Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inherited mutations of the BRCA2 gene give rise to a multi-site cancer phenotype which includes breast cancer (in female and males), ovarian, pancreatic and prostate cancer, ocular and other melanomas, laryngeal, colon and stomach cancers. Interpretation of test results and risk assessment is therefore complex. It has been proposed that families with mutations in the ovarian cancer cluster region (OCCR) of exon 11 (nucleotides 3035-6629) express a higher ratio of ovarian to breast cancer, than families with mutations elsewhere in the BRCA2 gene. In this study we have investigated the presence of 7 types of cancer (ovary, male breast, pancreas, prostate, colon, stomach and melanoma) in first- and second-degree relatives of mutation-positive individuals in 440 families with a BRCA2 mutation. We reviewed histories of cancer in relatives among families with mutations distributed throughout the gene. Families with ovarian cancer were more likely to harbour mutations in the OCCR (nucleotides 3035-6629) than elsewhere in the gene (OR = 2.21; P = 0.0002). We also compared cancer risks according to ethnic group. Ashkenazi Jewish families with the 6174delT founder mutation were more likely to have a family member with ovarian cancer (OR = 1.58; P = 0.002) and less likely to have a family member with prostate cancer (OR = 0.62; P = 0.04) than were non-Jewish families. In contrast, a reduced presence of ovarian cancer was found in families of French-Canadian ancestry, compared to other ancestries (OR = 0.37; P = 0.0026). A high risk of male breast cancer was observed with the 6503delTT mutation (OR = 15.7; P = 0.023). Families of Polish ancestry had a reduced frequency of pancreatic cancer (OR = 0.0; P = 0.03) compared to families of other ethnic origins. In conclusion, both the position of mutation and the ethnic background of the family appear to contribute to the phenotypic variation observed in families with BRCA2 mutations.
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PMID:Cancer variation associated with the position of the mutation in the BRCA2 gene. 1513 99

The dismal prognosis of ductal pancreatic adenocarcinoma is mainly attributable to advanced tumor stages at the time of diagnosis. Meanwhile, familial pancreatic cancer is an established hereditary tumor entity that is responsible for approximately 3% of pancreatic cancer (PC) cases. Therefore, analysis of the family history may help to identify individuals at increased risk of developing PC. These include members of families with a history of PC as well as those of families with distinct hereditary cancer syndromes such as Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma syndrome, hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colorectal cancer. In future, the identification of germline mutations in genes predisposing to PC, together with the analysis of exogenous risk factors, could be used for a more precise risk assessment for the development of PC. This may allow the application of invasive screening methods for the identification of early PC or, even better, its precursor lesions in high-risk individuals, providing the option of timely curative pancreatectomy.
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PMID:Familial pancreatic cancer. 1513 9

Germline CDKN2A mutations have been observed in approximately 20 percent of familial melanoma kindreds from North America, Europe and Australasia. There is also an increased risk of pancreatic cancer in a subset of families with mutations, however, the precise relationship between the CDKN2A gene and pancreatic cancer remains unknown. The relationships between familial melanoma, pancreatic cancer and germline CDKN2A mutations were examined using published data. There were 67 different CDKN2A mutations in 189 melanoma-prone families. Forty-two families (18 mutations) had pancreatic cancer reported. For families without reported pancreatic cancer, the most common types of mutations were missense (56%), frameshift (12%), and deletions (12%). For families with pancreatic cancer, missense (56%), splicing (17%), and frameshift (11%) mutations were most common. Seventy percent of the mutations were observed only once, while the remainder recurred in different families. Comparison of 147 melanoma-prone families without pancreatic cancer to the 42 families that had pancreatic cancer reported showed no significant differences in the types or locations of mutations. However, there was a significant difference (p=0.002) in the distribution of families across the four ankyrin repeats. This finding primarily resulted from the six most frequent mutations where the distribution of pancreatic cancer varied significantly (p=0.02) from at least 30% in c.301G>T (p.G101W), c.225_243del19 (p.P75fs), c.337_338insGTC (p.R112_L113insR), and c.377T>A (p.V126D) families to less than 10% in c.71G>C (p.R24P) and c.159G>C (p.M53I) families. Further research utilizing individual-specific data will be required to determine whether these patterns represent etiologic differences or incomplete reporting of cancer and mutation data.
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PMID:Familial melanoma, pancreatic cancer and germline CDKN2A mutations. 1514 71

