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Article: Four Superoxide Dismutases Contribute to Bacillus anthracis Virulence and Provide Spores with Redundant Protection from Oxidative Stress

Cybulski, Robert J. Jr / Sanz, Patrick / Alem, Farhang / Stibitz, Scott / Bull, Robert L / O'Brien, Alison D

Infection and immunity. 2009 Jan., v. 77, no. 1

2009

Abstract: ... Δsod15 ΔsodA1) mutant of B. anthracis Sterne strain 34F2 and assessed its lethality in an A/J mouse ... generated oxidative stress and to macrophage-mediated killing correlated with virulence in A/J mice. Allelic ...

Abstract	The Bacillus anthracis genome encodes four superoxide dismutases (SODs), enzymes capable of detoxifying oxygen radicals. That two of these SODs, SOD15 and SODA1, are present in the outermost layers of the B. anthracis spore is indicated by previous proteomic analyses of the exosporium. Given the requirement that spores must survive interactions with reactive oxygen species generated by cells such as macrophages during infection, we hypothesized that SOD15 and SODA1 protect the spore from oxidative stress and contribute to the pathogenicity of B. anthracis. To test these theories, we constructed a double-knockout (Δsod15 ΔsodA1) mutant of B. anthracis Sterne strain 34F2 and assessed its lethality in an A/J mouse intranasal infection model. The 50% lethal dose of the Δsod15 ΔsodA1 strain was similar to that of the wild type (34F2), but surprisingly, measurable whole-spore SOD activity was greater than that in 34F2. A quadruple-knockout strain (Δsod15 ΔsodA1 ΔsodC ΔsodA2) was then generated, and as anticipated, spore-associated SOD activity was diminished. Moreover, the quadruple-knockout strain, compared to the wild type, was attenuated more than 40-fold upon intranasal challenge of mice. Spore resistance to exogenously generated oxidative stress and to macrophage-mediated killing correlated with virulence in A/J mice. Allelic exchange that restored sod15 and sodA1 to their wild-type state restored wild-type characteristics. We conclude that SOD molecules within the spore afford B. anthracis protection against oxidative stress and enhance the pathogenicity of B. anthracis in the lung. We also surmise that the presence of four SOD alleles within the genome provides functional redundancy for this key enzyme.
Keywords	Bacillus anthracis ; alleles ; exine ; lethal dose ; macrophages ; mice ; models ; mutants ; oxidative stress ; proteomics ; reactive oxygen species ; spores ; superoxide dismutase ; virulence
Language	English
Size	p. 274-285.
Publishing place	American Society for Microbiology
Document type	Article
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Kelemen, Linda E / Earp, Madalene / Fridley, Brooke L / Chenevix-Trench, Georgia / Fasching, Peter A / Beckmann, Matthias W / Ekici, Arif B / Hein, Alexander / Lambrechts, Diether / Lambrechts, Sandrina / Van Nieuwenhuysen, Els / Vergote, Ignace / Rossing, Mary Anne / Doherty, Jennifer A / Chang-Claude, Jenny / Behrens, Sabine / Moysich, Kirsten B / Cannioto, Rikki / Lele, Shashikant /

Odunsi, Kunle / Goodman, Marc T / Shvetsov, Yurii B / Thompson, Pamela J / Wilkens, Lynne R / Dörk, Thilo / Antonenkova, Natalia / Bogdanova, Natalia / Hillemanns, Peter / Runnebaum, Ingo B / du Bois, Andreas / Harter, Philipp / Heitz, Florian / Schwaab, Ira / Butzow, Ralf / Pelttari, Liisa M / Nevanlinna, Heli / Modugno, Francesmary / Edwards, Robert P / Kelley, Joseph L / Ness, Roberta B / Karlan, Beth Y / Lester, Jenny / Orsulic, Sandra / Walsh, Christine / Kjaer, Susanne K / Jensen, Allan / Cunningham, Julie M / Vierkant, Robert A / Giles, Graham G / Bruinsma, Fiona / Southey, Melissa C / Hildebrandt, Michelle A T / Liang, Dong / Lu, Karen / Wu, Xifeng / Sellers, Thomas A / Levine, Douglas A / Schildkraut, Joellen M / Iversen, Edwin S / Terry, Kathryn L / Cramer, Daniel W / Tworoger, Shelley S / Poole, Elizabeth M / Bandera, Elisa V / Olson, Sara H / Orlow, Irene / Vestrheim Thomsen, Liv Cecilie / Bjorge, Line / Krakstad, Camilla / Tangen, Ingvild L / Kiemeney, Lambertus A / Aben, Katja K H / Massuger, Leon F A G / van Altena, Anne M / Pejovic, Tanja / Bean, Yukie / Kellar, Melissa / Cook, Linda S / Le, Nhu D / Brooks-Wilson, Angela / Gronwald, Jacek / Cybulski, Cezary / Jakubowska, Anna / Lubiński, Jan / Wentzensen, Nicolas / Brinton, Louise A / Lissowska, Jolanta / Hogdall, Estrid / Engelholm, Svend Aage / Hogdall, Claus / Lundvall, Lene / Nedergaard, Lotte / Pharoah, Paul D P / Dicks, Ed / Song, Honglin / Tyrer, Jonathan P / McNeish, Iain / Siddiqui, Nadeem / Carty, Karen / Glasspool, Rosalind / Paul, James / Campbell, Ian G / Eccles, Diana / Whittemore, Alice S / McGuire, Valerie / Rothstein, Joseph H / Sieh, Weiva / Narod, Steven A / Phelan, Catherine M / McLaughlin, John R / Risch, Harvey A / Anton-Culver, Hoda / Ziogas, Argyrios / Menon, Usha / Gayther, Simon A / Gentry-Maharaj, Aleksandra / Ramus, Susan J / Wu, Anna H / Pearce, Celeste Leigh / Lee, Alice W / Pike, Malcolm C / Kupryjanczyk, Jolanta / Podgorska, Agnieszka / Plisiecka-Halasa, Joanna / Sawicki, Wlodzimierz / Goode, Ellen L / Berchuck, Andrew

International journal of molecular sciences

2018 Volume 19, Issue 9

Abstract: Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported ... ...

