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Article ; Online: Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer.

Winham, Stacey J / Pirie, Ailith / Chen, Yian Ann / Larson, Melissa C / Fogarty, Zachary C / Earp, Madalene A / Anton-Culver, Hoda / Bandera, Elisa V / Cramer, Daniel / Doherty, Jennifer A / Goodman, Marc T / Gronwald, Jacek / Karlan, Beth Y / Kjaer, Susanne K / Levine, Douglas A / Menon, Usha / Ness, Roberta B / Pearce, Celeste L / Pejovic, Tanja /

Rossing, Mary Anne / Wentzensen, Nicolas / Bean, Yukie T / Bisogna, Maria / Brinton, Louise A / Carney, Michael E / Cunningham, Julie M / Cybulski, Cezary / deFazio, Anna / Dicks, Ed M / Edwards, Robert P / Gayther, Simon A / Gentry-Maharaj, Aleksandra / Gore, Martin / Iversen, Edwin S / Jensen, Allan / Johnatty, Sharon E / Lester, Jenny / Lin, Hui-Yi / Lissowska, Jolanta / Lubinski, Jan / Menkiszak, Janusz / Modugno, Francesmary / Moysich, Kirsten B / Orlow, Irene / Pike, Malcolm C / Ramus, Susan J / Song, Honglin / Terry, Kathryn L / Thompson, Pamela J / Tyrer, Jonathan P / van den Berg, David J / Vierkant, Robert A / Vitonis, Allison F / Walsh, Christine / Wilkens, Lynne R / Wu, Anna H / Yang, Hannah / Ziogas, Argyrios / Berchuck, Andrew / Chenevix-Trench, Georgia / Schildkraut, Joellen M / Permuth-Wey, Jennifer / Phelan, Catherine M / Pharoah, Paul D P / Fridley, Brooke L / Sellers, Thomas A / Goode, Ellen L

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2016 Volume 25, Issue 3, Page(s) 446–454

Abstract: Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding ... ...

Abstract	Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). Methods: The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. Impact: This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54. ©2016 AACR.
MeSH term(s)	Exome ; Female ; Genotype ; Humans ; Middle Aged ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/mortality ; Survival Rate
Language	English
Publishing date	2016-01-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1153420-5
ISSN	1538-7755 ; 1055-9965
ISSN (online)	1538-7755
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-15-0240
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer.

Block, Matthew S / Charbonneau, Bridget / Vierkant, Robert A / Fogarty, Zachary / Bamlet, William R / Pharoah, Paul D P / Rossing, Mary Anne / Cramer, Daniel / Pearce, Celeste Leigh / Schildkraut, Joellen / Menon, Usha / Kjaer, Susanne K / Levine, Douglas A / Gronwald, Jacek / Culver, Hoda Anton / Whittemore, Alice S / Karlan, Beth Y / Lambrechts, Diether / Wentzensen, Nicolas /

Kupryjanczyk, Jolanta / Chang-Claude, Jenny / Bandera, Elisa V / Hogdall, Estrid / Heitz, Florian / Kaye, Stanley B / Fasching, Peter A / Campbell, Ian / Goodman, Marc T / Pejovic, Tanja / Bean, Yukie T / Hays, Laura E / Lurie, Galina / Eccles, Diana / Hein, Alexander / Beckmann, Matthias W / Ekici, Arif B / Paul, James / Brown, Robert / Flanagan, James M / Harter, Philipp / du Bois, Andreas / Schwaab, Ira / Hogdall, Claus K / Lundvall, Lene / Olson, Sara H / Orlow, Irene / Paddock, Lisa E / Rudolph, Anja / Eilber, Ursula / Dansonka-Mieszkowska, Agnieszka / Rzepecka, Iwona K / Ziolkowska-Seta, Izabela / Brinton, Louise A / Yang, Hannah / Garcia-Closas, Montserrat / Despierre, Evelyn / Lambrechts, Sandrina / Vergote, Ignace / Walsh, Christine S / Lester, Jenny / Sieh, Weiva / McGuire, Valerie / Rothstein, Joseph H / Ziogas, Argyrios / Lubiński, Jan / Cybulski, Cezary / Menkiszak, Janusz / Jensen, Allan / Gayther, Simon A / Ramus, Susan J / Gentry-Maharaj, Aleksandra / Berchuck, Andrew / Wu, Anna H / Pike, Malcolm C / Van Den Berg, David / Terry, Kathryn L / Vitonis, Allison F / Ramirez, Starr M / Rider, David N / Knutson, Keith L / Sellers, Thomas A / Phelan, Catherine M / Doherty, Jennifer A / Johnatty, Sharon E / deFazio, Anna / Song, Honglin / Tyrer, Jonathan / Kalli, Kimberly R / Fridley, Brooke L / Cunningham, Julie M / Goode, Ellen L

