Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overrepresentation of chromosomal bands 3q25-q29 has been associated with shortened disease-specific survival in head and neck squamous cell carcinoma (HNSCC). To assess the prevalence of copy number gains (>4 signals per cell) and high-level amplifications (>8 signals per cell) from putative oncogenes in this chromosomal region (CCNL1, SNO, PIK3CA, TP73L), tissue microarray analysis was applied on 280 HNSCCs by fluorescence in situ hybridization. Overall frequency of additional copy numbers was 34.3% for CCNL1, 31.8% for SNO, 39.0% for PIK3CA and 38.3% for TP73L, respectively. In general, gains were more frequently detected in stage IV compared to stage I-III tumours. Performing multivariate logistic regression analysis, a significant association of CCNL1 gains and the presence of lymph node metastases was found, which was independent of anatomical site and T-stage of the primary tumour (P=0.049). Site-specific subgroup analysis further showed that copy number gains of CCNL1 and SNO occurred more frequently in oral carcinomas in advanced clinical stages as compared to N0 oral lesions (CCNL1: P=0.03; SNO: P=0.03). Finally, Kaplan-Meier analysis revealed that high-level amplifications of CCNL1 correlated with shorter overall survival of the patients. Our results indicate that CCNL1 plays a critical role in the loco-regional progression of HNSCC and may serve as an indicator for occult advanced tumour stages.
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PMID:Amplification of Cyclin L1 is associated with lymph node metastases in head and neck squamous cell carcinoma (HNSCC). 1570 36

Squamous cell carcinoma of the head and neck (SCCHN) is associated with high morbidity and mortality. Despite significant surgical advances and refinement in the delivery of chemotherapy and radiotherapy, prognosis has improved little in recent decades. Better local control has led to the late presentation of distant metastases and novel therapeutic agents are urgently required to prevent relapse, control disseminated disease and thus improve survival. PIK3CA encodes the p110alpha isoform of phosphoinositide 3-kinase (PI3-K) and is important in SCCHN, aberrations in its activity occurring early in the oncogenic process. PI3-K signalling promotes cell survival, proliferation, invasion and angiogenesis, all contributing to tumour progression. Activation of the PI3-K pathway may also mediate resistance to chemotherapy, radiotherapy and novel therapeutic agents such as epidermal growth factor receptor inhibitors. Elements of this signalling matrix, therefore, offer attractive therapeutic targets in SCCHN as inhibition of many malignant characteristics, as well as sensitisation to multiple treatment modalities, could be anticipated.
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PMID:The phosphoinositide 3-kinase signalling pathway as a therapeutic target in squamous cell carcinoma of the head and neck. 1608 42

Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery for siRNAs toward treatment of bone-metastatic cancer. Accordingly, we report here that i.v. injection of GL3 luciferase siRNA complexed with atelocollagen showed effective reduction of luciferase expression from bone-metastatic prostate tumor cells developed in mouse thorax, jaws, and/or legs. We also show that the siRNA/atelocollagen complex can be efficiently delivered to tumors 24 h after injection and can exist intact at least for 3 days. Furthermore, atelocollagen-mediated systemic administration of siRNAs such as enhancer of zeste homolog 2 and phosphoinositide 3'-hydroxykinase p110-alpha-subunit, which were selected as candidate targets for inhibition of bone metastasis, resulted in an efficient inhibition of metastatic tumor growth in bone tissues. In addition, upregulation of serum IL-12 and IFN-alpha levels was not associated with the in vivo administration of the siRNA/atelocollagen complex. Thus, for treatment of bone metastasis of prostate cancer, an atelocollagen-mediated systemic delivery method could be a reliable and safe approach to the achievement of maximal function of siRNA.
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PMID:Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo. 1609 73