Abstract	Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the
MeSH term(s)	Adenocarcinoma, Mucinous/genetics ; Adenocarcinoma, Mucinous/metabolism ; Adenocarcinoma, Mucinous/pathology ; Case-Control Studies ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Association Studies ; Humans ; Hydro-Lyases ; Logistic Models ; Middle Aged ; Odds Ratio ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Polymorphism, Single Nucleotide ; Proteins/genetics ; Proteins/metabolism ; Quantitative Trait Loci ; RNA, Antisense/genetics ; RNA, Antisense/metabolism ; Risk ; Signal Transduction ; Thymidylate Synthase/genetics ; Thymidylate Synthase/metabolism
Chemical Substances	Proteins ; RNA, Antisense ; TYMS protein, human (EC 2.1.1.45) ; Thymidylate Synthase (EC 2.1.1.45) ; ENOSF1 protein, human (EC 4.2.1.-) ; Hydro-Lyases (EC 4.2.1.-)
Language	English
Publishing date	2018-08-21
Publishing country	Switzerland
Document type	Journal Article ; Meta-Analysis
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms19092473
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Article ; Online: Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

Earp, Madalene / Tyrer, Jonathan P / Winham, Stacey J / Lin, Hui-Yi / Chornokur, Ganna / Dennis, Joe / Aben, Katja K H / Anton-Culver, Hoda / Antonenkova, Natalia / Bandera, Elisa V / Bean, Yukie T / Beckmann, Matthias W / Bjorge, Line / Bogdanova, Natalia / Brinton, Louise A / Brooks-Wilson, Angela / Bruinsma, Fiona / Bunker, Clareann H / Butzow, Ralf /

Campbell, Ian G / Carty, Karen / Chang-Claude, Jenny / Cook, Linda S / Cramer, Daniel W / Cunningham, Julie M / Cybulski, Cezary / Dansonka-Mieszkowska, Agnieszka / Despierre, Evelyn / Doherty, Jennifer A / Dörk, Thilo / du Bois, Andreas / Dürst, Matthias / Easton, Douglas F / Eccles, Diana M / Edwards, Robert P / Ekici, Arif B / Fasching, Peter A / Fridley, Brooke L / Gentry-Maharaj, Aleksandra / Giles, Graham G / Glasspool, Rosalind / Goodman, Marc T / Gronwald, Jacek / Harter, Philipp / Hein, Alexander / Heitz, Florian / Hildebrandt, Michelle A T / Hillemanns, Peter / Hogdall, Claus K / Høgdall, Estrid / Hosono, Satoyo / Iversen, Edwin S / Jakubowska, Anna / Jensen, Allan / Ji, Bu-Tian / Jung, Audrey Y / Karlan, Beth Y / Kellar, Melissa / Kiemeney, Lambertus A / Kiong Lim, Boon / Kjaer, Susanne K / Krakstad, Camilla / Kupryjanczyk, Jolanta / Lambrechts, Diether / Lambrechts, Sandrina / Le, Nhu D / Lele, Shashi / Lester, Jenny / Levine, Douglas A / Li, Zheng / Liang, Dong / Lissowska, Jolanta / Lu, Karen / Lubinski, Jan / Lundvall, Lene / Massuger, Leon F A G / Matsuo, Keitaro / McGuire, Valerie / McLaughlin, John R / McNeish, Iain / Menon, Usha / Milne, Roger L / Modugno, Francesmary / Moysich, Kirsten B / Ness, Roberta B / Nevanlinna, Heli / Odunsi, Kunle / Olson, Sara H / Orlow, Irene / Orsulic, Sandra / Paul, James / Pejovic, Tanja / Pelttari, Liisa M / Permuth, Jenny B / Pike, Malcolm C / Poole, Elizabeth M / Rosen, Barry / Rossing, Mary Anne / Rothstein, Joseph H / Runnebaum, Ingo B / Rzepecka, Iwona K / Schernhammer, Eva / Schwaab, Ira / Shu, Xiao-Ou / Shvetsov, Yurii B / Siddiqui, Nadeem / Sieh, Weiva / Song, Honglin / Southey, Melissa C / Spiewankiewicz, Beata / Sucheston-Campbell, Lara / Tangen, Ingvild L / Teo, Soo-Hwang / Terry, Kathryn L / Thompson, Pamela J / Thomsen, Lotte / Tworoger, Shelley S / van Altena, Anne M / Vergote, Ignace / Vestrheim Thomsen, Liv Cecilie / Vierkant, Robert A / Walsh, Christine S / Wang-Gohrke, Shan / Wentzensen, Nicolas / Whittemore, Alice S / Wicklund, Kristine G / Wilkens, Lynne R / Woo, Yin-Ling / Wu, Anna H / Wu, Xifeng / Xiang, Yong-Bing / Yang, Hannah / Zheng, Wei / Ziogas, Argyrios / Lee, Alice W / Pearce, Celeste L / Berchuck, Andrew / Schildkraut, Joellen M / Ramus, Susan J / Monteiro, Alvaro N A / Narod, Steven A / Sellers, Thomas A / Gayther, Simon A / Kelemen, Linda E / Chenevix-Trench, Georgia / Risch, Harvey A / Pharoah, Paul D P / Goode, Ellen L / Phelan, Catherine M

PloS one

2018 Volume 13, Issue 7, Page(s) e0197561

Abstract: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes ...