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2014 Volume 23, Issue 7, Page(s) 1421–1427

Abstract: Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an ... ...

Abstract	Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
MeSH term(s)	Adult ; Aged ; Carcinoma, Ovarian Epithelial ; Female ; Genotype ; Humans ; Middle Aged ; NF-kappa B/genetics ; Neoplasm Invasiveness ; Neoplasms, Glandular and Epithelial/genetics ; Neoplasms, Glandular and Epithelial/mortality ; Neoplasms, Glandular and Epithelial/pathology ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/mortality ; Ovarian Neoplasms/pathology ; Polymorphism, Single Nucleotide ; Proportional Hazards Models ; Signal Transduction/genetics
Chemical Substances	NF-kappa B
Language	English
Publishing date	2014-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1153420-5
ISSN	1538-7755 ; 1055-9965
ISSN (online)	1538-7755
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-13-0962
Database	MEDical Literature Analysis and Retrieval System OnLINE

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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
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome.

Charbonneau, Bridget / Moysich, Kirsten B / Kalli, Kimberly R / Oberg, Ann L / Vierkant, Robert A / Fogarty, Zachary C / Block, Matthew S / Maurer, Matthew J / Goergen, Krista M / Fridley, Brooke L / Cunningham, Julie M / Rider, David N / Preston, Claudia / Hartmann, Lynn C / Lawrenson, Kate / Wang, Chen / Tyrer, Jonathan / Song, Honglin / deFazio, Anna /

Johnatty, Sharon E / Doherty, Jennifer A / Phelan, Catherine M / Sellers, Thomas A / Ramirez, Starr M / Vitonis, Allison F / Terry, Kathryn L / Van Den Berg, David / Pike, Malcolm C / Wu, Anna H / Berchuck, Andrew / Gentry-Maharaj, Aleksandra / Ramus, Susan J / Diergaarde, Brenda / Shen, Howard / Jensen, Allan / Menkiszak, Janusz / Cybulski, Cezary / Lubiłski, Jan / Ziogas, Argyrios / Rothstein, Joseph H / McGuire, Valerie / Sieh, Weiva / Lester, Jenny / Walsh, Christine / Vergote, Ignace / Lambrechts, Sandrina / Despierre, Evelyn / Garcia-Closas, Montserrat / Yang, Hannah / Brinton, Louise A / Spiewankiewicz, Beata / Rzepecka, Iwona K / Dansonka-Mieszkowska, Agnieszka / Seibold, Petra / Rudolph, Anja / Paddock, Lisa E / Orlow, Irene / Lundvall, Lene / Olson, Sara H / Hogdall, Claus K / Schwaab, Ira / du Bois, Andreas / Harter, Philipp / Flanagan, James M / Brown, Robert / Paul, James / Ekici, Arif B / Beckmann, Matthias W / Hein, Alexander / Eccles, Diana / Lurie, Galina / Hays, Laura E / Bean, Yukie T / Pejovic, Tanja / Goodman, Marc T / Campbell, Ian / Fasching, Peter A / Konecny, Gottfried / Kaye, Stanley B / Heitz, Florian / Hogdall, Estrid / Bandera, Elisa V / Chang-Claude, Jenny / Kupryjanczyk, Jolanta / Wentzensen, Nicolas / Lambrechts, Diether / Karlan, Beth Y / Whittemore, Alice S / Culver, Hoda Anton / Gronwald, Jacek / Levine, Douglas A / Kjaer, Susanne K / Menon, Usha / Schildkraut, Joellen M / Pearce, Celeste Leigh / Cramer, Daniel W / Rossing, Mary Anne / Chenevix-Trench, Georgia / Pharoah, Paul D P / Gayther, Simon A / Ness, Roberta B / Odunsi, Kunle / Sucheston, Lara E / Knutson, Keith L / Goode, Ellen L

