coli (APC) gene and K-ras gene, in which mutations occur in the early stage of sporadic colorectal tumorigenesis. Thirty-one UCAN from 15 UC patients who had undergone colorectal resection at our institution were investigated. There were 8 lesions of invasive carcinoma, 15 high-grade dysplasia (HGD) and 8 low-grade dysplasia (LGD). DNA was extracted from each neoplastic lesion and corresponding non-neoplastic tissue by a microdissection method. MSI status at 9 microsatellite loci, loss of heterozygosity (LOH) at the APC locus, and K-ras codon 12 point mutation were examined. As for MSI, 4/31 (13%) UCAN (carcinoma: 1/8 (13%), HGD: 2/15 (13%), LGD: 1/8 (13%)) were MSI-high (3 or more unstable loci) and 12/31 (39%) UCAN (carcinoma: 3/8 (38%), HGD: 6/15 (40%), LGD: 3/8 (38%)) were MSI-low (1 or 2 unstable loci). LOH at the APC locus was not found in 9 UCAN from 6 informative (heterozygous) cases. The K-ras mutation rate of UCAN was 3/31 (9.7%) (carcinoma: 2/8 (25%), HGD: 1/15 (7%) and LGD: 0/8). MSI is relatively common in UCAN and is present at the early stage of tumorigenesis of UCAN, while the involvement of genetic alterations of the APC gene and K-ras gene is small. MSI may be one of the mechanisms of the increased neoplastic risk in UC, and UCAN may develop through a different carcinogenic pathway from sporadic carcinomas.
Topics: Adult; Age of Onset; Aged; Colitis, Ulcerative; Colorectal Neoplasms; Female; Genes, APC; Genes, ras; Genetic Markers; Humans; Loss of Heterozygosity; Male; Microsatellite Repeats; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Point Mutation; Retrospective Studies
PubMed: 10595736
DOI: 10.1111/j.1349-7006.1999.tb00681.x -
The Israel Medical Association Journal... Sep 2010Patients with multiple (< 100) colorectal adenomatous polyps are at increased risk for colorectal cancer. Genetic evaluation of those patients who test negative... (Clinical Trial)
Clinical Trial
BACKGROUND
Patients with multiple (< 100) colorectal adenomatous polyps are at increased risk for colorectal cancer. Genetic evaluation of those patients who test negative forAPCgene mutation is both a clinical and economic burden but is critical for counseling and surveillance. In Israel, this is confounded by the fact that national health insurance does not fully cover genetic evaluation of APC gene exon 16.
OBJECTIVES
To perform a comprehensive genetic evaluation of APC gene mutation-negative polyposis patients with the aim of developing a future evaluation protocol.
METHODS
Genetic analyses were performed in 29 APC gene mutation-negative Jewish individuals with 5 to > or = 40 colonic adenomas who did not fulfill Amsterdam (clinical) criteria for Lynch syndrome. Analyses included completion of APC gene exon 16 sequencing, analysis for APC gene copy number variations (deletions or duplications), MUTYH gene sequencing, and microsatellite instability in CRC patients fulfilling "Bethesda" (laboratory investigation) criteria for Lynch syndrome.
RESULTS
Completion of APC gene exon 16 sequencing revealed one patient with the E1317Q polymorphism. All were normal by APC multiplex ligation-dependent probe amplification analysis. Pathogenic MUTYH mutations were found in three patients, all of North African origin; two additional patients had variants of unknown significance. One of six patients with Bethesda-positive criteria was MSI-High with immunohistology consistent with MLH1 mutation.
CONCLUSIONS
Based on this small but well-characterized cohort with multiple colorectal adenomas, Lynch syndrome needs to be excluded if there are compatible criteria; otherwise MUTYH sequencing is probably the first step in evaluating APC-negative patients, especially for Jews of North African descent. Completing APC exon 16 sequencing and copy number variations analysis should probably be the last evaluations.
Topics: Adenomatous Polyposis Coli; Adult; Aged; Cohort Studies; Colorectal Neoplasms; DNA Glycosylases; Female; Genes, APC; Genetic Testing; Humans; Israel; Male; Middle Aged; Mutation; Polymorphism, Genetic; Predictive Value of Tests; Young Adult
PubMed: 21287799
DOI: No ID Found -
International Journal of Biological... 2020The 'adenoma-carcinoma sequence' is a well-recognized model of colorectal cancer (CRC) development. However, the interaction between gut microbiota and genetic...