Abstract	Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.
MeSH term(s)	A Kinase Anchor Proteins/genetics ; Carcinoma, Ovarian Epithelial/genetics ; Carcinoma, Ovarian Epithelial/pathology ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genotype ; Humans ; Monomeric GTP-Binding Proteins/genetics ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics ; Rho Guanine Nucleotide Exchange Factors/genetics ; Risk Factors
Chemical Substances	A Kinase Anchor Proteins ; AKAP6 protein, human ; ARHGEF10L protein, human ; Rho Guanine Nucleotide Exchange Factors ; Monomeric GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2018-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0197561
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Article ; Online: Publisher Correction: Shared heritability and functional enrichment across six solid cancers.

Jiang, Xia / Finucane, Hilary K / Schumacher, Fredrick R / Schmit, Stephanie L / Tyrer, Jonathan P / Han, Younghun / Michailidou, Kyriaki / Lesseur, Corina / Kuchenbaecker, Karoline B / Dennis, Joe / Conti, David V / Casey, Graham / Gaudet, Mia M / Huyghe, Jeroen R / Albanes, Demetrius / Aldrich, Melinda C / Andrew, Angeline S / Andrulis, Irene L / Anton-Culver, Hoda /

Antoniou, Antonis C / Antonenkova, Natalia N / Arnold, Susanne M / Aronson, Kristan J / Arun, Banu K / Bandera, Elisa V / Barkardottir, Rosa B / Barnes, Daniel R / Batra, Jyotsna / Beckmann, Matthias W / Benitez, Javier / Benlloch, Sara / Berchuck, Andrew / Berndt, Sonja I / Bickeböller, Heike / Bien, Stephanie A / Blomqvist, Carl / Boccia, Stefania / Bogdanova, Natalia V / Bojesen, Stig E / Bolla, Manjeet K / Brauch, Hiltrud / Brenner, Hermann / Brenton, James D / Brook, Mark N / Brunet, Joan / Brunnström, Hans / Buchanan, Daniel D / Burwinkel, Barbara / Butzow, Ralf / Cadoni, Gabriella / Caldés, Trinidad / Caligo, Maria A / Campbell, Ian / Campbell, Peter T / Cancel-Tassin, Géraldine / Cannon-Albright, Lisa / Campa, Daniele / Caporaso, Neil / Carvalho, André L / Chan, Andrew T / Chang-Claude, Jenny / Chanock, Stephen J / Chen, Chu / Christiani, David C / Claes, Kathleen B M / Claessens, Frank / Clements, Judith / Collée, J Margriet / Correa, Marcia Cruz / Couch, Fergus J / Cox, Angela / Cunningham, Julie M / Cybulski, Cezary / Czene, Kamila / Daly, Mary B / deFazio, Anna / Devilee, Peter / Diez, Orland / Gago-Dominguez, Manuela / Donovan, Jenny L / Dörk, Thilo / Duell, Eric J / Dunning, Alison M / Dwek, Miriam / Eccles, Diana M / Edlund, Christopher K / Edwards, Digna R Velez / Ellberg, Carolina / Evans, D Gareth / Fasching, Peter A / Ferris, Robert L / Liloglou, Triantafillos / Figueiredo, Jane C / Fletcher, Olivia / Fortner, Renée T / Fostira, Florentia / Franceschi, Silvia / Friedman, Eitan / Gallinger, Steven J / Ganz, Patricia A / Garber, Judy / García-Sáenz, José A / Gayther, Simon A / Giles, Graham G / Godwin, Andrew K / Goldberg, Mark S / Goldgar, David E / Goode, Ellen L / Goodman, Marc T / Goodman, Gary / Grankvist, Kjell / Greene, Mark H / Gronberg, Henrik / Gronwald, Jacek / Guénel, Pascal / Håkansson, Niclas / Hall, Per / Hamann, Ute / Hamdy, Freddie C / Hamilton, Robert J / Hampe, Jochen / Haugen, Aage / Heitz, Florian / Herrero, Rolando / Hillemanns, Peter / Hoffmeister, Michael / Høgdall, Estrid / Hong, Yun-Chul / Hopper, John L / Houlston, Richard / Hulick, Peter J / Hunter, David J / Huntsman, David G / Idos, Gregory / Imyanitov, Evgeny N / Ingles, Sue Ann / Isaacs, Claudine / Jakubowska, Anna / James, Paul / Jenkins, Mark A / Johansson, Mattias / Johansson, Mikael / John, Esther M / Joshi, Amit D / Kaneva, Radka / Karlan, Beth Y / Kelemen, Linda E / Kühl, Tabea / Khaw, Kay-Tee / Khusnutdinova, Elza / Kibel, Adam S / Kiemeney, Lambertus A / Kim, Jeri / Kjaer, Susanne K / Knight, Julia A / Kogevinas, Manolis / Kote-Jarai, Zsofia / Koutros, Stella / Kristensen, Vessela N / Kupryjanczyk, Jolanta / Lacko, Martin / Lam, Stephan / Lambrechts, Diether / Landi, Maria Teresa / Lazarus, Philip / Le, Nhu D / Lee, Eunjung / Lejbkowicz, Flavio / Lenz, Heinz-Josef / Leslie, Goska / Lessel, Davor / Lester, Jenny / Levine, Douglas A / Li, Li / Li, Christopher I / Lindblom, Annika / Lindor, Noralane M / Liu, Geoffrey / Loupakis, Fotios / Lubiński, Jan / Maehle, Lovise / Maier, Christiane / Mannermaa, Arto / Marchand, Loic Le / Margolin, Sara / May, Taymaa / McGuffog, Lesley / Meindl, Alfons / Middha, Pooja / Miller, Austin / Milne, Roger L / MacInnis, Robert J / Modugno, Francesmary / Montagna, Marco / Moreno, Victor / Moysich, Kirsten B / Mucci, Lorelei / Muir, Kenneth / Mulligan, Anna Marie / Nathanson, Katherine L / Neal, David E / Ness, Andrew R / Neuhausen, Susan L / Nevanlinna, Heli / Newcomb, Polly A / Newcomb, Lisa F / Nielsen, Finn Cilius / Nikitina-Zake, Liene / Nordestgaard, Børge G / Nussbaum, Robert L / Offit, Kenneth / Olah, Edith / Olama, Ali Amin Al / Olopade, Olufunmilayo I / Olshan, Andrew F / Olsson, Håkan / Osorio, Ana / Pandha, Hardev / Park, Jong Y / Pashayan, Nora / Parsons, Michael T / Pejovic, Tanja / Penney, Kathryn L / Peters, Wilbert H M / Phelan, Catherine M / Phipps, Amanda I / Plaseska-Karanfilska, Dijana / Pring, Miranda / Prokofyeva, Darya / Radice, Paolo / Stefansson, Kari / Ramus, Susan J / Raskin, Leon / Rennert, Gad / Rennert, Hedy S / van Rensburg, Elizabeth J / Riggan, Marjorie J / Risch, Harvey A / Risch, Angela / Roobol, Monique J / Rosenstein, Barry S / Rossing, Mary Anne / De Ruyck, Kim / Saloustros, Emmanouil / Sandler, Dale P / Sawyer, Elinor J / Schabath, Matthew B / Schleutker, Johanna / Schmidt, Marjanka K / Setiawan, V Wendy / Shen, Hongbing / Siegel, Erin M / Sieh, Weiva / Singer, Christian F / Slattery, Martha L / Sorensen, Karina Dalsgaard / Southey, Melissa C / Spurdle, Amanda B / Stanford, Janet L / Stevens, Victoria L / Stintzing, Sebastian / Stone, Jennifer / Sundfeldt, Karin / Sutphen, Rebecca / Swerdlow, Anthony J / Tajara, Eloiza H / Tangen, Catherine M / Tardon, Adonina / Taylor, Jack A / Teare, M Dawn / Teixeira, Manuel R / Terry, Mary Beth / Terry, Kathryn L / Thibodeau, Stephen N / Thomassen, Mads / Bjørge, Line / Tischkowitz, Marc / Toland, Amanda E / Torres, Diana / Townsend, Paul A / Travis, Ruth C / Tung, Nadine / Tworoger, Shelley S / Ulrich, Cornelia M / Usmani, Nawaid / Vachon, Celine M / Van Nieuwenhuysen, Els / Vega, Ana / Aguado-Barrera, Miguel Elías / Wang, Qin / Webb, Penelope M / Weinberg, Clarice R / Weinstein, Stephanie / Weissler, Mark C / Weitzel, Jeffrey N / West, Catharine M L / White, Emily / Whittemore, Alice S / Wichmann, H-Erich / Wiklund, Fredrik / Winqvist, Robert / Wolk, Alicja / Woll, Penella / Woods, Michael / Wu, Anna H / Wu, Xifeng / Yannoukakos, Drakoulis / Zheng, Wei / Zienolddiny, Shanbeh / Ziogas, Argyrios / Zorn, Kristin K / Lane, Jacqueline M / Saxena, Richa / Thomas, Duncan / Hung, Rayjean J / Diergaarde, Brenda / McKay, James / Peters, Ulrike / Hsu, Li / García-Closas, Montserrat / Eeles, Rosalind A / Chenevix-Trench, Georgia / Brennan, Paul J / Haiman, Christopher A / Simard, Jacques / Easton, Douglas F / Gruber, Stephen B / Pharoah, Paul D P / Price, Alkes L / Pasaniuc, Bogdan / Amos, Christopher I / Kraft, Peter / Lindström, Sara