Cancer immunology research

2014 Volume 2, Issue 4, Page(s) 332–340

Abstract: The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg- ... ...

Abstract	The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer.
MeSH term(s)	Female ; Gene Expression ; Gene Expression Profiling ; Genetic Predisposition to Disease ; Genetic Variation ; Germ-Line Mutation ; Humans ; Interleukin-2 Receptor alpha Subunit/genetics ; Neoplasm Grading ; Neoplasm Invasiveness ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/mortality ; Ovarian Neoplasms/pathology ; Patient Outcome Assessment ; Polymorphism, Single Nucleotide ; Prognosis ; T-Lymphocytes, Regulatory/metabolism
Chemical Substances	Interleukin-2 Receptor alpha Subunit
Language	English
Publishing date	2014-01-27
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.
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-13-0136
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10.

Charbonneau, Bridget / Block, Matthew S / Bamlet, William R / Vierkant, Robert A / Kalli, Kimberly R / Fogarty, Zachary / Rider, David N / Sellers, Thomas A / Tworoger, Shelley S / Poole, Elizabeth / Risch, Harvey A / Salvesen, Helga B / Kiemeney, Lambertus A / Baglietto, Laura / Giles, Graham G / Severi, Gianluca / Trabert, Britton / Wentzensen, Nicolas / Chenevix-Trench, Georgia /

Whittemore, Alice S / Sieh, Weiva / Chang-Claude, Jenny / Bandera, Elisa V / Orlow, Irene / Terry, Kathryn / Goodman, Marc T / Thompson, Pamela J / Cook, Linda S / Rossing, Mary Anne / Ness, Roberta B / Narod, Steven A / Kupryjanczyk, Jolanta / Lu, Karen / Butzow, Ralf / Dörk, Thilo / Pejovic, Tanja / Campbell, Ian / Le, Nhu D / Bunker, Clareann H / Bogdanova, Natalia / Runnebaum, Ingo B / Eccles, Diana / Paul, James / Wu, Anna H / Gayther, Simon A / Hogdall, Estrid / Heitz, Florian / Kaye, Stanley B / Karlan, Beth Y / Anton-Culver, Hoda / Gronwald, Jacek / Hogdall, Claus K / Lambrechts, Diether / Fasching, Peter A / Menon, Usha / Schildkraut, Joellen / Pearce, Celeste Leigh / Levine, Douglas A / Kjaer, Susanne Kruger / Cramer, Daniel / Flanagan, James M / Phelan, Catherine M / Brown, Robert / Massuger, Leon F A G / Song, Honglin / Doherty, Jennifer A / Krakstad, Camilla / Liang, Dong / Odunsi, Kunle / Berchuck, Andrew / Jensen, Allan / Lubinski, Jan / Nevanlinna, Heli / Bean, Yukie T / Lurie, Galina / Ziogas, Argyrios / Walsh, Christine / Despierre, Evelyn / Brinton, Louise / Hein, Alexander / Rudolph, Anja / Dansonka-Mieszkowska, Agnieszka / Olson, Sara H / Harter, Philipp / Tyrer, Jonathan / Vitonis, Allison F / Brooks-Wilson, Angela / Aben, Katja K / Pike, Malcolm C / Ramus, Susan J / Wik, Elisabeth / Cybulski, Cezary / Lin, Jie / Sucheston, Lara / Edwards, Robert / McGuire, Valerie / Lester, Jenny / du Bois, Andreas / Lundvall, Lene / Wang-Gohrke, Shan / Szafron, Lukasz M / Lambrechts, Sandrina / Yang, Hannah / Beckmann, Matthias W / Pelttari, Liisa M / Van Altena, Anne M / van den Berg, David / Halle, Mari K / Gentry-Maharaj, Aleksandra / Schwaab, Ira / Chandran, Urmila / Menkiszak, Janusz / Ekici, Arif B / Wilkens, Lynne R / Leminen, Arto / Modugno, Francesmary / Friel, Grace / Rothstein, Joseph H / Vergote, Ignace / Garcia-Closas, Montserrat / Hildebrandt, Michelle A T / Sobiczewski, Piotr / Kelemen, Linda E / Pharoah, Paul D P / Moysich, Kirsten / Knutson, Keith L / Cunningham, Julie M / Fridley, Brooke L / Goode, Ellen L

