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Your search keyword '"Spindler, TJ"' showing total 4 results
Start Over Author "Spindler, TJ" Topic ovarian neoplasms
4 results on '"Spindler, TJ"'

1. Identification of novel candidate biomarkers of epithelial ovarian cancer by profiling the secretomes of three-dimensional genetic models of ovarian carcinogenesis.

Author

Lawrenson K, Mhawech-Fauceglia P, Worthington J, Spindler TJ, O'Brien D, Lee JM, Spain G, Sharifian M, Wang G, Darcy KM, Pejovic T, Sowter H, Timms JF, and Gayther SA

Subjects
Adipokines metabolism, Apoptosis Regulatory Proteins metabolism, Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Chitinase-3-Like Protein 1, Fatty Acid Synthase, Type I metabolism, Female, Gas Chromatography-Mass Spectrometry methods, Gene Expression Regulation, Neoplastic, Humans, In Vitro Techniques, Lectins metabolism, Models, Genetic, Neoplasms, Glandular and Epithelial pathology, Nuclear Proteins metabolism, Ovarian Neoplasms pathology, Prognosis, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-myc metabolism, Proto-Oncogene Proteins p21(ras), ras Proteins metabolism, Biomarkers, Tumor metabolism, Neoplasms, Glandular and Epithelial genetics, Neoplasms, Glandular and Epithelial metabolism, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Proteomics methods, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-myc genetics, ras Proteins genetics
Abstract

Epithelial ovarian cancer (EOC) is still considered the most lethal gynecological malignancy and improved early detection of ovarian cancer is crucial to improving patient prognoses. To address this need, we tested whether candidate EOC biomarkers can be identified using three-dimensional (3D) in vitro models. We quantified changes in the abundance of secreted proteins in a 3D genetic model of early-stage EOC, generated by expressing CMYC and KRAS(G) (12) (V) in TERT-immortalized normal ovarian epithelial cells. Cellular proteins were labeled in live cells using stable isotopic amino acid analogues, and secreted proteins identified and quantified using liquid chromatography-tandem mass spectrometry. Thirty-seven and 55 proteins were differentially expressed by CMYC and CMYC+KRAS(G) (12) (V) expressing cells respectively (p < 0.05; >2-fold). We evaluated expression of the top candidate biomarkers in ∼210 primary EOCs: CHI3L1 and FKBP4 are both expressed by >96% of primary EOCs, and FASN and API5 are expressed by 86 and 75% of cases. High expression of CHI3L1 and FKBP4 was associated with worse patient survival (p = 0.042 and p = 0.002, respectively). Expression of LGALS3BP was positively associated with recurrence (p = 0.0001) and suboptimal debulking (p = 0.018) suggesting that these proteins may be novel prognostic biomarkers. Furthermore, within early stage tumours (I/II), high expression of API5, CHI3L1 and FASN was associated with high tumour grade (p = 3 × 10(-4) , p = 0.016, p = 0.010, respectively). We show in vitro cell biology models of early-stage cancer development can be used to identify novel candidate biomarkers for disease, and report the identification of proteins that represent novel potential candidate diagnostic and prognostic biomarkers for this highly lethal disease., (© 2014 UICC.)

Published
2015
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2. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