Nature communications

2019 Volume 10, Issue 1, Page(s) 4386

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

Abstract	An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Language	English
Publishing date	2019-09-23
Publishing country	England
Document type	Published Erratum
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-12095-8
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Article ; Online: Shared heritability and functional enrichment across six solid cancers.

Nature communications

2019 Volume 10, Issue 1, Page(s) 431

Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 ... ...

Abstract	Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r
MeSH term(s)	Breast Neoplasms/diagnosis ; Breast Neoplasms/ethnology ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Case-Control Studies ; Colorectal Neoplasms/diagnosis ; Colorectal Neoplasms/ethnology ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Head and Neck Neoplasms/diagnosis ; Head and Neck Neoplasms/ethnology ; Head and Neck Neoplasms/genetics ; Head and Neck Neoplasms/pathology ; Humans ; Inheritance Patterns ; Lung Neoplasms/diagnosis ; Lung Neoplasms/ethnology ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Male ; Mental Disorders/ethnology ; Mental Disorders/genetics ; Mental Disorders/physiopathology ; Neoplasm Proteins/genetics ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/ethnology ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Phenotype ; Polymorphism, Single Nucleotide ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/ethnology ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Smoking/ethnology ; Smoking/genetics ; Smoking/physiopathology ; White People
Chemical Substances	Neoplasm Proteins
Language	English
Publishing date	2019-01-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-018-08054-4
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Article ; Online: Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.

Kelemen, Linda E / Terry, Kathryn L / Goodman, Marc T / Webb, Penelope M / Bandera, Elisa V / McGuire, Valerie / Rossing, Mary Anne / Wang, Qinggang / Dicks, Ed / Tyrer, Jonathan P / Song, Honglin / Kupryjanczyk, Jolanta / Dansonka-Mieszkowska, Agnieszka / Plisiecka-Halasa, Joanna / Timorek, Agnieszka / Menon, Usha / Gentry-Maharaj, Aleksandra / Gayther, Simon A / Ramus, Susan J /