Cancer research

2013 Volume 74, Issue 3, Page(s) 852–861

Abstract: A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, ... ...

Abstract	A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.
MeSH term(s)	Case-Control Studies ; Female ; Genetic Association Studies ; Humans ; Interleukin-1alpha/genetics ; NF-kappa B/metabolism ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Polymorphism, Single Nucleotide ; Risk ; Signal Transduction ; TNF-Related Apoptosis-Inducing Ligand/genetics
Chemical Substances	Interleukin-1alpha ; NF-kappa B ; TNF-Related Apoptosis-Inducing Ligand ; TNFSF10 protein, human
Language	English
Publishing date	2013-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-13-1051
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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: Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

Chornokur, Ganna / Lin, Hui-Yi / Tyrer, Jonathan P / Lawrenson, Kate / Dennis, Joe / Amankwah, Ernest K / Qu, Xiaotao / Tsai, Ya-Yu / Jim, Heather S L / Chen, Zhihua / Chen, Ann Y / Permuth-Wey, Jennifer / Aben, Katja K H / Anton-Culver, Hoda / Antonenkova, Natalia / Bruinsma, Fiona / Bandera, Elisa V / Bean, Yukie T / Beckmann, Matthias W /

Bisogna, Maria / Bjorge, Line / Bogdanova, Natalia / Brinton, Louise A / Brooks-Wilson, Angela / 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 / du Bois, Andreas / Despierre, Evelyn / Dicks, Ed / Doherty, Jennifer A / Dörk, Thilo / Dürst, Matthias / Easton, Douglas F / Eccles, Diana M / Edwards, Robert P / Ekici, Arif B / Fasching, Peter A / Fridley, Brooke L / Gao, Yu-Tang / Gentry-Maharaj, Aleksandra / Giles, Graham G / Glasspool, Rosalind / Goodman, Marc T / Gronwald, Jacek / Harrington, Patricia / Harter, Philipp / Hein, Alexander / Heitz, Florian / Hildebrandt, Michelle A T / Hillemanns, Peter / Hogdall, Claus K / Hogdall, Estrid / Hosono, Satoyo / Jakubowska, Anna / Jensen, Allan / Ji, Bu-Tian / Karlan, Beth Y / Kelemen, Linda E / Kellar, Mellissa / Kiemeney, Lambertus A / Krakstad, Camilla / Kjaer, Susanne K / Kupryjanczyk, Jolanta / Lambrechts, Diether / Lambrechts, Sandrina / Le, Nhu D / Lee, Alice W / Lele, Shashi / Leminen, Arto / Lester, Jenny / Levine, Douglas A / Liang, Dong / Lim, Boon Kiong / 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 / Eilber, Ursula / Odunsi, Kunle / Olson, Sara H / Orlow, Irene / Orsulic, Sandra / Weber, Rachel Palmieri / Paul, James / Pearce, Celeste L / Pejovic, Tanja / Pelttari, Liisa M / Pike, Malcolm C / Poole, Elizabeth M / Risch, Harvey A / Rosen, Barry / Rossing, Mary Anne / Rothstein, Joseph H / Rudolph, Anja / Runnebaum, Ingo B / Rzepecka, Iwona K / Salvesen, Helga B / Schernhammer, Eva / Schwaab, Ira / Shu, Xiao-Ou / Shvetsov, Yurii B / Siddiqui, Nadeem / Sieh, Weiva / Song, Honglin / Southey, Melissa C / Spiewankiewicz, Beata / Sucheston, Lara / Teo, Soo-Hwang / Terry, Kathryn L / Thompson, Pamela J / Thomsen, Lotte / Tangen, Ingvild L / Tworoger, Shelley S / van Altena, Anne M / Vierkant, Robert A / Vergote, Ignace / Walsh, Christine S / 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 / Hasmad, Hanis N / Berchuck, Andrew / Iversen, Edwin S / Schildkraut, Joellen M / Ramus, Susan J / Goode, Ellen L / Monteiro, Alvaro N A / Gayther, Simon A / Narod, Steven A / Pharoah, Paul D P / Sellers, Thomas A / Phelan, Catherine M

PloS one

2015 Volume 10, Issue 6, Page(s) e0128106

Abstract: Background: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant ...

Abstract	Background: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. Results: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). Conclusion: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
MeSH term(s)	Black or African American ; Alleles ; Asian ; Biological Transport ; Carcinoma, Ovarian Epithelial ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Case-Control Studies ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Neoplasms, Glandular and Epithelial/epidemiology ; Neoplasms, Glandular and Epithelial/genetics ; Neoplasms, Glandular and Epithelial/pathology ; Odds Ratio ; Ovarian Neoplasms/epidemiology ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Polymorphism, Single Nucleotide ; Risk
Chemical Substances	Carrier Proteins
Language	English
Publishing date	2015-06-19
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.0128106
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Article ; Online: Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.

Kar, Siddhartha P / Tyrer, Jonathan P / Li, Qiyuan / Lawrenson, Kate / Aben, Katja K H / Anton-Culver, Hoda / Antonenkova, Natalia / Chenevix-Trench, Georgia / Baker, Helen / Bandera, Elisa V / Bean, Yukie T / Beckmann, Matthias W / Berchuck, Andrew / Bisogna, Maria / Bjørge, Line / Bogdanova, Natalia / Brinton, Louise / Brooks-Wilson, Angela / Butzow, Ralf /

