9 results on '"Mann, Graham"'
Search Results
2. Proteomic phenotyping of metastatic melanoma reveals putative signatures of MEK inhibitor response and prognosis.
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Krisp, Christoph, Parker, Robert, Pascovici, Dana, Hayward, Nicholas K., Wilmott, James S., Thompson, John F., Mann, Graham J., Long, Georgina V., Scolyer, Richard A., and Molloy, Mark P.
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RESEARCH ,GENETIC mutation ,MELANOMA ,HETEROCYCLIC compounds ,LIQUID chromatography ,PROTEIN kinase inhibitors ,RESEARCH methodology ,PROGNOSIS ,EVALUATION research ,MEDICAL cooperation ,PROTEOMICS ,SKIN tumors ,HYDROLASES ,TUMOR classification ,COMPARATIVE studies ,TRANSFERASES ,SURVIVAL analysis (Biometry) ,MASS spectrometry ,CELL lines ,MEMBRANE proteins ,ANTIGENS ,LONGITUDINAL method - Abstract
Background: Genotyping of melanomas is used to identify patients for treatment with BRAF and MEK inhibitors, but clinical responses are highly variable. This study investigated the utility of protein expression phenotyping to provide an integrated assessment of gene expression programs in BRAF/NRAS melanoma which would be useful for prognosis and may predict response to MEK inhibition.Methods: Mass spectrometry profiling of early passage cell lines established from Stage III cutaneous melanomas was conducted. Basal protein expression was correlated with in vitro response to the MEK inhibitor, selumetinib. Protein expression in a cohort of 32 drug naïve BRAF/NRAS metastatic melanoma specimens was examined. The prognostic utility of a subset of these proteins and mRNA transcripts from a separate cohort was determined.Results: Unsupervised analysis of basal cell line protein abundances delineated response to selumetinib, but BRAF/NRAS genotype did not. Resistance was associated with functions including cell motility, cell adhesion and cytoskeletal organization. Several of these response biomarkers were observed in lymph node biospecimens and correlated with melanoma-specific survival. Loss of ICAM-1 protein and mRNA expression was a strong prognosticator of diminished survival in BRAF/NRAS mutant melanoma.Conclusions: These results demonstrate the utility of proteomic phenotyping to identify both putative biomarkers of response to MEK inhibition and prognostication associated with metastatic melanoma. [ABSTRACT FROM AUTHOR]- Published
- 2018
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3. Mutation load in melanoma is affected by MC1R genotype.
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Johansson, Peter A., Pritchard, Antonia L., Patch, Ann ‐ Marie, Wilmott, James S., Pearson, John V., Waddell, Nicola, Scolyer, Richard A., Mann, Graham J., and Hayward, Nicholas K.
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NUCLEOTIDE sequencing ,GERM cells ,MELANOMA ,GENETIC mutation ,GENOTYPES ,ULTRAVIOLET radiation - Abstract
Whole-genome sequencing of matched germline and tumour pairs in a well-characterized cohort of melanoma patients allowed investigation of associations between melanoma body site, age at melanoma onset and MC1R variant status with overall mutation burden and specific base pair changes observed in the corresponding melanoma. We observed statistically significant associations between mutation burden in melanoma and body site, age at onset and MC1R genotype, for both ultraviolet radiation ( UVR) signature changes (C>T and CC> TT) and non- UVR base pair substitutions, as well as with overall variant load. [ABSTRACT FROM AUTHOR]
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- 2017
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4. Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway.
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Garrido, Maria, Botton, Thomas, Talevich, Eric, Yeh, Iwei, Wang, Nicholas J, Kakavand, Hojabr, Mann, Graham J, Thompson, John F, Olshen, Adam B, Gagnon, Alexander, Gray, Joe W, Scolyer, Richard A, Murali, Rajmohan, Bastian, Boris C, Sanborn, J Zachary, Chung, Jongsuk, Huh, Nam, Wiesner, Thomas, Shain, A Hunter, and Roy, Ritu
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DESMOPLASTIC small round cell tumor ,MELANOMA ,MITOGEN-activated protein kinase phosphatases ,GENETIC mutation ,PHYSIOLOGICAL effects of ultraviolet radiation ,COHORT analysis - Abstract
Desmoplastic melanoma is an uncommon variant of melanoma with sarcomatous histology, distinct clinical behavior and unknown pathogenesis. We performed low-coverage genome and high-coverage exome sequencing of 20 desmoplastic melanomas, followed by targeted sequencing of 293 genes in a validation cohort of 42 cases. A high mutation burden (median of 62 mutations/Mb) ranked desmoplastic melanoma among the most highly mutated cancers. Mutation patterns strongly implicate ultraviolet radiation as the dominant mutagen, indicating a superficially located cell of origin. Newly identified alterations included recurrent promoter mutations of NFKBIE, encoding NF-κB inhibitor ɛ (IκBɛ), in 14.5% of samples. Common oncogenic mutations in melanomas, in particular in BRAF (encoding p.Val600Glu) and NRAS (encoding p.Gln61Lys or p.Gln61Arg), were absent. Instead, other genetic alterations known to activate the MAPK and PI3K signaling cascades were identified in 73% of samples, affecting NF1, CBL, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, PTPN11, MET, RAC1, SOS2, NRAS and PIK3CA, some of which are candidates for targeted therapies. [ABSTRACT FROM AUTHOR]
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- 2015
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5. MicroRNA and mRNA expression profiling in metastatic melanoma reveal associations with BRAF mutation and patient prognosis.