Narod, Steven A / Risch, Harvey A / McLaughlin, John R / Siddiqui, Nadeem / Glasspool, Rosalind / Paul, James / Carty, Karen / Gronwald, Jacek / Lubiński, Jan / Jakubowska, Anna / Cybulski, Cezary / Kiemeney, Lambertus A / Massuger, Leon F A G / van Altena, Anne M / Aben, Katja K H / Olson, Sara H / Orlow, Irene / Cramer, Daniel W / Levine, Douglas A / Bisogna, Maria / Giles, Graham G / Southey, Melissa C / Bruinsma, Fiona / Kjaer, Susanne K / Høgdall, Estrid / Jensen, Allan / Høgdall, Claus K / Lundvall, Lene / Engelholm, Svend-Aage / Heitz, Florian / du Bois, Andreas / Harter, Philipp / Schwaab, Ira / Butzow, Ralf / Nevanlinna, Heli / Pelttari, Liisa M / Leminen, Arto / Thompson, Pamela J / Lurie, Galina / Wilkens, Lynne R / Lambrechts, Diether / Van Nieuwenhuysen, Els / Lambrechts, Sandrina / Vergote, Ignace / Beesley, Jonathan / Fasching, Peter A / Beckmann, Matthias W / Hein, Alexander / Ekici, Arif B / Doherty, Jennifer A / Wu, Anna H / Pearce, Celeste L / Pike, Malcolm C / Stram, Daniel / Chang-Claude, Jenny / Rudolph, Anja / Dörk, Thilo / Dürst, Matthias / Hillemanns, Peter / Runnebaum, Ingo B / Bogdanova, Natalia / Antonenkova, Natalia / Odunsi, Kunle / Edwards, Robert P / Kelley, Joseph L / Modugno, Francesmary / Ness, Roberta B / Karlan, Beth Y / Walsh, Christine / Lester, Jenny / Orsulic, Sandra / Fridley, Brooke L / Vierkant, Robert A / Cunningham, Julie M / Wu, Xifeng / Lu, Karen / Liang, Dong / Hildebrandt, Michelle A T / Weber, Rachel Palmieri / Iversen, Edwin S / Tworoger, Shelley S / Poole, Elizabeth M / Salvesen, Helga B / Krakstad, Camilla / Bjorge, Line / Tangen, Ingvild L / Pejovic, Tanja / Bean, Yukie / Kellar, Melissa / Wentzensen, Nicolas / Brinton, Louise A / Lissowska, Jolanta / Garcia-Closas, Montserrat / Campbell, Ian G / Eccles, Diana / Whittemore, Alice S / Sieh, Weiva / Rothstein, Joseph H / Anton-Culver, Hoda / Ziogas, Argyrios / Phelan, Catherine M / Moysich, Kirsten B / Goode, Ellen L / Schildkraut, Joellen M / Berchuck, Andrew / Pharoah, Paul D P / Sellers, Thomas A / Brooks-Wilson, Angela / Cook, Linda S / Le, Nhu D

Molecular nutrition & food research

2014 Volume 58, Issue 10, Page(s) 2023–2035

Abstract: Scope: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with ... ...

Abstract	Scope: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. Methods and results: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻⁵) and rs828054 (OR = 1.06; p = 1 × 10⁻⁴). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻⁶) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006). Conclusion: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.
MeSH term(s)	Carcinoma/epidemiology ; Carcinoma/etiology ; Carcinoma/genetics ; Carcinoma/prevention & control ; Case-Control Studies ; Diet/adverse effects ; Dietary Supplements ; Dihydrouracil Dehydrogenase (NADP)/genetics ; Dihydrouracil Dehydrogenase (NADP)/metabolism ; Energy Intake ; Female ; Folic Acid/administration & dosage ; Folic Acid/metabolism ; Folic Acid/therapeutic use ; Folic Acid Deficiency/diet therapy ; Folic Acid Deficiency/metabolism ; Folic Acid Deficiency/physiopathology ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Global Health ; Humans ; Multivariate Analysis ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Ovarian Neoplasms/epidemiology ; Ovarian Neoplasms/etiology ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/prevention & control ; Polymorphism, Single Nucleotide ; Risk Factors ; White People
Chemical Substances	Neoplasm Proteins ; Folic Acid (935E97BOY8) ; Dihydrouracil Dehydrogenase (NADP) (EC 1.3.1.2)
Language	English
Publishing date	2014-07-28
Publishing country	Germany
Document type	Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2160372-8
ISSN	1613-4133 ; 1613-4125
ISSN (online)	1613-4133
ISSN	1613-4125
DOI	10.1002/mnfr.201400068
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Article ; Online: Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.

Lee, Alice W / Tyrer, Jonathan P / Doherty, Jennifer A / Stram, Douglas A / Kupryjanczyk, Jolanta / Dansonka-Mieszkowska, Agnieszka / Plisiecka-Halasa, Joanna / Spiewankiewicz, Beata / Myers, Emily J / Chenevix-Trench, Georgia / Fasching, Peter A / Beckmann, Matthias W / Ekici, Arif B / Hein, Alexander / Vergote, Ignace / Van Nieuwenhuysen, Els / Lambrechts, Diether / Wicklund, Kristine G / Eilber, Ursula /