Campbell, Ian / Carty, Karen / Chang-Claude, Jenny / Chen, Yian Ann / Chen, Zhihua / Cook, Linda S / Cramer, Daniel / Cunningham, Julie M / Cybulski, Cezary / Dansonka-Mieszkowska, Agnieszka / Dennis, Joe / Dicks, Ed / Doherty, Jennifer A / Dörk, Thilo / du Bois, Andreas / Dürst, Matthias / Eccles, Diana / Easton, Douglas F / Edwards, Robert P / 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 / Grownwald, Jacek / Harrington, Patricia / Harter, Philipp / Hein, Alexander / Heitz, Florian / Hildebrandt, Michelle A T / Hillemanns, Peter / Hogdall, Estrid / Hogdall, Claus K / Hosono, Satoyo / Iversen, Edwin S / Jakubowska, Anna / Paul, James / Jensen, Allan / Ji, Bu-Tian / Karlan, Beth Y / Kjaer, Susanne K / Kelemen, Linda E / Kellar, Melissa / Kelley, Joseph / Kiemeney, Lambertus A / Krakstad, Camilla / Kupryjanczyk, Jolanta / Lambrechts, Diether / Lambrechts, Sandrina / Le, Nhu D / Lee, Alice W / Lele, Shashi / Leminen, Arto / Lester, Jenny / Levine, Douglas A / Liang, Dong / Lissowska, Jolanta / Lu, Karen / Lubinski, Jan / Lundvall, Lene / Massuger, Leon / Matsuo, Keitaro / McGuire, Valerie / McLaughlin, John R / McNeish, Iain A / Menon, Usha / Modugno, Francesmary / Moysich, Kirsten B / Narod, Steven A / Nedergaard, Lotte / Ness, Roberta B / Nevanlinna, Heli / Odunsi, Kunle / Olson, Sara H / Orlow, Irene / Orsulic, Sandra / Weber, Rachel Palmieri / Pearce, Celeste Leigh / 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 / Schildkraut, Joellen M / Schwaab, Ira / Shu, Xiao-Ou / Shvetsov, Yurii B / Siddiqui, Nadeem / Sieh, Weiva / Song, Honglin / Southey, Melissa C / Sucheston-Campbell, Lara E / Tangen, Ingvild L / Teo, Soo-Hwang / Terry, Kathryn L / Thompson, Pamela J / Timorek, Agnieszka / Tsai, Ya-Yu / Tworoger, Shelley S / van Altena, Anne M / 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 / Yang, Hannah / Zheng, Wei / Ziogas, Argyrios / Sellers, Thomas A / Monteiro, Alvaro N A / Freedman, Matthew L / Gayther, Simon A / Pharoah, Paul D P

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2015 Volume 24, Issue 10, Page(s) 1574–1584

Abstract: Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that ... ...

Abstract	Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.
MeSH term(s)	Cystadenocarcinoma, Serous/epidemiology ; Cystadenocarcinoma, Serous/genetics ; DNA, Neoplasm/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Global Health ; Humans ; Morbidity/trends ; Nuclear Proteins ; Ovarian Neoplasms/epidemiology ; Ovarian Neoplasms/genetics ; Risk Factors ; Transcription Factors/biosynthesis ; Transcription Factors/genetics
Chemical Substances	DNA, Neoplasm ; Nuclear Proteins ; Transcription Factors
Language	English
Publishing date	2015-07-24
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1153420-5
ISSN	1538-7755 ; 1055-9965
ISSN (online)	1538-7755
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-14-1270
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Article: Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC).

Jim, Heather S L / Lin, Hui-Yi / Tyrer, Jonathan P / Lawrenson, Kate / Dennis, Joe / Chornokur, Ganna / Chen, Zhihua / Chen, Ann Y / Permuth-Wey, Jennifer / Aben, Katja Kh / Anton-Culver, Hoda / Antonenkova, Natalia / Bruinsma, Fiona / Bandera, Elisa V / Bean, Yukie T / Beckmann, Matthias W / Bisogna, Maria / Bjorge, Line / Bogdanova, Natalia /