The 'adenoma-carcinoma sequence' is a well-recognized model of colorectal cancer (CRC) development. However, the interaction between gut microbiota and genetic variation in the initiation of CRC is not clear. Our study attempts to demonstrate the relationship between gut microbiota and host genetics in patients with intestinal adenomatous polyps. The entire exon region of the APC gene was sequenced in 35 patients with pathologically diagnosed adenomatous polyps. Patients with highly pathogenic APC mutation were classified as the case group, while the others were classified as the control group. The patients'stool and serum samples were respectively collected for metagenomics and metabolomics measurements. In the analysis of gut microbiome, there were three most important species, in which Fusobacterium_mortiferum was significantly increased while Faecalibacterium_prausnitzii and Bifidobacterium_pseudocatenulatum were significantly decreased in the case group. The significantly low abundance of the Photosynthesis pathway in patients with APC mutation was due to the low abundance of species Faecalibacterium_prausnitzii and Bifidobacterium_pseudocatenulatum. Moreover, there were two clusters of KEGG pathways correlated with two clusters of species characterized by Faecalibacterium_prausnitzii and Fusobacterium_mortiferum. As to serum metabolomics, the abundance of (R)-3-Hydroxybutyric acid and 2-Hydroxyphenethylamine were significantly higher in patients with APC mutation, while the abundance of 1-Aminocyclopropanecarboxylic acid,7-Ketocholesterol, DL-lactate, and L-Pyroglutamic acid were significantly higher in controlgroup. After analyzing the metabolome and microbiome data by sparCCmethod, we found that there was a significantly negative correlation between the abundance of Faecalibacterium_prausnitzii and Fusobacterium_mortiferum, and a significantly positive correlation between Faecalibacterium_prausnitzii abundance and the steroid hormone Hydrocortisone (Cortisol) in serum. Host's APC mutation was closely related to the changes of gut microbiota and serum metabolites, and some species of gut microbiome like Faecalibacterium_prausnitzii and Fusobacterium_mortiferum might have the potential to predict the development of CRC from intestinal adenomatous polyps.
Topics: Adenomatous Polyps; Aged; Colorectal Neoplasms; Faecalibacterium prausnitzii; Female; Gastrointestinal Microbiome; Genes, APC; Humans; Male; Metagenomics; Middle Aged; Mutation
PubMed: 31892851
DOI: 10.7150/ijbs.37399 -
Nucleic Acids Research Jan 1997A large number of different mutations in the APC and p53 tumor suppressor genes have been identified in various types of cancer. This substantial increase since our...
A large number of different mutations in the APC and p53 tumor suppressor genes have been identified in various types of cancer. This substantial increase since our previous reports can enable analyses which were not previously possible. In order to capture all these new data, the software permitting analysis has been improved. This report describes the various improvements since the second release of the database.
Topics: Databases, Factual; Genes, APC; Genes, p53; Humans; Mutation; Software
PubMed: 9016523
DOI: 10.1093/nar/25.1.138 -
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 -
BMC Medical Genetics Apr 2007Germline mutations in the adenomatous polyposis gene (APC) result in familial adenomatous polyposis (FAP). FAP is an autosomal dominantly inherited disorder predisposing...
BACKGROUND
Germline mutations in the adenomatous polyposis gene (APC) result in familial adenomatous polyposis (FAP). FAP is an autosomal dominantly inherited disorder predisposing to colorectal cancer. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extracolonic manifestations. An attenuated form of polyposis (AFAP) is characterized by less than 100 adenomas and later onset of the disease.
METHODS
Here, we analyzed the APC gene for germline mutations in 59 Czech and 15 Slovak FAP patients. In addition, 50 apparently APC mutation negative Czech probands and 3 probands of Slovak origin were screened for large deletions encompassing the APC gene. Mutation screening was performed using denaturing gradient gel electrophoresis and/or protein truncation test. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. Screening for large deletions was performed by multiplex ligation dependent probe amplification. The extent of deletions was analyzed using following microsatellite markers: D5S299, D5S82, D5S134 and D5S346.
RESULTS
In the set of Czech and Slovak patients, we identified 46 germline mutations among 74 unrelated probands. Total mutation capture is 62,2% including large deletions. Thirty seven mutations were detected in 49 patients presenting a classical FAP phenotype (75,5%) and 9 mutations in 25 patients with attenuated FAP (36%). We report 20 novel germline APC mutations and 3 large deletions (6%) encompassing the whole-gene deletions and/or exon 14 deletion. In the patients with novel mutations, correlations of the mutation localization are discussed in context of the classical and/or attenuated phenotype of the disease.