Wang-Gohrke, Shan / Chang-Claude, Jenny / Rudolph, Anja / Sucheston-Campbell, Lara / Odunsi, Kunle / Moysich, Kirsten B / Shvetsov, Yurii B / Thompson, Pamela J / Goodman, Marc T / Wilkens, Lynne R / Dörk, Thilo / Hillemanns, Peter / Dürst, Matthias / Runnebaum, Ingo B / Bogdanova, Natalia / Pelttari, Liisa M / Nevanlinna, Heli / Leminen, Arto / Edwards, Robert P / Kelley, Joseph L / Harter, Philipp / Schwaab, Ira / Heitz, Florian / du Bois, Andreas / Orsulic, Sandra / Lester, Jenny / Walsh, Christine / Karlan, Beth Y / Hogdall, Estrid / Kjaer, Susanne K / Jensen, Allan / Vierkant, Robert A / Cunningham, Julie M / Goode, Ellen L / Fridley, Brooke L / Southey, Melissa C / Giles, Graham G / Bruinsma, Fiona / Wu, Xifeng / Hildebrandt, Michelle A T / Lu, Karen / Liang, Dong / Bisogna, Maria / Levine, Douglas A / Weber, Rachel Palmieri / Schildkraut, Joellen M / Iversen, Edwin S / Berchuck, Andrew / Terry, Kathryn L / Cramer, Daniel W / Tworoger, Shelley S / Poole, Elizabeth M / Olson, Sara H / Orlow, Irene / Bandera, Elisa V / Bjorge, Line / Tangen, Ingvild L / Salvesen, Helga B / Krakstad, Camilla / Massuger, Leon F A G / Kiemeney, Lambertus A / Aben, Katja K H / van Altena, Anne M / Bean, Yukie / Pejovic, Tanja / Kellar, Melissa / Le, Nhu D / Cook, Linda S / Kelemen, Linda E / Brooks-Wilson, Angela / Lubinski, Jan / Gronwald, Jacek / Cybulski, Cezary / Jakubowska, Anna / Wentzensen, Nicolas / Brinton, Louise A / Lissowska, Jolanta / Yang, Hannah / Nedergaard, Lotte / Lundvall, Lene / Hogdall, Claus / Song, Honglin / Campbell, Ian G / Eccles, Diana / Glasspool, Rosalind / Siddiqui, Nadeem / Carty, Karen / Paul, James / McNeish, Iain A / Sieh, Weiva / McGuire, Valerie / Rothstein, Joseph H / Whittemore, Alice S / McLaughlin, John R / Risch, Harvey A / Phelan, Catherine M / Anton-Culver, Hoda / Ziogas, Argyrios / Menon, Usha / Ramus, Susan J / Gentry-Maharaj, Aleksandra / Harrington, Patricia / Pike, Malcolm C / Modugno, Francesmary / Rossing, Mary Anne / Ness, Roberta B / Pharoah, Paul D P / Stram, Daniel O / Wu, Anna H / Pearce, Celeste Leigh

Gynecologic oncology

2014 Volume 136, Issue 3, Page(s) 542–548

Abstract: Objective: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized ... ...

Abstract	Objective: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. Methods: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. Results: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). Conclusions: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
MeSH term(s)	Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Case-Control Studies ; Female ; Genetic Markers ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Gonadotropins/metabolism ; Humans ; Logistic Models ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Polymorphism, Single Nucleotide ; Risk Factors ; Signal Transduction
Chemical Substances	Biomarkers, Tumor ; Genetic Markers ; Gonadotropins
Language	English
Publishing date	2014-12-17
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2014.12.017
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Article ; Online: Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA.

Earp, Madalene A / Kelemen, Linda E / Magliocco, Anthony M / Swenerton, Kenneth D / Chenevix-Trench, Georgia / Lu, Yi / Hein, Alexander / Ekici, Arif B / Beckmann, Matthias W / Fasching, Peter A / Lambrechts, Diether / Despierre, Evelyn / Vergote, Ignace / Lambrechts, Sandrina / Doherty, Jennifer A / Rossing, Mary Anne / Chang-Claude, Jenny / Rudolph, Anja / Friel, Grace /

Moysich, Kirsten B / Odunsi, Kunle / Sucheston-Campbell, Lara / Lurie, Galina / Goodman, Marc T / Carney, Michael E / Thompson, Pamela J / Runnebaum, Ingo B / Dürst, Matthias / Hillemanns, Peter / Dörk, Thilo / Antonenkova, Natalia / Bogdanova, Natalia / Leminen, Arto / Nevanlinna, Heli / Pelttari, Liisa M / Butzow, Ralf / Bunker, Clareann H / Modugno, Francesmary / Edwards, Robert P / Ness, Roberta B / du Bois, Andreas / Heitz, Florian / Schwaab, Ira / Harter, Philipp / Karlan, Beth Y / Walsh, Christine / Lester, Jenny / Jensen, Allan / Kjær, Susanne K / Høgdall, Claus K / Høgdall, Estrid / Lundvall, Lene / Sellers, Thomas A / Fridley, Brooke L / Goode, Ellen L / Cunningham, Julie M / Vierkant, Robert A / Giles, Graham G / Baglietto, Laura / Severi, Gianluca / Southey, Melissa C / Liang, Dong / Wu, Xifeng / Lu, Karen / Hildebrandt, Michelle A T / Levine, Douglas A / Bisogna, Maria / Schildkraut, Joellen M / Iversen, Edwin S / Weber, Rachel Palmieri / Berchuck, Andrew / Cramer, Daniel W / Terry, Kathryn L / Poole, Elizabeth M / Tworoger, Shelley S / Bandera, Elisa V / Chandran, Urmila / Orlow, Irene / Olson, Sara H / Wik, Elisabeth / Salvesen, Helga B / Bjorge, Line / Halle, Mari K / van Altena, Anne M / Aben, Katja K H / Kiemeney, Lambertus A / Massuger, Leon F A G / Pejovic, Tanja / Bean, Yukie T / Cybulski, Cezary / Gronwald, Jacek / Lubinski, Jan / Wentzensen, Nicolas / Brinton, Louise A / Lissowska, Jolanta / Garcia-Closas, Montserrat / Dicks, Ed / Dennis, Joe / Easton, Douglas F / Song, Honglin / Tyrer, Jonathan P / Pharoah, Paul D P / Eccles, Diana / Campbell, Ian G / Whittemore, Alice S / McGuire, Valerie / Sieh, Weiva / Rothstein, Joseph H / Flanagan, James M / Paul, James / Brown, Robert / Phelan, Catherine M / Risch, Harvey A / McLaughlin, John R / Narod, Steven A / Ziogas, Argyrios / Anton-Culver, Hoda / Gentry-Maharaj, Aleksandra / Menon, Usha / Gayther, Simon A / Ramus, Susan J / Wu, Anna H / Pearce, Celeste L / Pike, Malcolm C / Dansonka-Mieszkowska, Agnieszka / Rzepecka, Iwona K / Szafron, Lukasz M / Kupryjanczyk, Jolanta / Cook, Linda S / Le, Nhu D / Brooks-Wilson, Angela

Human genetics

2013 Volume 133, Issue 5, Page(s) 481–497

Abstract: Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association ... ...