Author

Lawrenson K, Li Q, Kar S, Seo JH, Tyrer J, Spindler TJ, Lee J, Chen Y, Karst A, Drapkin R, Aben KK, Anton-Culver H, Antonenkova N, Baker H, Bandera EV, Bean Y, Beckmann MW, Berchuck A, Bisogna M, Bjorge L, Bogdanova N, Brinton LA, Brooks-Wilson A, Bruinsma F, Butzow R, Campbell IG, Carty K, Chang-Claude J, Chenevix-Trench G, Chen A, Chen Z, Cook LS, Cramer DW, Cunningham JM, Cybulski C, Dansonka-Mieszkowska A, Dennis J, Dicks E, Doherty JA, Dörk T, du Bois A, Dürst M, Eccles D, Easton DT, Edwards RP, Eilber U, Ekici AB, Fasching PA, Fridley BL, Gao YT, Gentry-Maharaj A, Giles GG, Glasspool R, Goode EL, Goodman MT, Grownwald J, Harrington P, Harter P, Hasmad HN, Hein A, Heitz F, Hildebrandt MA, Hillemanns P, Hogdall E, Hogdall C, Hosono S, Iversen ES, Jakubowska A, James P, Jensen A, Ji BT, Karlan BY, Kruger Kjaer S, Kelemen LE, Kellar M, Kelley JL, Kiemeney LA, Krakstad C, Kupryjanczyk J, Lambrechts D, Lambrechts S, Le ND, Lee AW, Lele S, Leminen A, Lester J, Levine DA, Liang D, Lissowska J, Lu K, Lubinski J, Lundvall L, Massuger LF, Matsuo K, McGuire V, McLaughlin JR, Nevanlinna H, McNeish I, Menon U, Modugno F, Moysich KB, Narod SA, Nedergaard L, Ness RB, Azmi MA, Odunsi K, Olson SH, Orlow I, Orsulic S, Weber RP, Pearce CL, Pejovic T, Pelttari LM, Permuth-Wey J, Phelan CM, Pike MC, Poole EM, Ramus SJ, Risch HA, Rosen B, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Rzepecka IK, Salvesen HB, Schildkraut JM, Schwaab I, Sellers TA, Shu XO, Shvetsov YB, Siddiqui N, Sieh W, Song H, Southey MC, Sucheston L, Tangen IL, Teo SH, Terry KL, Thompson PJ, Timorek A, Tsai YY, Tworoger SS, van Altena AM, Van Nieuwenhuysen E, Vergote I, Vierkant RA, Wang-Gohrke S, Walsh C, Wentzensen N, Whittemore AS, Wicklund KG, Wilkens LR, Woo YL, Wu X, Wu AH, Yang H, Zheng W, Ziogas A, Monteiro A, Pharoah PD, Gayther SA, and Freedman ML

Subjects
Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Neoplasm Proteins metabolism, Neoplasms, Glandular and Epithelial metabolism, Nuchal Cord, Ovarian Neoplasms metabolism, Protein Binding, Genetic Association Studies, Neoplasm Proteins genetics, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics, Quantitative Trait Loci
Abstract

Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

Published
2015
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3. Genome-wide significant risk associations for mucinous ovarian carcinoma.

Author

Kelemen LE, Lawrenson K, Tyrer J, Li Q, Lee JM, Seo JH, Phelan CM, Beesley J, Chen X, Spindler TJ, Aben KK, Anton-Culver H, and Antonenkova N

Subjects
Base Sequence, Cell Line, Tumor, Cell Nucleus metabolism, Chromosomes, Human, Pair 2 genetics, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies methods, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Microscopy, Fluorescence, Molecular Sequence Data, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Quantitative Trait Loci genetics, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Adenocarcinoma, Mucinous genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

Published
2015
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4. Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Author