Mutations in the PIK3CA gene have recently been reported in different human neoplasms, including breast cancer. This paper reports the results of a systematic analysis of PIK3CA mutations in different histological types of breast carcinoma. One hundred and eighty invasive breast carcinomas, comprising 74 ductal, 56 lobular, 22 mucinous, 20 medullary, and eight papillary, were selected on the basis of their histological type in a consecutive series of 780 breast cancers. Exons 1-20 of the PIK3CA gene were subjected to SSCP analysis followed by direct sequencing. PIK3CA mutations were observed in 46 (26%) of the 180 tumours examined: 23 (50%) mutations were located in exon 9, and 23 (50%) in exon 20. Mutations were frequent in lobular (46%), less frequent in ductal (22%), and uncommon in medullary (10%), mucinous (5%), and papillary tumours (12%) (p = 0.0002). Mutations in exon 9 were more frequent in lobular carcinomas (30% of cases) than in the other histological types (less than 5% of cases) (p = 0.00014). No significant differences were observed in the distribution of mutations in exon 20. There was no significant correlation between PIK3CA mutations and other clinicopathological and biological variables, including age, tumour size, lymph node metastases, oestrogen receptor (ER) status, progesterone receptor (PgR) status, p53 gene mutations, and p53 protein expression. The findings indicate that in invasive breast carcinomas, PIK3CA alterations are mainly present in lobular and ductal tumours, whereas the other histological types, known to be associated with a favourable prognosis, show a very low incidence of PIK3CA mutations.
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PMID:PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma. 1635 68

Recent studies have shown that the PIK3CA gene, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinases, is mutated in human cancers. To determine whether PIK3CA is altered in cutaneous melanoma, we screened a series of 101 melanoma metastases. We identified PIK3CA missense mutations in three metastases (3%). Interestingly, these mutations were observed only in tumours that were negative for NRAS mutations. Using immunohistochemistry, we also analysed our metastases for the expression of phosphorylated Akt. These analyses revealed a moderate to strong phosphorylated Akt expression in 78% (21 of 27) of metastases with NRAS mutations and in 73% (54 of 74) of metastases without NRAS mutations. Interestingly, the three metastases with mutations in PIK3CA all exhibited a strong expression of phosphorylated Akt. Taken together, our results show that PIK3CA is mutated in a minority of melanomas and suggest that mutations in this gene may represent an alternative mechanism of Akt activation in cutaneous melanoma.
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PMID:Mutations of PIK3CA are rare in cutaneous melanoma. 1656 76

Oral squamous cell carcinoma (OSCC) is a common worldwide malignancy. However, it is unclear what, if any, genomic alterations occur as the disease progresses to invasive and metastatic OSCC. This study used genomewide array-CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases. We used array-based comparative genomic hybridization (array-CGH) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC. In addition, 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes. The highest frequencies of gains were detected in LMYC, REL, TERC, PIK3CA, MYB, MDR1, HRAS, GARP, CCND2, FES, HER2, SIS, and SRY. The highest frequencies of losses were detected in p44S10, TIF1, LPL, MTAP, BMI1, EGR2, and MAP2K5. Genomic alterations in TGFbeta2, cellular retinoid-binding protein 1 gene (CRBP1), PIK3CA, HTR1B, HRAS, ERBB3, and STK6 differed significantly between primary OSCC and their metastatic counterparts. Genomic alterations in PRKCZ, ABL1, and FGF4 were significantly different in patients who died compared with those who survived. Immunohistochemistry confirmed high PIK3CA immunoreactivity in primary and metastatic OSCC. Higher FGF4 immunoreactivity in primary OSCC is associated with a worse prognosis. Loss of CRBP1 immunoreactivity is evident in primary and metastatic OSCC. Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC. As our understanding of these changes grow, this profiling may become a practical tool for clinical evaluation.
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PMID:Array-comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas. 1667 65

Somatic mutations of the PIK3CA gene have recently been detected in various human cancers, including sporadic colorectal cancer. However, mutations of the PIK3CA gene in hereditary colorectal cancers have not been clarified. To elucidate the mutation status in familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC), which are the most common hereditary colorectal cancers, we investigated PIK3CA mutations in 163 colorectal tumors, including adenomas, intramucosal carcinomas and invasive carcinomas. For comparison, we also analyzed mutations of the same gene in 160 sporadic colorectal tumors at various histopathological stages. Analysis at exons 1, 7, 9 and 20 of the PIK3CA gene revealed somatic mutations in 21% (8 of 39) of FAP invasive carcinomas, 21% (7 of 34) of HNPCC invasive carcinomas, 15% (8 of 52) of sporadic invasive carcinomas, and 14% (7 of 50) of sporadic colorectal metastases in the liver. Mutations in FAP and HNPCC carcinomas predominantly occurred in the kinase domain (exon 20), while the majority of mutations in sporadic cases occurred in the helical domain (exon 9). Adenomas and intramucosal carcinomas from all patients exhibited no mutations (0 of 148). Our data suggest that PIK3CA mutations contribute to the invasion step from intramucosal carcinoma to invasive carcinoma in colorectal carcinogenesis in FAP and HNPCC patients at a similar extent to that seen in sporadic patients.
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PMID:Mutations of the PIK3CA gene in hereditary colorectal cancers. 1754 93