CONCLUSION
The results of the molecular genetic testing are used both in the establishment of the predictive diagnosis and in the clinical management of patients. In some cases this study has also shown the difficulty to classify clinically between the classical and the attenuated form of FAP according to the established criteria. Interfamilial and/or intrafamilial phenotype variability was also confirmed in some cases which did not fit well with predicted genotype-phenotype correlation. All these findings have to be taken into consideration both in the genetic counselling and in the patient care.
Topics: Adenomatous Polyposis Coli; Base Sequence; Czech Republic; Exons; Gene Deletion; Genes, APC; Germ-Line Mutation; Humans; Molecular Sequence Data; Phenotype; Slovakia
PubMed: 17411426
DOI: 10.1186/1471-2350-8-16 -
International Journal of Molecular... Feb 2023The activation of Wnt/β-catenin signalling is a prerequisite for odontogenesis. APC, a member of the AXIN-CK1-GSK3β-APC β-catenin destruction complex, functions to...
The activation of Wnt/β-catenin signalling is a prerequisite for odontogenesis. APC, a member of the AXIN-CK1-GSK3β-APC β-catenin destruction complex, functions to modulate Wnt/β-catenin signalling to establish regular teeth number and positions. APC loss-of-function mutations are associated with the over-activation of WNT/β-catenin signalling and subsequent familial adenomatous polyposis (FAP; MIM 175100) with or without multiple supernumerary teeth. The ablation of Apc function in mice also results in the constitutive activation of β-catenin in embryonic mouse epithelium and causes supernumerary tooth formation. The objective of this study was to investigate if genetic variants in the gene were associated with supernumerary tooth phenotypes. We clinically, radiographically, and molecularly investigated 120 Thai patients with mesiodentes or isolated supernumerary teeth. Whole exome and Sanger sequencing identified three extremely rare heterozygous variants (c.3374T>C, p.Val1125Ala; c.6127A>G, p.Ile2043Val; and c.8383G>A, p.Ala2795Thr) in in four patients with mesiodentes or a supernumerary premolar. An additional patient with mesiodens was compound as heterozygous for two variants (c.2740T>G, p.Cys914Gly, and c.5722A>T, p.Asn1908Tyr). Rare variants in in our patients are likely to contribute to isolated supernumerary dental phenotypes including isolated mesiodens and an isolated supernumerary tooth.
Topics: Animals; Humans; Mice; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; beta Catenin; Genes, APC; Tooth, Supernumerary
PubMed: 36901686
DOI: 10.3390/ijms24054255 -
Ai Zheng = Aizheng = Chinese Journal of... Jan 2007Detection of circulating tumor markers is one of current hot spots in tumor research. Free tumor DNA may exist in the peripheral blood of malignant tumor patients....
BACKGROUND & OBJECTIVE
Detection of circulating tumor markers is one of current hot spots in tumor research. Free tumor DNA may exist in the peripheral blood of malignant tumor patients. Identical DNA mutations existing in both peripheral serum and primary tumor are found in many kinds of malignant tumors. This study used adenomatous polyposis coli (APC) gene promoter hypermethylation as a tumor marker to investigate the correlations of free tumor DNA to primary tumor and clinicopathologic features of breast cancer.
METHODS
The methylation status of APC gene in tumor tissue, paracancer normal tissue, and paired peripheral serum from 84 patients with breast cancer and 10 patients with benign breast diseases were detected by methylation-specific polymerase chain reaction (MSP).
RESULTS
The detection rate of APC gene promoter hypermethylation was 45.2% in tumor tissues and 31.0% in paired peripheral sera. APC gene hypermethylation in peripheral serum was significantly correlated to that in tumor tissue (r=0.977, P=0.002). The sensitivity of detecting APC gene hypermethylation in peripheral serum was 68.4%; the specificity was 97.8%. The aberrant methylation of APC gene in tumor tissue and peripheral serum had no correlation to patients' age, tumor stage, tumor size, histological type, and receptor status (P>0.05). No aberrant methylation of APC gene was found in the serum samples from healthy control and the patients without gene methylation in tumor tissue.
CONCLUSION
The aberrant tumor gene methylation in peripheral serum of breast cancer patients is significantly correlated to that in primary tumor.
Topics: Adult; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; DNA Methylation; DNA, Neoplasm; Female; Genes, APC; Humans; Middle Aged; Neoplasm Staging; Promoter Regions, Genetic
PubMed: 17222366
DOI: No ID Found -
World Journal of Gastroenterology May 2016To identify prognostic factors and to correlate APC mutations with clinical features, including extracolic manifestations.