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Tembe, Varsha, Schramm, Sarah ‐ Jane, Stark, Mitchell S., Patrick, Ellis, Jayaswal, Vivek, Tang, Yue Hang, Barbour, Andrew, Hayward, Nicholas K., Thompson, John F., Scolyer, Richard A., Yang, Yee Hwa, and Mann, Graham J.
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MICRORNA ,MESSENGER RNA ,GENE expression profiling ,MELANOMA prognosis ,BRAF genes ,GENETIC mutation ,CARCINOGENESIS ,BIOMARKERS - Abstract
The role of microRNAs (miRNAs) in melanoma is unclear. We examined global miRNA expression profiles in fresh-frozen metastatic melanomas in relation to clinical outcome and BRAF mutation, with validation in independent cohorts of tumours and sera. We integrated miRNA and mRNA information from the same samples and elucidated networks associated with outcome and mutation. Associations with prognosis were replicated for miR-150-5p, miR-142-3p and miR-142-5p. Co-analysis of miRNA and mRNA uncovered a network associated with poor prognosis ( PP) that paradoxically favoured expression of miRNAs opposing tumorigenesis. These miRNAs are likely part of an autoregulatory response to oncogenic drivers, rather than drivers themselves. Robust association of miR-150-5p and the miR-142 duplex with good prognosis and earlier stage metastatic melanoma supports their potential as biomarkers. miRNAs overexpressed in association with PP in an autoregulatory fashion will not be suitable therapeutic targets. [ABSTRACT FROM AUTHOR]
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- 2015
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6. Low prevalence of RAS-RAF-activating mutations in Spitz melanocytic nevi compared with other melanocytic lesions.
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Indsto, James O., Kumar, Swapna, Lixiang Wang, Crotty, Kerry A., Arbuckle, Susan M., and Mann, Graham J.
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MELANOMA ,METASTASIS ,ONCOGENES ,CELL proliferation ,GERM cells ,GENETIC mutation - Abstract
Melanocytic lesions, including Spitz nevi (SN), common benign nevi (CBN) and cutaneous metastatic melanoma (CMM), were analyzed for activating mutations in NRAS, HRAS and BRAF oncogenes, which induce cellular proliferation via the MAP kinase pathway. One of 22 (4.5%) SN tested showed an HRAS G61L mutation. Another lesion, a ‘halo’ SN, showed a BRAF V600E (T1796A) mutation. BRAF V600E mutations were found in two thirds (20/31) of CBN, while a further 19% (6/31) showed NRAS codon 61 mutations. One third of CMM (10/30) had various BRAF mutations of codon 600, and a further 6% (2/31) showed NRAS codon 61 mutations. Seventeen SN tested for loss of heterozygosity (LOH) at 9p and 10q regions, known to be frequently deleted in melanoma, showed LOH at the 9p loci D9S942 and IFNA. A further lesion was found with low-level microsatellite instability at one locus, D10S214. The low rate of RAS-RAF mutations (2/22, 9.1%) observed in SN suggests that these lesions harbor as yet undetected activating mutations in other components of the RAS-RAF-MEK-ERK-MAPK pathway. Germline DNA from members of 111 multiple-case melanoma families, representing a range of known ( CDKN2A) and unknown predisposing gene defects, was analyzed for germline BRAF mutations, but none was found. [ABSTRACT FROM AUTHOR]
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- 2007
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7. EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer.