The hereditary predisposition to cancer dates historically to interest piqued by physicians as well as family members wherein striking phenotypic features were shown to cluster in families, inclusive of the rather grotesque cutaneous findings in von Recklinghausen's neurofibromatosis, which date back to the sixteenth century. The search for the role of primary genetic factors was heralded by studies at the infrahuman level, particularly on laboratory mouse strains with strong susceptibility to carcinogen-induced cancer, and conversely, with resistance to the same carcinogens. These studies, developed in the 19th and 20th centuries, continue today. This article traces the historical aspects of hereditary cancer dealing with identification and ultimate molecular genetic confirmation of commonly occurring cancers, particularly of the colon in the case of familial adenomatous polyposis and its attenuated form, both due to the APC germline mutation; the Lynch syndrome due to mutations in mismatch repair genes, the most common of which were found to be MSH2, MLH1, and MSH6 germline mutations; the hereditary breast-ovarian cancer syndrome with BRCA1 and BRCA2 germline mutations; the Li-Fraumeni (SBLA) syndrome due to the p53 mutation; and the familial atypical multiple mole melanoma in association with pancreatic cancer due to the CDKN2A (p16) germline mutation. These and other hereditary cancer syndromes have been discussed in some detail relevant to their characterization, which, for many conditions, took place in the late 18th century and, in the more modern molecular genetic era, during the past two decades. Emphasis has been placed upon the manner in which improved cancer control will emanate from these discoveries.
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PMID:Inherited predisposition to cancer: a historical overview. 1526 68

Heat shock proteins (HSPs) exist ubiquitously across all species and function as chaperones stabilizing and delivering peptides. Tumor-derived HSP-peptide complex has been known to induce immunity against the original tumor in preclinical studies. HSP-based vaccines work across tumor types and bypass the need for identifying the responsible peptide(s) for inducing immunity. These vaccines are tumor- and patient-specific in that they capture the tumor cells' fingerprints. HSP-based vaccines have been studied in early phase clinical trials, mostly using HSP glycoprotein 96, for various types of malignancies including melanoma, renal cell carcinoma, gastric cancer, pancreatic cancer, low-grade lymphoma, colorectal cancer and chronic myelogenous leukemia. All showed minimal toxicity and potential efficacy. Phase III studies for melanoma and renal cell carcinoma are ongoing. HSP-based vaccines are a novel vaccine preparation with a promising role in cancer management. Further studies to determine the administering strategy and specific indication are warranted.
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PMID:Heat shock protein-based cancer vaccines. 1527 Jun 45

Selective antitumor chemotherapy can be achieved by using antibody-drug conjugates that recognize surface proteins upregulated in cancer cells. One such receptor is integrin alpha3beta1, which is overexpressed on malignant melanoma, prostate carcinoma, and glioma cells. We previously identified a human single-chain Fv antibody (scFv), denoted Pan10, specific for integrin alpha3beta1 that is internalized by human pancreatic cancer cells. Herein, we describe the chemical introduction of reactive thiol groups onto Pan10, the specific conjugation of the modified scFv to maleimide-derivatized analogs of the potent cytotoxic agent duocarmycin SA, and the properties of the resultant conjugates. Our findings provide evidence that Pan10-drug conjugates maintain the internalizing capacity of the parent scFv and are cytotoxic at nanomolar concentrations. Our Pan10-drug conjugates may be promising candidates for targeted chemotherapy of malignant diseases associated with overexpression of integrin alpha3beta1.
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PMID:A human single-chain antibody specific for integrin alpha3beta1 capable of cell internalization and delivery of antitumor agents. 1527 48