Kuchenbaecker KB, Ramus SJ, Tyrer J, Lee A, Shen HC, Beesley J, Lawrenson K, McGuffog L, Healey S, Lee JM, Spindler TJ, Lin YG, Pejovic T, Bean Y, Li Q, Coetzee S, Hazelett D, Miron A, Southey M, Terry MB, Goldgar DE, Buys SS, Janavicius R, Dorfling CM, van Rensburg EJ, Neuhausen SL, Ding YC, Hansen TV, Jønson L, Gerdes AM, Ejlertsen B, Barrowdale D, Dennis J, Benitez J, Osorio A, Garcia MJ, Komenaka I, Weitzel JN, Ganschow P, Peterlongo P, Bernard L, Viel A, Bonanni B, Peissel B, Manoukian S, Radice P, Papi L, Ottini L, Fostira F, Konstantopoulou I, Garber J, Frost D, Perkins J, Platte R, Ellis S, Godwin AK, Schmutzler RK, Meindl A, Engel C, Sutter C, Sinilnikova OM, Damiola F, Mazoyer S, Stoppa-Lyonnet D, Claes K, De Leeneer K, Kirk J, Rodriguez GC, Piedmonte M, O'Malley DM, de la Hoya M, Caldes T, Aittomäki K, Nevanlinna H, Collée JM, Rookus MA, Oosterwijk JC, Tihomirova L, Tung N, Hamann U, Isaccs C, Tischkowitz M, Imyanitov EN, Caligo MA, Campbell IG, Hogervorst FB, Olah E, Diez O, Blanco I, Brunet J, Lazaro C, Pujana MA, Jakubowska A, Gronwald J, Lubinski J, Sukiennicki G, Barkardottir RB, Plante M, Simard J, Soucy P, Montagna M, Tognazzo S, Teixeira MR, Pankratz VS, Wang X, Lindor N, Szabo CI, Kauff N, Vijai J, Aghajanian CA, Pfeiler G, Berger A, Singer CF, Tea MK, Phelan CM, Greene MH, Mai PL, Rennert G, Mulligan AM, Tchatchou S, Andrulis IL, Glendon G, Toland AE, Jensen UB, Kruse TA, Thomassen M, Bojesen A, Zidan J, Friedman E, Laitman Y, Soller M, Liljegren A, Arver B, Einbeigi Z, Stenmark-Askmalm M, Olopade OI, Nussbaum RL, Rebbeck TR, Nathanson KL, Domchek SM, Lu KH, Karlan BY, Walsh C, Lester J, Hein A, Ekici AB, Beckmann MW, Fasching PA, Lambrechts D, Van Nieuwenhuysen E, Vergote I, Lambrechts S, Dicks E, Doherty JA, Wicklund KG, Rossing MA, Rudolph A, Chang-Claude J, Wang-Gohrke S, Eilber U, Moysich KB, Odunsi K, Sucheston L, Lele S, Wilkens LR, Goodman MT, Thompson PJ, Shvetsov YB, Runnebaum IB, Dürst M, Hillemanns P, Dörk T, Antonenkova N, Bogdanova N, Leminen A, Pelttari LM, Butzow R, Modugno F, Kelley JL, Edwards RP, Ness RB, du Bois A, Heitz F, Schwaab I, Harter P, Matsuo K, Hosono S, Orsulic S, Jensen A, Kjaer SK, Hogdall E, Hasmad HN, Azmi MA, Teo SH, Woo YL, Fridley BL, Goode EL, Cunningham JM, Vierkant RA, Bruinsma F, Giles GG, Liang D, Hildebrandt MA, Wu X, Levine DA, Bisogna M, Berchuck A, Iversen ES, Schildkraut JM, Concannon P, Weber RP, Cramer DW, Terry KL, Poole EM, Tworoger SS, Bandera EV, Orlow I, Olson SH, Krakstad C, Salvesen HB, Tangen IL, Bjorge L, van Altena AM, Aben KK, Kiemeney LA, Massuger LF, Kellar M, Brooks-Wilson A, Kelemen LE, Cook LS, Le ND, Cybulski C, Yang H, Lissowska J, Brinton LA, Wentzensen N, Hogdall C, Lundvall L, Nedergaard L, Baker H, Song H, Eccles D, McNeish I, Paul J, Carty K, Siddiqui N, Glasspool R, Whittemore AS, Rothstein JH, McGuire V, Sieh W, Ji BT, Zheng W, Shu XO, Gao YT, Rosen B, Risch HA, McLaughlin JR, Narod SA, Monteiro AN, Chen A, Lin HY, Permuth-Wey J, Sellers TA, Tsai YY, Chen Z, Ziogas A, Anton-Culver H, Gentry-Maharaj A, Menon U, Harrington P, Lee AW, Wu AH, Pearce CL, Coetzee G, Pike MC, Dansonka-Mieszkowska A, Timorek A, Rzepecka IK, Kupryjanczyk J, Freedman M, Noushmehr H, Easton DF, Offit K, Couch FJ, Gayther S, Pharoah PP, Antoniou AC, and Chenevix-Trench G

Subjects
Adolescent, Adult, Alleles, Carcinoma, Ovarian Epithelial, Female, Genes, Reporter, Genotype, Heterozygote, Humans, Mutation, Quantitative Trait Loci, Risk, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Published
2015
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