Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Duplicon-mediated microdeletions around the NF1 gene are frequently associated with a severe form of neurofibromatosis type I in a subgroup of patients who show an earlier onset of cutaneous neurofibromas, dysmorphic facial features, and lower IQ values. To clarify the discrepancies between published maps of the NF1 tumor-suppressor gene region as well as the length of gaps in these assemblies and to validate the recently described tandem duplication of the human NF1 locus, we assembled a contiguous high-density map of BAC and PAC clones from different genomic libraries. Although two WI-12393-derived low-copy fragments are known to occur at the proximal and distal boundaries of the 1.5-Mb segment that is usually deleted in NF1 microdeletion patients, we identified an additional WI-12393-related segment between the MGC13061 and the NF1 gene, which appears to trigger interstitial deletions of smaller size as observed in two patients. Moreover, we completed the genomic organization and cDNA structure of all functional genes, CYTOR4, FLJ12735, FLJ22729, CENTA2, MGC13061, NF1, OMG, EVI2B, EVI2A, KIAA1821, MGC11316, HCA66, KIAA0160, and WI-12393, from this region. A comparison of the human map to the orthologous region on mouse chromosome 11 revealed significant differences in the number and arrangement of genes, indicating that many chromosomal breaks with partial duplications, inversions, and deletions occurred predominantly in the primate lineage.
 ...
PMID:Complete physical map and gene content of the human NF1 tumor suppressor region in human and mouse. 1269 59

As many as 5% of human cancers appear to be of hereditable etiology. Of the more than 50 characterized familial cancer syndromes, most involve disease affecting multiple organs and many can be traced to one or more abnormalities in specific genes. Studying these syndromes in humans is a difficult task, especially when it comes to genes that may manifest themselves early in gestation. It has been made somewhat easier with the development of genetically engineered mice (GEM) that phenotypically mimic many of these inheritable human cancers. The past 15 years has seen the establishment of mouse lines heterozygous or homozygous null for genes known or suspected of being involved in human cancer syndromes, including APC, ATM, BLM, BRCA1, BRCA2, LKB1, MEN1, MLH, MSH, NF1, TP53, PTEN, RB1, TSC1, TSC2, VHL, and XPA. These lines not only provide models for clinical disease and pathology, but also provide avenues to investigate molecular pathology, gene-gene and protein-tissue interaction, and, ultimately, therapeutic intervention. Possibly of even greater importance, they provide a means of looking at placental and fetal tissues, where genetic abnormalities are often first detected and where they may be most easily corrected. We will review these mouse models, examine their usefulness in medical research, and furnish sources of animals and references.
 ...
PMID:Mouse models of human familial cancer syndromes. 1520 8

Detailed analysis of mechanisms of genetic loss for specific tumor suppressor genes (TSGs; e.g., RB1, APC and NF1) indicates that TSG inactivation can occur by allelic loss of heterozygosity (LOH), without any alteration in DNA copy number. However, the role and prevalence of such events in the pathogenesis of specific malignancies remains to be established on a genome-wide basis. We undertook a detailed molecular assessment of chromosomal defects in a panel of nine cell lines derived from primary medulloblastomas, the most common malignant brain tumors of childhood, by parallel genome-wide assessment of LOH (allelotyping) and copy number aberrations (comparative genomic hybridization and fluorescence in situ hybridization). The majority of genetic losses observed were detected by both copy number and LOH methods, indicating they arise through the physical deletion of chromosomal material. However, a significant proportion of losses (17/42, 40%) represented regions of allelic LOH without any associated copy number reduction; these events involved both whole chromosomes (10/17) and sub-chromosomal regions (7/17). Using this approach, we identified medulloblastoma-characteristic alterations, e.g., isochromosome for 17q, MYC amplification and losses on chromosomes 10, 11, and 16, alongside novel regions of genetic loss (e.g., 10q21.1-26.3, 11q24.1-qter). This detailed genetic characterization of the majority of medulloblastoma cell lines provides important precedent for the widespread involvement of copy number-neutral genetic losses in medulloblastoma and demonstrates that combined assessment of copy number aberrations and LOH will be necessary to accurately determine the contribution of chromosomal defects to tumor development.
 ...
PMID:Combined genome-wide allelotyping and copy number analysis identify frequent genetic losses without copy number reduction in medulloblastoma. 1614 64