An evolutionary recombination hotspot around the GSDML-GSDM locus at human chromosome 17q21 is closely linked to an oncogenomic recombination hotspot around the PPP1R1B-STARD3-TCAP-PNMT-PERLD1 (MGC9753)-ERBB2-C17orf37 (MGC14832)-GRB7 locus at human chromosome 17q12. Here, we identified DFNA5L (GSDMDC1) gene related to GSDM and GSDML genes by using bioinformatics. Human DFNA5L gene at chromosome 8q24.3 was linked to ZC3HDC3, PP3856, EEF1D, and TIGD5 genes. NM_024736.4 (AK127941.1), AK022212.1, BC008904.2, and BC069000.1 cDNAs were derived from human DFNA5L gene. BC008904.2 was the representative human DFNA5L cDNA, while NM_024736.4 was an aberrant human DFNA5L cDNA with frame shifts due to the retention of introns 1, 3, 4, 5 and 8. Human DFNA5L mRNA was expressed in placenta, pancreatic cancer, prostate cancer, melanoma, salivary gland tumor, Jarkat T cells, and Ramos B cells. Complete coding sequence of rat Dfna5l cDNA was determined by assembling 11 exons of rat Dfna5l gene within AC120830.4 genome sequence, and that of mouse Dfna5l cDNA was derived from 1810036L03 (NM_026960.1). Exon-intron boundaries were conserved among human DFNA5L and rodent Dfna5l genes. Human DFNA5L (484 aa) showed 59.5% total-amino-acid identity with rat Dfna5l (488 aa), and 58.7% total-amino-acid identity with mouse Dfna5l (487 aa). DFNA5L orthologs were DNFA5 (GSDM) domain containing DFNA5 DC or GSDMDC proteins with Coiled-coil and Leucine zipper domains. Human DFNA5L, GSDM, GSDML, MLZE, DFNA5 and their mammalian orthologs were found to constitute the DFNA5 DC (GSDMDC) family. Because DFNA5 and MLZE are cancer-associated genes, DFNA5L, GSDM, and GSDML are predicted cancer associated genes.
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PMID:Identification and characterization of human DFNA5L, mouse Dfna5l, and rat Dfna5l genes in silico. 1528 81

It has been shown that the polyunsaturated fatty acid docosahexaenoic acid (DHA) can sensitize various tumor cells to reactive oxygen species (ROS)-inducing anticancer agents. Recently, we demonstrated that DHA also enhances the apoptotic effect of clinically achievable concentrations (1-2 microM) of arsenic trioxide (As2O3) in several As2O3-resistant human leukemic cell lines via a ROS-dependent mechanism. The aim of the present study was to evaluate whether this combined effect of As2O3 and DHA is also applicable to As2O3-resistant solid tumor cells. We have tested 12 different tumor cell lines, including MDA-MB-468, SK-BR-3, MCF-7 (breast cancer), ES-2, SKOV-3 (ovarian cancer), HT-29, SW-620, LS-174T (colon cancer), PC-3 (prostate cancer), HeLa (cervical cancer), PANC-1 (pancreatic cancer) and one primary melanoma cell line. With the exception of MDA-MB-468 and ES-2, all cells were resistant to treatment with either As2O3 or DHA alone. However, combined treatment with As2O3 and DHA significantly reduced viability in 7 of the 10 As2O3-resistant solid tumors tested. The cytotoxic effect of As2O3 and DHA was associated with the induction of apoptosis and a concomitant increase of intracellular lipid peroxidation products. Importantly, the combined effect of As2O3 and DHA was selectively toxic for malignant cells since no cytotoxic effect was observed in normal skin fibroblasts, human microvascular endothelial cells and peripheral blood mononuclear cells derived from healthy donors. Our data indicate that DHA may help to extend the therapeutic spectrum of As2O3 in the treatment of solid tumors since it may overcome de novo or acquired resistance to As2O3.
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PMID:Enhancement of arsenic trioxide-mediated apoptosis using docosahexaenoic acid in arsenic trioxide-resistant solid tumor cells. 1538 55