AIM
To identify prognostic factors and to correlate APC mutations with clinical features, including extracolic manifestations.
METHODS
One hundred thirty-five patients who underwent surgical procedures for familial adenomatous polyposis (FAP) were included. FAP was diagnosed when the number of adenomatous polyps was > 100. Data related to patient, extracoloic manifestations, cancer characteristics, operative procedure, follow up and surveillance were collected. APC mutation testing was performed in the 30 most recent patients. DNA was extracted from peripheral blood and polymerase chain reaction products using 31 primer pairs on APC gene were sequenced. A retrospective study was performed to investigate a causal relationship between prognosis and feature of patient.
RESULTS
The mean age of the 51 patients with colorectal cancer (CRC) was older than that of those without CRC (30.5 vs 36.9, P = 0.002). Older individuals were more likely to have colon cancer at the time of FAP diagnosis [odds ratio, 4.75 (95%CI: 1.71-13.89) and 5.91(1.76-22.12) for 40-49 years and age > 50 vs age < 30). The number of confirmed deaths was 13 and the median age at death was 40 years (range, 27 to 85 years). Ten of the deaths (76.9%) were from CRC. Another cause of two cases of death were desmoid tumors (15.4%). Development of cancer on remnant rectal or ileal mucosa after surgery was not observed. The APC mutation testing revealed 23 pathogenic mutations and one likely pathogenic mutation, among which were four novel mutations. The correlation between mutational status and clinical manifestations was investigated. Mutations that could prodict poor prognosis were at codon 1309 which located on mutation cluster region, codon 1465 and codon 1507.
CONCLUSION
Identification of APC mutations should aid in the diagnosis and counseling of family members in terms of early diagnosis and management of FAP.
Topics: Adenomatous Polyposis Coli; Adult; Aged; Aged, 80 and over; Female; Genes, APC; Humans; Male; Middle Aged; Mutation; Polyps; Prognosis; Retrospective Studies; Stomach Neoplasms
PubMed: 27158207
DOI: 10.3748/wjg.v22.i17.4380 -
The American Journal of Pathology May 2010Epigenetic in vitro and in vivo studies suggest that suppressor of cytokine signaling-2 (SOCS2) may normally limit tumorigenesis in the intestine; however, this theory...
Epigenetic in vitro and in vivo studies suggest that suppressor of cytokine signaling-2 (SOCS2) may normally limit tumorigenesis in the intestine; however, this theory has not been directly tested. We hypothesized that SOCS2 deficiency promotes spontaneous intestinal tumorigenesis in Apc(Min/+) mice. Therefore, we quantified tumor number, size, and load in the small intestine and colon using SOCS2(+/+)/Apc(Min/+), SOCS2(+/-)/Apc(Min/+), and SOCS2(-/-)/Apc(Min/+) mice and assayed hematocrit as an indirect marker of disease severity. Biochemical and histological assays were used to assess mechanisms. Heterozygous and homozygous disruption of SOCS2 alleles promoted 166 and 441% increases in tumor load in the small intestine, respectively, accelerated development of colon tumors, and caused severe anemia. SOCS2 deletion promoted significant increases in intestinal insulin-like growth factor-I mRNA but did not affect plasma insulin-like growth factor-I. Western blots and immunohistochemical analysis demonstrated that tumor and nontumor intestinal tissue of SOCS2(-/-)/Apc(Min/+) mice had increased serine 727 phosphorylation of signal transducer and activator of transcription 3 compared with SOCS2(+/+)/Apc(Min/+) mice. Moreover, electromobility shift assays showed that SOCS2 deletion did not alter signal transducer and activator of transcription 3 DNA binding. However, tumors and small intestine from SOCS2(-/-)/Apc(Min/+) showed dramatic increases in activator protein-1 (AP-1) DNA binding, and SOCS2 overexpression in vitro reduced levels of AP-1. These studies indicate that SOCS2 deletion promotes the spontaneous development of intestinal tumors driven by mutations in the adenomatous polyposis coli/beta-catenin pathway and activates AP-1. Therefore, reduced expression or epigenetic silencing of SOCS2 may serve as a useful biomarker for colorectal cancer risk.
Topics: Alleles; Animals; Biomarkers, Tumor; Epigenesis, Genetic; Gene Deletion; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, APC; Homozygote; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Suppressor of Cytokine Signaling Proteins; Transcription Factor AP-1
PubMed: 20348236
DOI: 10.2353/ajpath.2010.090684