Brinton, Louise A / Brooks-Wilson, Angela / 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 / du Bois, Andreas / Despierre, Evelyn / Sieh, Weiva / Doherty, Jennifer A / Dörk, Thilo / Dürst, Matthias / Easton, Douglas F / Eccles, Diana M / Edwards, Robert P / Ekici, Arif B / Fasching, Peter A / Fridley, Brooke L / Gao, Yu-Tang / Gentry-Maharaj, Aleksandra / Giles, Graham G / Glasspool, Rosalind / Goodman, Marc T / Gronwald, Jacek / Harter, Philipp / Hasmad, Hanis N / Hein, Alexander / Heitz, Florian / Hildebrandt, Michelle A T / Hillemanns, Peter / Hogdall, Claus K / Hogdall, Estrid / Hosono, Satoyo / Iversen, Edwin S / Jakubowska, Anna / Jensen, Allan / Ji, Bu-Tian / Karlan, Beth Y / Kellar, Melissa / Kiemeney, Lambertus A / Krakstad, Camilla / Kjaer, Susanne K / Kupryjanczyk, Jolanta / Vierkant, Robert A / Lambrechts, Diether / Lambrechts, Sandrina / Le, Nhu D / Lee, Alice W / Lele, Shashi / Leminen, Arto / Lester, Jenny / Levine, Douglas A / Liang, Dong / Lim, Boon Kiong / Lissowska, Jolanta / Lu, Karen / Lubinski, Jan / Lundvall, Lene / Massuger, Leon F A G / Matsuo, Keitaro / McGuire, Valerie / McLaughlin, John R / McNeish, Ian / Menon, Usha / Milne, Roger L / Modugno, Francesmary / Thomsen, Lotte / Moysich, Kirsten B / Ness, Roberta B / Nevanlinna, Heli / Eilber, Ursula / Odunsi, Kunle / Olson, Sara H / Orlow, Irene / Orsulic, Sandra / Palmieri Weber, Rachel / Paul, James / Pearce, Celeste L / Pejovic, Tanja / Pelttari, Liisa M / Pike, Malcolm C / Poole, Elizabeth M / Schernhammer, Eva / Risch, Harvey A / Rosen, Barry / Rossing, Mary Anne / Rothstein, Joseph H / Rudolph, Anja / Runnebaum, Ingo B / Rzepecka, Iwona K / Salvesen, Helga B / Schwaab, Ira / Shu, Xiao-Ou / Shvetsov, Yurii B / Siddiqui, Nadeem / Song, Honglin / Southey, Melissa C / Spiewankiewicz, Beata / Sucheston-Campbell, Lara / Teo, Soo-Hwang / Terry, Kathryn L / Thompson, Pamela J / Tangen, Ingvild L / Tworoger, Shelley S / van Altena, Anne M / Vergote, Ignace / Walsh, Christine S / 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 / Amankwah, Ernest / Berchuck, Andrew / Schildkraut, Joellen M / Kelemen, Linda E / Ramus, Susan J / Monteiro, Alvaro N A / Goode, Ellen L / Narod, Steven A / Gayther, Simon A / Pharoah, Paul D P / Sellers, Thomas A / Phelan, Catherine M

Journal of genetics and genome research

2015 Volume 2, Issue 2

Abstract: Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. ... ...

Abstract	Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes
Language	English
Publishing date	2015-09-15
Publishing country	United States
Document type	Journal Article
ISSN	2378-3648
ISSN	2378-3648
DOI	10.23937/2378-3648/1410017
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Article ; Online: Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk.

Amankwah, Ernest K / Lin, Hui-Yi / Tyrer, Jonathan P / Lawrenson, Kate / Dennis, Joe / Chornokur, Ganna / Aben, Katja K H / Anton-Culver, Hoda / Antonenkova, Natalia / Bruinsma, Fiona / Bandera, Elisa V / Bean, Yukie T / Beckmann, Matthias W / Bisogna, Maria / Bjorge, Line / Bogdanova, Natalia / Brinton, Louise A / Brooks-Wilson, Angela / Bunker, Clareann H /