Pancreatic cancer (PC) is the most fatal of all gastrointestinal cancers, wherein its mortality compares strikingly with its incidence. Unfortunately, 80-90% of PCs are diagnosed in the nonresectable stage. While the lifetime risk of PC in developed countries is approximately 1-3%, it is the fifth most common cause of cancer deaths among both males and females in Western countries. It occurs in excess in Jews. Approximately 5-10% of PC shows familial clustering. Examination of such familial clusters must take into consideration cancers of diverse anatomic sites, such as malignant melanoma in the familial atypical multiple melanoma (FAMMM) syndrome due to the CDKN2A (p16) germline mutation, and combinations of colorectal and endometrial carcinoma, ovarian carcinoma, and several other cancers in hereditary nonpolyposis colorectal cancer (HNPCC), which are due to mismatch repair germline mutations, the most common of which are MSH2 and MLH1 . Other hereditary disorders predisposing to PC include Peutz-Jeghers syndrome, due to the STK11 mutation, familial pancreatitis due to the cationic trypsinogen gene, site-specific familial pancreatic cancer which may be due to the 4q32-34 mutation, hereditary breast-ovarian cancer (HBOC) syndrome that is due to BRCA2 and possibly some families with HBOC that is due to BRCA1 , familial adenomatous polyposis due to the ATP gene, and ataxia telangiectasia due to the ATM germline mutation. This extant heterogeneity mandates that the physician be knowledgeable about these PC-prone syndromes which play such an important role when considering the differential diagnosis of hereditary PC. Unfortunately, there are no PC screening programs with acceptable sensitivity and specificity. However, the gold standard for screening at this time is endoscopic ultrasound. Clearly, there is a great need for the development of novel screening approaches with acceptable sensitivity and specificity. Further research is needed to elucidate those etiologic factors that contribute to the apparent excess of PC in Ashkenazi Jews. Attention should also be given to the search for mutations predisposing to PC in Jews so that opportunities to learn more about the disease's pathogenesis, as well as screening and control, may take place.
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PMID:Familial pancreatic carcinoma in Jews. 1551 47

Sonic hedgehog (SHH), Indian hedgehog (IHH) and Desert hedgehog (DHH) are Hedgehog family ligands, which play key roles in embryogenesis and carcinogenesis, especially in pancreatic cancer and gastric cancer. Drosophila Costal-2 (Cos2) is a Hedgehog signaling regulator, interacting with Smoothened (Smo), Cubitus interruptus (Ci), Fused (Fu) and microtubule. KIF27 is one of the mammalian orthologs for Drosophila Cos2. KIF7 gene is the paralog of KIF27 gene; however, complete coding sequence (CDS) of KIF7 remains elusive. Here we characterized human KIF7 gene by using bioinformatics. Human LOC374654 cDNA (NM_198525.1) was a 5'-truncated partial KIF7 cDNA, corresponding to the nucleotide position 1418-4538 of KIF7 complete CDS. KIF7 gene, consisting of 19 exons, was found to encode a 1343-amino-acid KIF7 protein. Human KIF7 showed 43.6% total-amino-acid identity with human KIF27. Kinesin motor catalytic (KISc) domain (codon 15-347 of KIF7) and novel KIF7-KIF27 homologous (KIF727H) domain (codon 699-1196 of KIF7) were well conserved between KIF7 and KIF27. Three coiled-coil regions were located within the KIF727H domain. KIF7 and KIF27 were N-type Kinesins with the KIF727H domain. KIF7 mRNA was expressed in embryonic stem (ES) cells, melanotic melanoma and Jurkat T cells, while KIF27 mRNA was expressed in testis, pancreatic islet, germ cell tumors and Jurkat T cells. This is the first report on the characterization of the KIF7 gene as well as on the identification of KIF727H domain.
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PMID:Characterization of KIF7 gene in silico. 1554 30


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