PIK3CA, which encodes the catalytic subunit, p110-alpha, of phosphatidylinositol 3-kinase (PI3K), is implicated in the development and progression of numerous neoplasias including head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated the occurrence of PIK3CA hot-spot mutations in exons 9 and 20, the genomic gain and amplification of PIK3CA, the expression of PIK3CA mRNA and the p110 alpha protein, as well as the expression of phosphorylated-Akt (pAkt) in 33 cases of HNSCC and compared the results with the clinicopathological data. No non-synonymous mutations were detected. PIK3CA copy number gain and amplification were found in 36.4 and 9% of the cases, respectively, whereas mRNA overexpression was observed in 48.5% of the cases. No correlations could be stated between DNA gain, DNA amplification and mRNA expression, either between DNA or mRNA status and p110 alpha expression. Direct associations were found between PIK3CA gain and lymph node metastases (p=0.025) and between mRNA expression and tumour stage (p=0.015). A strong correlation was detected between p110 alpha and pAkt expression (p<0.001). Concluding, PIK3CA could be an oncogene implicated in HNSCC development. However, our data suggest that amplifications or mutations of this gene seldom occur in HNSCC and that epigenetic events can play an important role in advanced tumour stages.
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PMID:Analysis of PIK3CA and Akt/protein kinase B in head and neck squamous cell carcinoma. 1754 76

Malignant melanoma originates in melanocytes, the pigment-producing cells of the skin and eye, and is one of the most deadly human cancers with no effective cure for metastatic disease. Like many other cancers, melanoma has both environmental and genetic components. For more than 20 years, the melanoma genome has been subject to extensive scrutiny, which has led to the identification of several genes that contribute to melanoma genesis and progression. Three molecular pathways have been found to be nearly invariably dysregulated in melanocytic tumors, including the RAS-RAF-MEK-ERK pathway (through mutation of BRAF, NRAS or KIT), the p16 INK4A-CDK4-RB pathway (through mutation of INK4A or CDK4) and the ARF-p53 pathway (through mutation of ARF or TP53). Less frequently targeted pathways include the PI3K-AKT pathway (through mutation of NRAS, PTEN or PIK3CA) and the canonical Wnt signaling pathway (through mutation of CTNNB1 or APC). Beyond the specific and well-characterized genetic events leading to activation of proto-oncogenes or inactivation of tumor suppressor genes in these pathways, systematic high-resolution genomic analysis of melanoma specimens has revealed recurrent DNA copy number aberrations as well as perturbations of DNA methylation patterns. Melanoma provides one of the best examples of how genomic analysis can lead to a better understanding of tumor biology. We review current knowledge of the genes involved in the development of melanoma and the molecular pathways in which these genes operate.
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PMID:The genome and epigenome of malignant melanoma. 1804 49

Anaplastic thyroid cancer (ATC) is a rare malignancy. While external beam radiation therapy has improved locoregional control, the median survival of approximately 4 months has not changed in more than half a century due to uncontrolled systemic metastases. The objective of this study was to review the literature in order to identify potential new strategies for treating this highly lethal cancer. PubMed searches were the principal source of articles reviewed. The molecular pathogenesis of ATC includes mutations in BRAF, RAS, catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN, and APC genes, and chromosomal abnormalities are common. Several microarray studies have identified genes and pathways preferentially affected, and dysregulated microRNA profiles differ from differentiated thyroid cancers. Numerous proteins involving transcription factors, signaling pathways, mitosis, proliferation, cell cycle, apoptosis, adhesion, migration, epigenetics, and protein degradation are affected. A variety of agents have been successful in controlling ATC cell growth both in vitro and in nude mice xenografts. While many of these new compounds are in cancer clinical trials, there are few studies being conducted in ATC. With the recent increased knowledge of the many critical genes and proteins affected in ATC, and the extensive array of targeted therapies being developed for cancer patients, there are new opportunities to design clinical trials based upon tumor molecular profiling and preclinical studies of potentially synergistic combinatorial novel therapies.
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PMID:Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. 1898 68


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