Butzow, Ralf / Campbell, Ian G / Carty, Karen / Chen, Zhihua / Chen, Y Ann / Chang-Claude, Jenny / Cook, Linda S / Cramer, Daniel W / Cunningham, Julie M / Cybulski, Cezary / Dansonka-Mieszkowska, Agnieszka / du Bois, Andreas / Despierre, Evelyn / Dicks, Ed / Doherty, Jennifer A / Dörk, Thilo / Dürst, Matthias / Easton, Douglas F / Eccles, Diana M / Edwards, Robert P / Ekici, Arif B / Fasching, Peter A / Fridley, Brooke L / Gao, Yu-Tang / Gentry-Maharaj, Aleksandra / Giles, Graham G / Glasspool, Rosalind / Goodman, Marc T / Gronwald, Jacek / Harrington, Patricia / Harter, Philipp / Hasmad, Hanis N / Hein, Alexander / Heitz, Florian / Hildebrandt, Michelle A T / Hillemanns, Peter / Hogdall, Claus K / Hogdall, Estrid / Hosono, Satoyo / Iversen, Edwin S / Jakubowska, Anna / Jensen, Allan / Ji, Bu-Tian / Karlan, Beth Y / Jim, Heather / Kellar, Melissa / Kiemeney, Lambertus A / Krakstad, Camilla / Kjaer, Susanne K / Kupryjanczyk, Jolanta / Lambrechts, Diether / Lambrechts, Sandrina / Le, Nhu D / Lee, Alice W / Lele, Shashi / Leminen, Arto / Lester, Jenny / Levine, Douglas A / Liang, Dong / Lim, Boon Kiong / Lissowska, Jolanta / Lu, Karen / Lubinski, Jan / Lundvall, Lene / Massuger, Leon F A G / Matsuo, Keitaro / McGuire, Valerie / McLaughlin, John R / McNeish, Ian / Menon, Usha / Milne, Roger L / Modugno, Francesmary / Moysich, Kirsten B / Ness, Roberta B / Nevanlinna, Heli / Eilber, Ursula / Odunsi, Kunle / Olson, Sara H / Orlow, Irene / Orsulic, Sandra / Weber, Rachel Palmieri / Paul, James / Pearce, Celeste L / Pejovic, Tanja / Pelttari, Liisa M / Permuth-Wey, Jennifer / Pike, Malcolm C / Poole, Elizabeth M / Risch, Harvey A / Rosen, Barry / Rossing, Mary Anne / Rothstein, Joseph H / Rudolph, Anja / Runnebaum, Ingo B / Rzepecka, Iwona K / Salvesen, Helga B / Schernhammer, Eva / Schwaab, Ira / Shu, Xiao-Ou / Shvetsov, Yurii B / Siddiqui, Nadeem / Sieh, Weiva / Song, Honglin / Southey, Melissa C / Spiewankiewicz, Beata / Sucheston-Campbell, Lara / Teo, Soo-Hwang / Terry, Kathryn L / Thompson, Pamela J / Thomsen, Lotte / Tangen, Ingvild L / Tworoger, Shelley S / van Altena, Anne M / Vierkant, Robert A / Vergote, Ignace / Walsh, Christine S / 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 / Kelemen, Linda E / Berchuck, Andrew / Schildkraut, Joellen M / Ramus, Susan J / Goode, Ellen L / Monteiro, Alvaro N A / Gayther, Simon A / Narod, Steven A / Pharoah, Paul D P / Sellers, Thomas A / Phelan, Catherine M

Genetic epidemiology

2015 Volume 39, Issue 8, Page(s) 689–697

Abstract: Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that ... ...

Abstract	Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
MeSH term(s)	Adult ; Aged ; Carcinoma, Ovarian Epithelial ; Epithelial-Mesenchymal Transition/genetics ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Humans ; Middle Aged ; Neoplasms, Glandular and Epithelial/epidemiology ; Neoplasms, Glandular and Epithelial/genetics ; Odds Ratio ; Ovarian Neoplasms/epidemiology ; Ovarian Neoplasms/genetics ; Polymorphism, Single Nucleotide/genetics ; Risk ; White People
Language	English
Publishing date	2015-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605785-8
ISSN	1098-2272 ; 0741-0395
ISSN (online)	1098-2272
ISSN	0741-0395
DOI	10.1002/gepi.21921
Database	MEDical Literature Analysis and Retrieval System OnLINE

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