Author: "Hogdall, Estrid" / Topic: genetics - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Hogdall, Estrid"' showing total 25 results

Start Over Author "Hogdall, Estrid" Topic genetics

25 results on '"Hogdall, Estrid"'

1. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

Author: Quinn, Michael CJ, McCue, Karen, Shi, Wei, Johnatty, Sharon E, Beesley, Jonathan, Civitarese, Andrew, O'Mara, Tracy A, Glubb, Dylan M, Tyrer, Jonathan P, Armasu, Sebastian M, Ong, Jue-Sheng, Gharahkhani, Puya, Lu, Yi, Gao, Bo, Patch, Ann-Marie, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Edwards, Digna R Velez, Beeghly-Fadiel, Alicia, Benitez, Javier, Garcia, Maria J, Goodman, Marc T, Dörk, Thilo, Dürst, Matthias, Modugno, Francesmary, Moysich, Kirsten, du Bois, Andreas, Pfisterer, Jacobus, Bauman, Klaus, Group, for the AGO Study, Karlan, Beth Y, Lester, Jenny, Cunningham, Julie M, Larson, Melissa C, McCauley, Bryan M, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus K, Hogdall, Estrid, Schildkraut, Joellen M, Riggan, Marjorie J, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Bjorge, Line, Webb, Penelope M, Group, for the OPAL Study, Friedlander, Michael, Pejovic, Tanja, Moffitt, Melissa, Glasspool, Rosalind, May, Taymaa, Ene, Gabrielle EV, Huntsman, David G, Woo, Michelle, Carney, Michael E, Hinsley, Samantha, Heitz, Florian, Fereday, Sian, Kennedy, Catherine J, Edwards, Stacey L, Winham, Stacey J, deFazio, Anna, Group, for Australian Ovarian Cancer Study, Pharoah, Paul DP, Goode, Ellen L, MacGregor, Stuart, and Chenevix-Trench, Georgia
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Ovarian Cancer, Rare Diseases, Cancer, Women's Health, Human Genome, 2.1 Biological and endogenous factors, Autophagy-Related Protein-1 Homolog, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Female, Gene Knockout Techniques, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Progression-Free Survival, AGO Study Group, OPAL Study Group, for Australian Ovarian Cancer Study Group, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundMany loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.MethodsWe carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.ResultsWe found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro.ConclusionsThe locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association.ImpactThis finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.
Published: 2021

2. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

Author: Kelemen, Linda E, Earp, Madalene, Fridley, Brooke L, Chenevix-Trench, Georgia, Australian Ovarian Cancer Study Group, 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 AT, 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 KH, Massuger, Leon FAG, 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 DP, Dicks, Ed, Song, Honglin, Tyrer, Jonathan P, McNeish, Iain, Siddiqui, Nadeem, and Carty, Karen
Subjects: Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Humans, Adenocarcinoma, Mucinous, Ovarian Neoplasms, Hydro-Lyases, Thymidylate Synthase, Proteins, RNA, Antisense, Logistic Models, Odds Ratio, Risk, Case-Control Studies, Signal Transduction, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Middle Aged, Female, Genetic Association Studies, consortia, enolase superfamily member 1, expression quantitative trait locus, genetics, gynecology, ovarian neoplasms, single-nucleotide polymorphism, thymidylate synthase, Ovarian Cancer, Rare Diseases, Biotechnology, Cancer, Digestive Diseases, Genetics, Chemical Physics, Other Chemical Sciences, Other Biological Sciences
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 TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
Published: 2018

3. Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

Author: Glubb, Dylan M, Johnatty, Sharon E, Quinn, Michael CJ, O’Mara, Tracy A, Tyrer, Jonathan P, Gao, Bo, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vergote, Ignace, Velez Edwards, Digna R, Beeghly-Fadiel, Alicia, Benitez, Javier, Garcia, Maria J, Goodman, Marc T, Thompson, Pamela J, Dörk, Thilo, Dürst, Matthias, Modungo, Francesmary, Moysich, Kirsten, Heitz, Florian, du Bois, Andreas, Pfisterer, Jacobus, Hillemanns, Peter, Karlan, Beth Y, Lester, Jenny, Goode, Ellen L, Cunningham, Julie M, Winham, Stacey J, Larson, Melissa C, McCauley, Bryan M, Kjær, Susanne Krüger, Jensen, Allan, Schildkraut, Joellen M, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Salvesen, Helga B, Bjorge, Line, Webb, Penny M, Grant, Peter, Pejovic, Tanja, Moffitt, Melissa, Hogdall, Claus K, Hogdall, Estrid, Paul, James, Glasspool, Rosalind, Bernardini, Marcus, Tone, Alicia, Huntsman, David, Woo, Michelle, Group, AOCS, deFazio, Anna, Kennedy, Catherine J, Pharoah, Paul DP, MacGregor, Stuart, and Chenevix-Trench, Georgia
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Biotechnology, Human Genome, Genetics, Cancer, Women's Health, Ovarian Cancer, 2.1 Biological and endogenous factors, ovarian cancer outcome, genetic association, gene regulation, meta-analysis, Oncology and carcinogenesis
Abstract: We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p
Published: 2017

4. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

Author: Permuth, Jennifer B, Reid, Brett, Earp, Madalene, Chen, Y Ann, Monteiro, Alvaro NA, Chen, Zhihua, Group, AOCS Study, Chenevix-Trench, Georgia, Fasching, Peter A, Beckmann, Matthias W, Lambrechts, Diether, Vanderstichele, Adriaan, Van Niewenhuyse, Els, Vergote, Ignace, Rossing, Mary Anne, Doherty, Jennifer Anne, Chang-Claude, Jenny, Moysich, Kirsten, Odunsi, Kunle, Goodman, Marc T, Shvetsov, Yurii B, Wilkens, Lynne R, Thompson, Pamela J, Dörk, Thilo, Bogdanova, Natalia, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa, Leminen, Arto, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, Kelley, Joseph, Heitz, Florian, Karlan, Beth, Lester, Jenny, Kjaer, Susanne K, Jensen, Allan, Giles, Graham, Hildebrandt, Michelle, Liang, Dong, Lu, Karen H, Wu, Xifeng, Levine, Douglas A, Bisogna, Maria, Berchuck, Andrew, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Poole, Elizabeth M, Bandera, Elisa V, Fridley, Brooke, Cunningham, Julie, Winham, Stacey J, Olson, Sara H, Orlow, Irene, Bjorge, Line, Kiemeney, Lambertus A, Massuger, Leon, Pejovic, Tanja, Moffitt, Melissa, Le, Nhu, Cook, Linda S, Brooks-Wilson, Angela, Kelemen, Linda E, Gronwald, Jacek, Lubinski, Jan, Wentzensen, Nicolas, Brinton, Louise A, Lissowska, Jolanta, Yang, Hanna, Hogdall, Estrid, Hogdall, Claus, Lundvall, Lene, Pharoah, Paul DP, Song, Honglin, Campbell, Ian, Eccles, Diana, McNeish, Iain, Whittemore, Alice, McGuire, Valerie, Sieh, Weiva, Rothstein, Joseph, Phelan, Catherine M, Risch, Harvey, Narod, Steven, McLaughlin, John, Anton-Culver, Hoda, Ziogas, Argyrios, Menon, Usha, Gayther, Simon, Ramus, Susan J, Gentry-Maharaj, Aleksandra, Pearce, Celeste Leigh, Wu, Anna H, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Schildkraut, Joellen M, Cheng, Jin Q, and Goode, Ellen L
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Ovarian Cancer, Women's Health, Cancer, Human Genome, Rare Diseases, 2.1 Biological and endogenous factors, Animals, Disease Susceptibility, Female, Genetic Variation, Humans, Middle Aged, Ovarian Neoplasms, Polymorphism, Single Nucleotide, RNA Editing, polymorphisms, RNA editing, ovarian cancer risk, AOCS Study Group, Oncology and carcinogenesis
Abstract: RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P
Published: 2016

5. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author: 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 KH, 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 AT, 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 FAG, Matsuo, Keitaro, and McGuire, Valeria
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Rare Diseases, Genetics, Ovarian Cancer, Cancer, Women's Health, 2.1 Biological and endogenous factors, Adenocarcinoma, Clear Cell, Adult, Aged, Carcinoma, Ovarian Epithelial, Female, Gene Expression Regulation, Neoplastic, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Risk Factors, T-Lymphocytes, Regulatory, ovarian cancer, immunosuppression, biomarkers, genetic variation, TGFBR2, Oncology and carcinogenesis
Abstract: BackgroundRegulatory 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.MethodsIn 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.ResultsThe 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).ConclusionsCommon 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.
Published: 2016

6. Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk

Author: Permuth, Jennifer B, Pirie, Ailith, Chen, Y Ann, Lin, Hui-Yi, Reid, Brett M, Chen, Zhihua, Monteiro, Alvaro, Dennis, Joe, Mendoza-Fandino, Gustavo, Group, AOCS Study, Study, Australian Cancer, Anton-Culver, Hoda, Bandera, Elisa V, Bisogna, Maria, Brinton, Louise, Brooks-Wilson, Angela, Carney, Michael E, Chenevix-Trench, Georgia, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, D’Aloisio, Aimee A, Doherty, Jennifer Anne, Earp, Madalene, Edwards, Robert P, Fridley, Brooke L, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Goodman, Marc T, Gronwald, Jacek, Hogdall, Estrid, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Karlan, Beth Y, Kelemen, Linda E, Kjaer, Suzanne K, Kraft, Peter, Le, Nhu D, Levine, Douglas A, Lissowska, Jolanta, Lubinski, Jan, Matsuo, Keitaro, Menon, Usha, Modugno, Rosemary, Moysich, Kirsten B, Nakanishi, Toru, Ness, Roberta B, Olson, Sara, Orlow, Irene, Pearce, Celeste L, Pejovic, Tanja, Poole, Elizabeth M, Ramus, Susan J, Rossing, Mary Anne, Sandler, Dale P, Shu, Xiao-Ou, Song, Honglin, Taylor, Jack A, Teo, Soo-Hwang, Terry, Kathryn L, Thompson, Pamela J, Tworoger, Shelley S, Webb, Penelope M, Wentzensen, Nicolas, Wilkens, Lynne R, Winham, Stacey, Woo, Yin-Ling, Wu, Anna H, Yang, Hannah, Zheng, Wei, Ziogas, Argyrios, Phelan, Catherine M, Schildkraut, Joellen M, Berchuck, Andrew, Goode, Ellen L, Pharoah, Paul DP, Sellers, Thomas A, and Consortium, on behalf of the Ovarian Cancer Association
Subjects: Biological Sciences, Genetics, Ovarian Cancer, Women's Health, Cancer, Human Genome, Rare Diseases, 2.1 Biological and endogenous factors, Actins, Biotinidase, Carcinoma, Ovarian Epithelial, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Keratin-13, Neoplasm Proteins, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Receptor, Melanocortin, Type 2, AOCS Study Group, Australian Cancer Study, Ovarian Cancer Association Consortium, Medical and Health Sciences, Genetics & Heredity
Abstract: Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P P≥5.0 ×10 - 7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 - 5; PSKAT-o = 9.23 × 10 - 4) and KRT13 (PAML = 1.67 × 10 - 4; PSKAT-o = 1.07 × 10 - 5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.
Published: 2016

7. Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer

Author: French, Juliet D, Johnatty, Sharon E, Lu, Yi, Beesley, Jonathan, Gao, Bo, Kalimutho, Murugan, Henderson, Michelle J, Russell, Amanda J, Kar, Siddhartha, Chen, Xiaoqing, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, O’Reilly, Martin, Wang, Chen, Korbie, Darren J, Group, Australian Ovarian Cancer Study, Study, Australian Cancer, Lambrechts, Diether, Despierre, Evelyn, Van Nieuwenhuysen, Els, Lambrechts, Sandrina, Vergote, Ignace, Karlan, Beth, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Matsuo, Keitaro, Hosono, Satoyo, Pisterer, Jacobus, Hillemanns, Peter, Nakanishi, Toru, Yatabe, Yasushi, Goodman, Marc T, Lurie, Galina, Matsuno, Rayna K, Thompson, Pamela J, Pejovic, Tanja, Bean, Yukie, Heitz, Florian, Harter, Philipp, du Bois, Andreas, Schwaab, Ira, Hogdall, Estrid, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus, Lundvall, Lene, Engelholm, Svend Aage, Brown, Bob, Flanagan, James M, Metcalf, Michelle D, Siddiqui, Nadeem, Sellers, Thomas, Fridley, Brooke, Cunningham, Julie, Schildkraut, Joellen M, Iversen, Ed, Weber, Rachel Palmieri, Brennan, Donal, Berchuck, Andrew, Pharoah, Paul, Harnett, Paul, Norris, Murray D, Haber, Michelle, Goode, Ellen L, Lee, Jason S, Khanna, Kum Kum, Meyer, Kerstin B, Chenevix-Trench, Georgia, deFazio, Anna, Edwards, Stacey L, MacGregor, Stuart, and Consortium, on behalf of the Ovarian Cancer Association
Subjects: Genetics, Rare Diseases, Human Genome, Ovarian Cancer, Cancer, Aetiology, 2.1 Biological and endogenous factors, Adaptor Proteins, Signal Transducing, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Chromatin Immunoprecipitation, Cohort Studies, Cystadenocarcinoma, Serous, Electrophoretic Mobility Shift Assay, Enhancer Elements, Genetic, Fallopian Tube Neoplasms, Female, Follow-Up Studies, Germ-Line Mutation, Humans, Ovarian Neoplasms, Peritoneal Neoplasms, Polymorphism, Single Nucleotide, Prognosis, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Transcription Factors, Tumor Cells, Cultured, epithelial ovarian cancer, progression free survival, genome-wide association study, PSIP1, chromosome conformation capture, Australian Ovarian Cancer Study Group, Australian Ovarian Cancer Study, Ovarian Cancer Association Consortium, Oncology and Carcinogenesis
Abstract: Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.
Published: 2016

8. Evidence of a genetic link between endometriosis and ovarian cancer

Author: Lee, Alice W, Templeman, Claire, Stram, Douglas A, Beesley, Jonathan, Tyrer, Jonathan, Berchuck, Andrew, Pharoah, Paul P, Chenevix-Trench, Georgia, Pearce, Celeste Leigh, Consortium, Ovarian Cancer Association, Ness, Roberta B, Dansonka-Mieszkowska, Agnieszka, Gentry-Maharaj, Aleksandra, Hein, Alexander, Whittemore, Alice S, Jensen, Allan, du Bois, Andreas, Brooks-Wilson, Angela, Rudolph, Anja, Jakubowska, Anna, Wu, Anna H, Ziogas, Argyrios, Ekici, Arif B, Leminen, Arto, Study, Australian Cancer, Group, Australian Ovarian Cancer Study, Rosen, Barry, Spiewankiewicz, Beata, Karlan, Beth Y, Trabert, Britton, Fridley, Brooke L, Gilks, C Blake, Krakstad, Camilla, Phelan, Catherine M, Cybulski, Cezary, Walsh, Christine, Hogdall, Claus, Cramer, Daniel W, Huntsman, David G, Eccles, Diana, Lambrechts, Diether, Liang, Dong, Levine, Douglas A, Iversen, Edwin S, Bandera, Elisa V, Poole, Elizabeth M, Goode, Ellen L, Van Nieuwenhuysen, Els, Hogdall, Estrid, Bruinsma, Fiona, Heitz, Florian, Modugno, Francesmary, Giles, Graham G, Risch, Harvey A, Baker, Helen, Salvesen, Helga B, Nevanlinna, Heli, Anton-Culver, Hoda, Song, Honglin, McNeish, Iain, Campbell, Ian G, Vergote, Ignace, Runnebaum, Ingo B, Tangen, Ingvild L, Schwaab, Ira, Gronwald, Jacek, Paul, James, Lubinski, Jan, Doherty, Jennifer A, Chang-Claude, Jenny, Lester, Jenny, Schildkraut, Joellen M, McLaughlin, John R, Lissowska, Jolanta, Kupryjanczyk, Jolanta, Kelley, Joseph L, Rothstein, Joseph H, Cunningham, Julie M, Lu, Karen, Carty, Karen, Terry, Kathryn L, Aben, Katja KH, Moysich, Kirsten B, Wicklund, Kristine G, Odunsi, Kunle, Kiemeney, Lambertus A, Sucheston-Campbell, Lara, Lundvall, Lene, Massuger, Leon FAG, Pelttari, Liisa M, Kelemen, Linda E, Cook, Linda S, Bjorge, Line, Nedergaard, Lotte, Brinton, Louise A, Wilkens, Lynne R, Pike, Malcolm C, Goodman, Marc T, and Bisogna, Maria
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Women's Health, Ovarian Cancer, Endometriosis, Cancer, Clinical Research, Rare Diseases, 2.1 Biological and endogenous factors, Case-Control Studies, Computational Biology, Databases, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasm Grading, Ovarian Neoplasms, Phenotype, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Ovarian Cancer Association Consortium, SNPs, genetic variation, ovarian cancer, Clinical Sciences, Paediatrics and Reproductive Medicine, Public Health and Health Services, Obstetrics & Reproductive Medicine, Reproductive medicine
Abstract: ObjectiveTo evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer.DesignPooled genetic analysis.SettingUniversity hospital.Patient(s)Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies.Intervention(s)None.Main outcome measure(s)Endometriosis-associated genetic variation and ovarian cancer.Result(s)There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected.Conclusion(s)By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions.
Published: 2016

9. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk.

Author: Amankwah, Ernest K, Lin, Hui-Yi, Tyrer, Jonathan P, Lawrenson, Kate, Dennis, Joe, Chornokur, Ganna, 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, 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 AT, 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 FAG, 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, and Weber, Rachel Palmieri
Subjects: Georgia Chenevix-Trench on behalf of the AOCS management group, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Odds Ratio, Risk, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Genome-Wide Association Study, Epithelial-Mesenchymal Transition, Carcinoma, Ovarian Epithelial, epithelial-mesenchymal transition, ovarian cancer, single-nucleotide polymorphisms, Neoplasms, Glandular and Epithelial, Polymorphism, Single Nucleotide, Carcinoma, Ovarian Epithelial, Epidemiology, Public Health and Health Services, Genetics
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
Published: 2015

10. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Author: 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 KH, 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 AT, 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 FAG, 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, Azmi, Mat Adenan Noor, Odunsi, Kunle, and Olson, Sara H
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biotechnology, Women's Health, Ovarian Cancer, Cancer, Clinical Research, Cancer Genomics, Human Genome, Genetic Testing, Prevention, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, Carcinoma, Ovarian Epithelial, Case-Control Studies, Checkpoint Kinase 2, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Australian Cancer Study, Australian Ovarian Cancer Study Group, Oncology & Carcinogenesis, Oncology and carcinogenesis
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.
Published: 2015

11. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.

Author: Kar, Siddhartha P, Tyrer, Jonathan P, Li, Qiyuan, Lawrenson, Kate, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Chenevix-Trench, Georgia, Australian Cancer Study, Australian Ovarian Cancer Study Group, 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 AT, 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, and Orlow, Irene
Subjects: Australian Cancer Study, Australian Ovarian Cancer Study Group, Humans, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Genetic Predisposition to Disease, Nuclear Proteins, Transcription Factors, DNA, Neoplasm, Morbidity, Risk Factors, Gene Expression Regulation, Neoplastic, Genotype, Female, Genome-Wide Association Study, Global Health, Ovarian Cancer, Biotechnology, Cancer, Genetics, Rare Diseases, Prevention, Human Genome, 2.1 Biological and endogenous factors, Epidemiology, Medical and Health Sciences
Abstract: BackgroundGenome-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.MethodsWe 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).ResultsGene 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.ConclusionWe identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.ImpactNetwork analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.
Published: 2015

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

Author: Lawrenson, Kate, Li, Qiyuan, Kar, Siddhartha, Seo, Ji-Heui, Tyrer, Jonathan, Spindler, Tassja J, Lee, Janet, Chen, Yibu, Karst, Alison, Drapkin, Ronny, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Australian Ovarian Cancer Study Group, Baker, Helen, Bandera, Elisa V, Bean, Yukie, Beckmann, Matthias W, Berchuck, Andrew, 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, Anne, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, 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 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, Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, James, Paul, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kruger Kjaer, Susanne, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph L, 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 FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, Nevanlinna, Heli, McNeish, Ian, and Menon, Usha
Subjects: Australian Ovarian Cancer Study Group, Cell Line, Tumor, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Homeodomain Proteins, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Protein Binding, Quantitative Trait Loci, Female, Nuchal Cord, Genetic Association Studies, Carcinoma, Ovarian Epithelial, Cell Line, Tumor, Neoplasms, Glandular and Epithelial, Gene Expression Regulation, Neoplastic, Carcinoma, Ovarian Epithelial, Rare Diseases, Prevention, Ovarian Cancer, Biotechnology, Human Genome, Cancer, Genetics, 2.1 Biological and endogenous factors
Abstract: Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P
Published: 2015