Abstract	Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
MeSH term(s)	Alleles ; Carcinoma, Ovarian Epithelial ; DNA/genetics ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Neoplasms, Glandular and Epithelial/genetics ; Ovarian Neoplasms/genetics ; Polymorphism, Single Nucleotide ; Quality Control
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2013-11-05
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-013-1383-3
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Article ; Online: Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer.

Hampras, Shalaka S / Sucheston-Campbell, Lara E / Cannioto, Rikki / Chang-Claude, Jenny / Modugno, Francesmary / Dörk, Thilo / Hillemanns, Peter / Preus, Leah / Knutson, Keith L / Wallace, Paul K / Hong, Chi-Chen / Friel, Grace / Davis, Warren / Nesline, Mary / Pearce, Celeste L / Kelemen, Linda E / Goodman, Marc T / Bandera, Elisa V / Terry, Kathryn L /

Schoof, Nils / Eng, Kevin H / Clay, Alyssa / Singh, Prashant K / Joseph, Janine M / Aben, Katja K H / Anton-Culver, Hoda / Antonenkova, Natalia / Baker, Helen / Bean, Yukie / Beckmann, Matthias W / Bisogna, Maria / Bjorge, Line / Bogdanova, Natalia / Brinton, Louise A / Brooks-Wilson, Angela / Bruinsma, Fiona / Butzow, Ralf / Campbell, Ian G / Carty, Karen / Cook, Linda S / Cramer, Daniel W / Cybulski, Cezary / Dansonka-Mieszkowska, Agnieszka / Dennis, Joe / Despierre, Evelyn / Dicks, Ed / Doherty, Jennifer A / du Bois, Andreas / Dürst, Matthias / Easton, Doug / Eccles, Diana / Edwards, Robert P / Ekici, Arif B / Fasching, Peter A / Fridley, Brooke L / Gao, Yu-Tang / Gentry-Maharaj, Aleksandra / Giles, Graham G / Glasspool, Rosalind / Gronwald, Jacek / Harrington, Patricia / Harter, Philipp / Hasmad, Hanis Nazihah / Hein, Alexander / Heitz, Florian / Hildebrandt, Michelle A T / Hogdall, Claus / Hogdall, Estrid / Hosono, Satoyo / Iversen, Edwin S / Jakubowska, Anna / Jensen, Allan / Ji, Bu-Tian / Karlan, Beth Y / Kellar, Melissa / Kelley, Joseph L / Kiemeney, Lambertus A / Klapdor, Rüdiger / Kolomeyevskaya, Nonna / Krakstad, Camilla / Kjaer, Susanne K / Kruszka, Bridget / Kupryjanczyk, Jolanta / Lambrechts, Diether / Lambrechts, Sandrina / Le, Nhu D / Lee, Alice W / Lele, Shashikant / Leminen, Arto / Lester, Jenny / Levine, Douglas A / Liang, Dong / Lissowska, Jolanta / Liu, Song / Lu, Karen / Lubinski, Jan / Lundvall, Lene / Massuger, Leon F A G / Matsuo, Keitaro / McGuire, Valeria / McLaughlin, John R / McNeish, Ian / Menon, Usha / Moes-Sosnowska, Joanna / Narod, Steven A / Nedergaard, Lotte / Nevanlinna, Heli / Nickels, Stefan / Olson, Sara H / Orlow, Irene / Weber, Rachel Palmieri / Paul, James / Pejovic, Tanja / Pelttari, Liisa M / Perkins, Barbara / Permuth-Wey, Jenny / Pike, Malcolm C / Plisiecka-Halasa, Joanna / Poole, Elizabeth M / Risch, Harvey A / Rossing, Mary Anne / Rothstein, Joseph H / Rudolph, Anja / Runnebaum, Ingo B / Rzepecka, Iwona K / Salvesen, Helga B / Schernhammer, Eva / Schmitt, Kristina / Schwaab, Ira / Shu, Xiao-Ou / Shvetsov, Yurii B / Siddiqui, Nadeem / Sieh, Weiva / Song, Honglin / Southey, Melissa C / Tangen, Ingvild L / Teo, Soo-Hwang / Thompson, Pamela J / Timorek, Agnieszka / Tsai, Ya-Yu / Tworoger, Shelley S / Tyrer, Jonathan / van Altena, Anna M / Vergote, Ignace / Vierkant, Robert A / Walsh, Christine / Wang-Gohrke, Shan / Wentzensen, Nicolas / Whittemore, Alice S / Wicklund, Kristine G / Wilkens, Lynne R / Wu, Anna H / Wu, Xifeng / Woo, Yin-Ling / Yang, Hannah / Zheng, Wei / Ziogas, Argyrios / Gayther, Simon A / Ramus, Susan J / Sellers, Thomas A / Schildkraut, Joellen M / Phelan, Catherine M / Berchuck, Andrew / Chenevix-Trench, Georgia / Cunningham, Julie M / Pharoah, Paul P / Ness, Roberta B / Odunsi, Kunle / Goode, Ellen L / Moysich, Kirsten B

Oncotarget

2016 Volume 7, Issue 43, Page(s) 69097–69110

Abstract: Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.: Methods: In a population ... ...