Cancers arise from the sequential acquisition of genetic alterations in specific genes. The high number of mutations in cancer cells led to the hypothesis that an early step in tumor progression is the generation of a genetic instability. The potent role of genetic instability in initiation and progression of colorectal cancers has been well defined in hereditary nonpolyposis colon cancer (HNPCC) syndrome. HNPCC is a common hereditary disorder caused by germline mutations of DNA mismatch repair (MMR) genes. Somatic loss of the normal allele of the predisposition gene leads to a strong "mutator phenotype", characterized by a high rate of mutations in repetitive sequences. Nevertheless, the observation of frequent alterations of key growth regulatory genes in MMR-deficient cells such as NF1, APC, p53, K-Ras, with no significant excess of frameshift mutations and changes at short coding repeats, suggest that even in the presence of an inherited tendency to genomic instability, tumor progression is mainly driven by a process of natural selection.
 ...
PMID:Mutational targets in colorectal cancer cells with microsatellite instability. 1652 6

Tumors of the nervous system most often occur in both children and adults as sporadic events with no family history of the disease, but they are also among the clinical manifestations of a significant number of familial cancer syndromes, including familial retinoblastoma, neurofibromatosis 1 and 2, tuberous sclerosis, and Cowden, Turcot, Li-Fraumeni and nevoid basal cell carcinoma (Gorlin) syndromes. All of these syndromes involve transmissible genetic risk resulting from loss of a functional allele, or inheritance of a structurally defective allele, of a specific gene. These genes include RB1, NF1, NF2, TSC1, TSC2, TP53, PTEN, APC, hMLH1, hPSM2, and PTCH, most of which function as tumor suppressor genes. The same genes are also observed in mutated and inactive forms, or are deleted, in tumor cells in sporadic cases of the same tumors. The nature of the mutational events that give rise to these inactivated alleles suggests a possible role of environmental mutagens in their causation. However, only external ionizing radiation at high doses is clearly established as an environmental cause of brain, nerve and meningeal tumors in humans. Transplacental carcinogenesis studies in rodents and other species emphasize the extraordinary susceptibility of the developing mammalian nervous system to carcinogenesis, but the inverse relationship of latency to dose suggests that low transplacental exposures to genotoxicants are more likely to result in brain tumors late in life, rather than in childhood. While not all neurogenic tumor-related genes in humans have similar effects in experimental rodents, genetically engineered mice (GEM) increasingly provide useful insights into the combined effects of multiple tumor suppressor genes and of gene-environment interactions in the genesis of brain tumors, especially pediatric brain tumors such as medulloblastoma.
 ...
PMID:Inducible and transmissible genetic events and pediatric tumors of the nervous system. 1701 46

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
 ...
PMID:Somatic mutations affect key pathways in lung adenocarcinoma. 1894 47

The recent progress of the biology of the locally aggressive sarcomas of soft tissues and related connective tissue tumors enabled to reclassify molecular and histological entities of the disease. Six subgroups of sarcomas are identified with specific molecular alterations, the targeted treatments of which are the object of this article: 1) sarcomas with specific translocations with fusion oncogenes (DFSP, PVNS); 2) sarcomas with tyrosine kinase mutations (KIT in GIST); 3) tumors with deletion of tumor suppressor genes (TSC in the PEComes, NF1 involved in type 1 neurofibromatosis; 4) sarcomas with MDM2/CDK4 amplification in the 12q13-15 amplicon, i.e. well differentiated or dedifferentiated liposarcomas; 5) sarcomas with complex genetics present more unrefined genetic changes (leiomyosarcomas, osteosarcomas). On top these 5 groups, desmoids tumors characterized by alterations of the Wnt, beta catenin, APC, and giant cell tumors of the bone, in which RANK/RANKL operates a complex interaction between the cellular stroma and giant tumor cells. The identification of these abnormal ways of road marking to licence the development of effective targeted therapeutic agents against certain rare histological connective subcategories of sarcomas and tumors with local aggressiveness, in particular DFSP, PVNS, GCST, PEComes, endometrial stromal sarcomas, Ewing sarcomas, etc. Imatinib is used in the treatment of DFSP, characterized by a translocation of the gene PDGF, or in pigmented villonodular synovitis (PVNS), a tumor of soft part also locally aggressive, caused by an abnormality of the gene coding for the M-CSF. Several clinical trials of phase I and II trials demonstrated the antitumor activity of anti-IGF1R antibodies in Ewing, whose fusion gene downregulates IGFBP3. Inhibitors of MDM2 are in the course of clinical evaluation in liposarcomas. Inhibitors of mTOR (sirolimus, temsirolimus) demonstrated an antitumoral activity in the PEComas. The molecular characterization of sarcomas allowed to develop therapeutic targeted to correct the responsible abnormalities. Translational research is and will be an essential tool for the development of new treatments and the identification of the mechanisms of answer and resistance set up by these tumors.
 ...
PMID:[Targeted treatment of rare connective tissue tumors and sarcomas]. 2049 11

