Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human LATS1 and LATS2) (LATS1/2) are tumor suppressors that have been shown to be mutated or downregulated in several human cancers including leukemia, lung, prostate and breast cancers. However, the precise mechanisms and the proteins modulated by LATS1/2 that are responsible for these events remain largely unknown. To elucidate potential signaling pathways, the current study investigated the expression profile in HeLa cells with reduced expression of LATS1/2. Using RNA-mediated interference, both LATS1 and LATS2 were substantially knocked-down, and accordingly, this lead to an increase in multiple phenotypes associated with tumor progression, including enhanced cell proliferation, resistance to drug-induced cell death, and increased cell migration. Using whole human genome Oligo (60-mer) arrays (Agilent), genes modulated by loss of LATS1/2 were identified and functionally grouped into categories including cell proliferation, cell death, cell adhesion and motility, as well as cell communication. Selected genes, including known tumor suppressor genes and oncogenes such as CDKN1A, WISP2, SLIT2, TP53INP1, BIRC4BP, SPRY2, SPRY4, SPRED1, FAT4, and CYR61 were confirmed by qRT-PCR to be significantly differentially expressed. Importantly, the collection of genes identified suggests that LATS1/2 function through diverse mechanisms and multiple signaling pathways including the Hippo signaling pathway, as well as the p53, Ras-ERK, or WNT networks, to inhibit tumor progression.
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PMID:Identification of LATS transcriptional targets in HeLa cells using whole human genome oligonucleotide microarray. 1979 73

Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.
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PMID:Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. 2300 Feb 26

Gastric cancer imposes a considerable health burden around the globe despite its declining incidence. The disease is often diagnosed in advanced stages and is associated with a poor prognosis for patients. An in-depth understanding of the molecular underpinnings of gastric cancer has lagged behind many other cancers of similar incidence and morbidity, owing to our limited knowledge of germline susceptibility traits for risk and somatic drivers of progression (to identify novel therapeutic targets). A few germline (PLCE1) and somatic (ERBB2, ERBB3, PTEN, PI3K/AKT/mTOR, FGF, TP53, CDH1 and MET) alterations are emerging and some are being pursued clinically. Novel somatic gene targets (ARID1A, FAT4, MLL and KMT2C) have also been identified and are of interest. Variations in the therapeutic approaches dependent on geographical region are evident for localized gastric cancer-differences that are driven by preferences for the adjuvant strategies and the extent of surgery coupled with philosophical divides. However, greater uniformity in approach has been noted in the metastatic cancer setting, an incurable condition. Having realized only modest successes, momentum is building for carrying out more phase III comparative trials, with some using biomarker-based patient selection strategies. Overall, rapid progress in biotechnology is improving our molecular understanding and can help with new drug discovery. The future prospects are excellent for defining biomarker-based subsets of patients and application of specific therapeutics. However, many challenges remain to be tackled. Here, we review representative molecular and clinical dimensions of gastric cancer.
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PMID:Gastric cancer-molecular and clinical dimensions. 2406 Oct 39

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.
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PMID:Genetic landscape of esophageal squamous cell carcinoma. 2515 57

Differentiating primary endometrioid or mucinous ovarian tumors from secondary ovarian tumors can be challenging. We compared somatic mutation profiles of primary and secondary ovarian cancers to investigate if these profiles can help diagnose ovarian tumors. Cancer-related genes (n = 115) were screened by target-enriched next-generation sequencing in formalin-fixed, paraffin-embedded tumor tissue from 43 primary endometrioid and mucinous ovarian carcinomas and 28 proven colorectal cancer metastases to the ovary. Results were validated by high-resolution melting curve analysis and Sanger sequencing. TP53, NOTCH1, PIK3CA, and FAT4 versus APC, TP53, KRAS, and FAT4 mutations were the most common in the primary ovarian tumors and ovarian colorectal cancer metastases, respectively. An inactivating APC mutation was found in 4.7% of primary ovarian tumors (2 of 43; 95% CI, 1.6%-10.9%). In contrast, inactivating APC mutations were identified in 71% of colorectal cancer metastases (20 of 28; 95% CI, 55%-88%) (P < 0.001; sensitivity: 71.4%, 95% CI, 51.1%-86.0%; specificity: 95.4%, 95% CI, 82.9%-99.1%). Loss of heterozygosity and APC promoter hypermethylation did not differ significantly between the primary and secondary ovarian tumors. NOTCH1 mutations were observed specifically in primary ovarian tumors, although at a low frequency, but not in metastases (6 of 41; 14.6%; 95% CI, 3.8%-25.4%). APC mutation analysis can be used to differentiate primary endometrioid and mucinous ovarian tumors from colorectal cancer metastases to the ovary.
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PMID:Target-enriched next-generation sequencing reveals differences between primary and secondary ovarian tumors in formalin-fixed, paraffin-embedded tissue. 2554 8