Abstract	Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. Results: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
MeSH term(s)	Adenocarcinoma, Clear Cell/genetics ; Adenocarcinoma, Clear Cell/immunology ; Adult ; Aged ; Carcinoma, Ovarian Epithelial ; Female ; Gene Expression Regulation, Neoplastic ; Gene Frequency ; Genetic Predisposition to Disease/genetics ; Genotype ; Humans ; Middle Aged ; Neoplasms, Glandular and Epithelial/genetics ; Neoplasms, Glandular and Epithelial/immunology ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/immunology ; Polymorphism, Single Nucleotide ; Protein Serine-Threonine Kinases/genetics ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, Transforming Growth Factor beta/genetics ; Risk Factors ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism
Chemical Substances	Receptors, Transforming Growth Factor beta ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Receptor, Transforming Growth Factor-beta Type II (EC 2.7.11.30)
Language	English
Publishing date	2016-08-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.10215
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Article ; Online: Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer.

Lawrenson, Kate / Iversen, Edwin S / Tyrer, Jonathan / Weber, Rachel Palmieri / Concannon, Patrick / Hazelett, Dennis J / Li, Qiyuan / Marks, Jeffrey R / Berchuck, Andrew / Lee, Janet M / Aben, Katja K H / Anton-Culver, Hoda / Antonenkova, Natalia / Bandera, Elisa V / Bean, Yukie / Beckmann, Matthias W / Bisogna, Maria / Bjorge, Line / Bogdanova, Natalia /

Brinton, Louise A / Brooks-Wilson, Angela / Bruinsma, Fiona / Butzow, Ralf / Campbell, Ian G / Carty, Karen / Chang-Claude, Jenny / Chenevix-Trench, Georgia / Chen, Ann / Chen, Zhihua / Cook, Linda S / Cramer, Daniel W / Cunningham, Julie M / Cybulski, Cezary / Plisiecka-Halasa, Joanna / Dennis, Joe / Dicks, Ed / Doherty, Jennifer A / Dörk, Thilo / du Bois, Andreas / Eccles, Diana / Easton, Douglas T / Edwards, Robert P / Eilber, Ursula / Ekici, Arif B / Fasching, Peter A / Fridley, Brooke L / Gao, Yu-Tang / Gentry-Maharaj, Aleksandra / Giles, Graham G / Glasspool, Rosalind / Goode, Ellen L / Goodman, Marc T / Gronwald, Jacek / Harter, Philipp / Hasmad, Hanis Nazihah / Hein, Alexander / Heitz, Florian / Hildebrandt, Michelle A T / Hillemanns, Peter / Hogdall, Estrid / Hogdall, Claus / Hosono, Satoyo / Jakubowska, Anna / Paul, James / Jensen, Allan / Karlan, Beth Y / Kjaer, Susanne Kruger / Kelemen, Linda E / Kellar, Melissa / Kelley, Joseph L / Kiemeney, Lambertus A / Krakstad, Camilla / Lambrechts, Diether / Lambrechts, Sandrina / Le, Nhu D / Lee, Alice W / Cannioto, Rikki / Leminen, Arto / Lester, Jenny / Levine, Douglas A / Liang, Dong / Lissowska, Jolanta / Lu, Karen / Lubinski, Jan / Lundvall, Lene / Massuger, Leon F A G / Matsuo, Keitaro / McGuire, Valerie / McLaughlin, John R / Nevanlinna, Heli / McNeish, Iain / Menon, Usha / Modugno, Francesmary / Moysich, Kirsten B / Narod, Steven A / Nedergaard, Lotte / Ness, Roberta B / Noor Azmi, Mat Adenan / Odunsi, Kunle / Olson, Sara H / Orlow, Irene / Orsulic, Sandra / Pearce, Celeste L / Pejovic, Tanja / Pelttari, Liisa M / Permuth-Wey, Jennifer / Phelan, Catherine M / Pike, Malcolm C / Poole, Elizabeth M / Ramus, Susan J / Risch, Harvey A / Rosen, Barry / Rossing, Mary Anne / Rothstein, Joseph H / Rudolph, Anja / Runnebaum, Ingo B / Rzepecka, Iwona K / Salvesen, Helga B / Budzilowska, Agnieszka / Sellers, Thomas A / Shu, Xiao-Ou / Shvetsov, Yurii B / Siddiqui, Nadeem / Sieh, Weiva / Song, Honglin / Southey, Melissa C / Sucheston, Lara / Tangen, Ingvild L / Teo, Soo-Hwang / Terry, Kathryn L / Thompson, Pamela J / Timorek, Agnieszka / Tworoger, Shelley S / Van Nieuwenhuysen, Els / Vergote, Ignace / Vierkant, Robert A / Wang-Gohrke, Shan / Walsh, Christine / Wentzensen, Nicolas / Whittemore, Alice S / Wicklund, Kristine G / Wilkens, Lynne R / Woo, Yin-Ling / Wu, Xifeng / Wu, Anna H / Yang, Hannah / Zheng, Wei / Ziogas, Argyrios / Coetzee, Gerhard A / Freedman, Matthew L / Monteiro, Alvaro N A / Moes-Sosnowska, Joanna / Kupryjanczyk, Jolanta / Pharoah, Paul D / Gayther, Simon A / Schildkraut, Joellen M

Carcinogenesis

2015 Volume 36, Issue 11, Page(s) 1341–1353

Abstract: Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide ... ...

Abstract	Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
MeSH term(s)	Carcinoma, Ovarian Epithelial ; Case-Control Studies ; Checkpoint Kinase 2/genetics ; Female ; Genetic Loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Neoplasms, Glandular and Epithelial/genetics ; Ovarian Neoplasms/genetics ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Risk Factors
Chemical Substances	Checkpoint Kinase 2 (EC 2.7.1.11) ; CHEK2 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2015-09-29
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	603134-1
ISSN	1460-2180 ; 0143-3334
ISSN (online)	1460-2180
ISSN	0143-3334
DOI	10.1093/carcin/bgv138
Database	MEDical Literature Analysis and Retrieval System OnLINE

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