Heterozygous whole gene deletions (WGDs), and intragenic microdeletions, account for a significant proportion of mutations underlying cancer predisposition syndromes. We analyzed the frequency and genotype-phenotype correlations of microdeletions in 12 genes (BRCA1, BRCA2, TP53, MSH2, MLH1, MSH6, PMS2, NF1, NF2, APC, PTCH1, and VHL) representing seven tumor predisposition syndromes in 5,897 individuals (2,611 families) from our center. Overall, microdeletions accounted for 14% of identified mutations. As expected, smaller deletions or duplications were more common (12%) than WGDs (2.2%). Where a WGD was identified in the germline in NF2, the mechanism of somatic second hit was not deletion, as previously described for NF1. For neurofibromatosis type 1 and 2, we compared the mechanism of germline deletion. Unlike NF1, where three specific deletion sizes account for most germline WGDs, NF2 deletion breakpoints were different across seven samples tested. One of these deletions was 3.93 Mb and conferred a severe phenotype, thus refining the region for a potential NF2 modifier gene to a 2.04-Mb region on chromosome 22. The milder phenotype of NF2 WGDs may be due to the apparent absence of chromosome 22 loss as the second hit. These observations of WGD phenotypes will be helpful for interpreting incidental findings from microarray analysis and next-generation sequencing.
...
PMID:The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes. 2661 84

Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767-BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767-BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro, but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors.
 ...
PMID:Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition. 2809 67

Background: The promising aspect of circulating tumor DNA (ctDNA) is its rapid turnaround and non-invasive nature. According to the American Society of Clinical Oncology (ASCO) and College of American Pathologists joint ctDNA review published in March 2018, there is not sufficient evidence to support the use of ctDNA in practice for GI cancers. However, there were numerous studies presented at ASCO Annual Meeting supporting its value. We aimed to summarize on its role in the management of gastrointestinal cancers based on the studies presented recently, and future directions. Methods: We limited our search to keywords "ctDNA," "circulating tumor DNA," "cell-free DNA (cfDNA)" and/or "liquid biopsy," at the 2018 ASCO Annual Meeting library abstracts and presentations. Results: There were 35 studies that revolved around ctDNA as a diagnostic tool, prognostic marker and/or a measure of tumor heterogeneity in gastrointestinal cancers. Depending on the assay used, the results of several studies showed that ctDNA was able to identify relevant mutations or fusions including RAS, HER2/Neu, BRAF, MET, BRCA2, APC, TP53, ALK, ROS1, PTEN, and NF1. The prognosis in terms of tumor mutation burden, objective response rate, metastasis and survival were also estimated by various studies based on ctDNA. The findings showed that higher baseline ctDNA levels and/or increased number of mutations detected in ctDNA were associated with poor survival and multi-site metastasis. Right-sided colon cancer was associated with higher number of mutations in ctDNA than left-sided colon and rectal cancers. Similarly, tubular adenocarcinoma subtype of gastric cancer was more likely to have higher ctDNA levels than signet-ring cell subtype. The feasibility of assessing response to therapy and residual metastatic disease by using ctDNA which was otherwise not detected on imaging was also presented. Conclusions: The studies presented at ASCO 2018 report on the many ways ctDNA is of value in patients with gastrointestinal malignancies. Experts and discussants at the meeting argued that this may well indeed be ready for prime time for certain GI malignancies including colorectal cancers, especially in the metastatic setting. These findings alongside ongoing studies showing its feasibility into practice would likely lead to revision of the current guidelines for metastatic GI cancers.
 ...
PMID:Role of Circulating Tumor DNA in Gastrointestinal Cancers: Update From Abstracts and Sessions at ASCO 2018. 3113 61


<< Previous 1 2 3 Next >>