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Clancy, Jennifer L, Henderson, Michelle J, Russell, Amanda J, Anderson, David W, Bova, Ronaldo J, Campbell, Ian G, Choong, David YH, Macdonald, Graeme A, Mann, Graham J, Nolan, Tania, Brady, Ged, Olopade, Olufunmilayo I, Woollatt, Erica, Davies, Michael J, Segara, Davendra, Hacker, Neville F, Henshall, Susan M, Sutherland, Robert L, and Watts, Colin KW
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TUMOR suppressor genes ,CANCER genetics ,GENE expression ,GENETIC mutation ,GENETICS - Abstract
EDD (E3 isolated by differential display), located at chromosome 8q22.3, is the human orthologue of the Drosophila melanogaster tumour suppressor gene ‘hyperplastic discs’ and encodes a HECT domain E3 ubiquitin protein-ligase. To investigate the possible involvement of EDD in human cancer, several cancers from diverse tissue sites were analysed for allelic gain or loss (allelic imbalance, AI) at the EDD locus using an EDD-specific microsatellite, CEDD, and other polymorphic microsatellites mapped in the vicinity of the 8q22.3 locus. Of 143 cancers studied, 38 had AI at CEDD (42% of 90 informative cases). In 14 of these cases, discrete regions of imbalance encompassing 8q22.3 were present, while the remainder had more extensive 8q aberrations. AI of CEDD was most frequent in ovarian cancer (22/47 informative cases, 47%), particularly in the serous subtype (16/22, 73%), but was rare in benign and borderline ovarian tumours. AI was also common in breast cancer (31%), hepatocellular carcinoma (46%), squamous cell carcinoma of the tongue (50%) and metastatic melanoma (18%). AI is likely to represent amplification of the EDD gene locus rather than loss of heterozygosity, as quantitative RT-PCR and immunohistochemistry showed that EDD mRNA and protein are frequently overexpressed in breast and ovarian cancers, while among breast cancer cell lines EDD overexpression and increased gene copy number were correlated. These results demonstrate that AI at the EDD locus is common in a diversity of carcinomas and that the EDD gene is frequently overexpressed in breast and ovarian cancer, implying a potential role in cancer progression.Oncogene (2003) 22, 5070-5081. doi:10.1038/sj.onc.1206775 [ABSTRACT FROM AUTHOR]
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- 2003
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8. Geographical variation in the penetrance of CDKN2A mutations for melanoma.
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Bishop, D. Timothy, Demenais, Florence, Goldstein, Alisa M., Bergman, Wilma, Bishop, Julia Newton, Bressac-de Paillerets, Brigitte, Chompret, Agnès, Ghiorzo, Paola, Gruis, Nelleke, Hansson, Johan, Harland, Mark, Hayward, Nicholas, Holland, Elizabeth A., Mann, Graham J., Mantelli, Michela, Nancarrow, Derek, Platz, Anton, Tucker, Margaret A., Chompret, Agnès, and Melanoma Genetics Consortium
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MELANOMA ,GENETIC mutation ,CHROMOSOMES ,COMPARATIVE studies ,DISEASE susceptibility ,FAMILIES ,GENETICS ,RESEARCH methodology ,MEDICAL cooperation ,ONCOGENES ,POPULATION geography ,PROTEINS ,RESEARCH ,EVALUATION research - Abstract
Background: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium.Methods: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14ARF protein, and population melanoma incidence rates. All statistical tests were two-sided.Results: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P =.003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia.Conclusions: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance. [ABSTRACT FROM AUTHOR]- Published
- 2002
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9. Functional impairment of p16INK4A due to CDKN2A p.Gly23Asp missense mutation
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Scaini, Maria Chiara, Rossi, Elisabetta, de Siqueira Torres, Paula Lobao Antunes, Zullato, Daniela, Callegaro, Monia, Casella, Cinzia, Quaggio, Monica, Agata, Simona, Malacrida, Sandro, Chiarion-Sileni, Vanna, Vecchiato, Antonella, Alaibac, Mauro, Montagna, Marco, Mann, Graham J., Menin, Chiara, and D’Andrea, Emma
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CELL physiology , *GENETIC code , *GENETIC mutation , *TUMOR suppressor proteins , *CELL cycle , *CELLULAR control mechanisms , *GERM cells , *FAMILIAL diseases - Abstract
Abstract: The CDKN2A locus encodes for two distinct tumor suppressor proteins, p16INK4A and p14ARF, involved in cell cycle regulation. CDKN2A germline mutations have been associated with familial predisposition to melanoma and other tumor types. Besides bona-fide pathogenic mutations, many sequence variants have been identified, but their effect is not well known. We detected the p.Gly23Asp missense mutation in one of the two tested melanoma patients of a family with three melanoma cases. Even though the mutated amino acid is located in a conserved domain that specifically binds to and blocks the function of CDK4/6, its lack of segregation with disease suggested a series of functional assays to discriminate between a pathogenic variant and a neutral polymorphism. The effect of this mutation has been investigated exploiting four p16INK4A properties: its ability (i) to bind CDK4, (ii) to inhibit pRb phosphorylation, (iii) to evenly localize in the cell, and (iv) to cause cell cycle arrest. The mutant protein properties were evaluated transfecting three different cell lines (U2-OS and NM-39, both p16-null, and SaOS 2, p53 and pRb-null) with plasmids expressing either p16wt, p1623Asp, or the p1632Pro pathogenic variant. We found that p1623Asp was less efficient than p16wt in CDK4 binding, in inhibiting pRb phosphorylation, in inducing G1 cell cycle arrest; moreover, its pattern of distribution throughout the cell was suggestive of protein aggregation, thus assessing a pathogenic role for p1623Asp in familial melanoma. [Copyright &y& Elsevier]
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- 2009
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