Gastric cancer (GC) is one of the most common malignancies worldwide. Although some driver genes have been identified in GC, the molecular compositions of GC have not been fully understood. The development of next-generation sequencing (NGS) provides a high-throughput and systematic method to identify all genetic alterations in the cancer genome, especially in the field of mutation detection. NGS studies in GC have discovered some novel driver mutations. In this review, we focused on novel gene mutations discovered by NGS studies, along with some well-known driver genes in GC. We organized mutated genes from the perspective of related biological pathways. Mutations in genes relating to genome integrity (TP53, BRCA2), chromatin remodeling (ARID1A), cell adhesion (CDH1, FAT4, CTNNA1), cytoskeleton and cell motility (RHOA), Wnt pathway (CTNNB1, APC, RNF43), and RTK pathway (RTKs, RAS family, MAPK pathway, PIK pathway) are discussed. Efforts to establish a molecular classification based on NGS data which is valuable for future targeted therapy for GC are introduced. Comprehensive dissection of the molecular profile of GC cannot only unveil the molecular basis for GC but also identify genes of clinical utility, especially potential and specific therapeutic targets for GC.
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PMID:Gene mutations in gastric cancer: a review of recent next-generation sequencing studies. 2636 57

Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK-STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer-related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples. Several recurrent somatic mutations involving BCOR (32%), TP53 (16%), DDX3X (12%), FAT4 (8%), NRAS (8%), MLL3 (12%), and MIR17HG (8%) were identified. The pattern of BCOR aberrations (1 nonsense and 5 frame-shift mutations, a mutation leading to a splicing error, and gene loss) suggested that loss of function of BCOR was the functionally important outcome of such changes. The literature was reviewed and the public data on BCOR aberrations was reanalyzed and it was found that the aberrations were frequently found in myeloid neoplasms, but, interestingly, were highly specific to ENKTL among lymphoid malignancies. Given the high frequency and pattern of aberration, BCOR is likely to play an important role in ENKTL pathogenesis as a tumor suppressor gene.
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PMID:Frequent BCOR aberrations in extranodal NK/T-Cell lymphoma, nasal type. 2677 34

Endogenous bornavirus-like nucleoprotein elements (EBLNs) have been discovered in the genomes of various animals including humans, whose functions have been seldom studied. To explore the biological functions of human EBLNs, we constructed a lentiviral vector expressing a short-hairpin RNA against human EBLN1, which successfully inhibited EBLN1 expression by above 80% in infected human oligodendroglia cells (OL cells). We found that EBLN1 silencing suppressed cell proliferation, induced G2/M phase arrest, and promoted apoptosis in OL cells. Gene expression profiling demonstrated that 1067 genes were up-regulated, and 2004 were down-regulated after EBLN1 silencing. The top 10 most upregulated genes were PI3, RND3, BLZF1, SOD2, EPGN, SBSN, INSIG1, OSMR, CREB3L2, and MSMO1, and the top 10 most-downregulated genes were KRTAP2-4, FLRT2, DIDO1, FAT4, ESCO2, ZNF804A, SUV420H1, ZC3H4, YAE1D1, and NCOA5. Pathway analysis revealed that these differentially expressed genes were mainly involved in pathways related to the cell cycle, the mitogen-activated protein kinase pathway, p53 signaling, and apoptosis. The gene expression profiles were validated by using quantitative reverse transcription polymerase chain reaction (RT-PCR) for detecting these 20 most-changed genes. Three genes closely related to glioma, RND3, OSMR, and CREB3L2, were significantly upregulated and might be the key factors in EBLN1 regulating the proliferation and apoptosis of OL cells. This study provides evidence that EBLN1 plays a key role in regulating cell life and death, thereby opening several avenues of investigation regarding EBLN1 in the future.
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PMID:Knock-Down of Endogenous Bornavirus-Like Nucleoprotein 1 Inhibits Cell Growth and Induces Apoptosis in Human Oligodendroglia Cells. 2702 21

E-cadherin (CDH1) is a glycoprotein that mediates adhesion between epithelial cells and also suppresses cancer invasion. Mutation or deletion of the CDH1 gene has been reported in 30-60% cases of invasive lobular carcinoma (ILC). However, little is known about genomic differences between ILC with and without a CDH1 alteration. Therefore, we analyzed whole genome sequencing data of 169 ILC cases from The Cancer Genome Atlas (TCGA) to address this deficiency. Our study shows that CDH1 gene was altered in 59.2% (100/169) of ILC. No significant difference was identified between CDH1-altered and -unaltered ILC cases for any of the examined demographic, clinical or pathologic characteristics, including histologic grade, tumor stage, lymph node metastases, or ER/PR/HER2 states. Seven recurrent mutations (PTEN, MUC16, ERBB2, FAT4, PCDHGA2, HERC1 and FLNC) and four chromosomal changes with recurrent copy number variation (CNV) (11q13, 17q12-21, 8p11 and 8q11) were found in ILC, which correlated with a positive or negative CDH1 alteration status, respectively. The prevalence of the most common breast cancer driver abnormalities including TP53 and PIK3CA mutations and MYC and ERBB2 amplifications showed no difference between the two groups. However, CDH1-altered ILC with an ERBB2 mutation shows a significantly worse prognosis compared to its counterparts without such a mutation. Our study suggests that CDH1-altered ILC patients with ERBB2 mutations may represent an actionable group of patients who could benefit from targeted breast cancer therapy.
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PMID:ERBB2 mutation is associated with a worse prognosis in patients with CDH1 altered invasive lobular cancer of the breast. 2781 64

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C>T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.
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PMID:A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer. 2855 81


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