13. Genome-wide significant risk associations for mucinous ovarian carcinoma

Author: Kelemen, Linda E, Lawrenson, Kate, Tyrer, Jonathan, Li, Qiyuan, Lee, Janet M, Seo, Ji-Heui, Phelan, Catherine M, Beesley, Jonathan, Chen, Xiaoqing, Spindler, Tassja J, Aben, Katja KH, Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, 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, Chen, Y Ann, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Dennis, Joe, Dicks, Ed, Doherty, Jennifer A, Doerk, Thilo, du Bois, Andreas, Duerst, Matthias, Eccles, Diana, Easton, Douglas T, Edwards, Robert P, Eilber, Ursula, Ekici, Arif B, Engelholm, Svend Aage, 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, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kellar, Melissa, Kelley, Joseph L, 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, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon FAG, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R, McNeish, Iain, Menon, Usha, Modugno, Francesmary, Moes-Sosnowska, Joanna, and Moysich, Kirsten B
Subjects: Rare Diseases, Prevention, Ovarian Cancer, Genetics, Cancer, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Mucinous, Base Sequence, Cell Line, Tumor, Cell Nucleus, Chromosomes, Human, Pair 2, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Green Fluorescent Proteins, Homeodomain Proteins, Humans, Microscopy, Fluorescence, Molecular Sequence Data, Neoplasm Proteins, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Australian Cancer Study, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
Published: 2015

14. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci

Author: Coetzee, Simon G, Shen, Howard C, Hazelett, Dennis J, Lawrenson, Kate, Kuchenbaecker, Karoline, Tyrer, Jonathan, Rhie, Suhn K, Levanon, Keren, Karst, Alison, Drapkin, Ronny, Ramus, Susan J, Consortium, The Consortium of Investigators of Modifiers of BRCA1 2 The Ovarian Cancer Association, Couch, Fergus J, Offit, Kenneth, Chenevix-Trench, Georgia, Monteiro, Alvaro NA, Antoniou, Antonis, Freedman, Matthew, Coetzee, Gerhard A, Pharoah, Paul DP, Noushmehr, Houtan, Gayther, Simon A, Anton-Culver, Hoda, Antonenkova, Natalia, Baker, Helen, Bandera, Elisa V, Bean, Yukie, Beckmann, Matthias W, Berchuck, Andrew, Bisogna, Maria, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Chen, Ann, Chen, Zhihua, Cook, Linda S, Cramer, Daniel W, 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, 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, Grownwald, Jacek, Harrington, Patricia, Harter, Philipp, Hasmad, Hanis Nazihah, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Estrid, Hogdall, Claus, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, James, Paul, Jensen, Allan, Ji, Bu-Tian, Karlan, Beth Y, Kjaer, Susanne Kruger, Kelemen, Linda E, Kellar, Melissa, Kelley, Joseph L, Kiemeney, Lambertus A, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lele, Shashi, Leminen, Arto, Lester, Jenny, Levine, Douglas A, Liang, Dong, and Lissowska, Jolanta
Subjects: Biological Sciences, Genetics, Rare Diseases, Women's Health, Cancer Genomics, Ovarian Cancer, Human Genome, Cancer, Prevention, 2.1 Biological and endogenous factors, Chromatin, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Histones, Humans, Organ Specificity, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Ovarian Cancer Association Consortium, The Consortium of Investigators of Modifiers of BRCA1/2, Ovarian Cancer Association Consortium The Consortium of Investigators of Modifiers of BRCA1/2, Medical and Health Sciences, Genetics & Heredity
Abstract: Understanding the regulatory landscape of the human genome is a central question in complex trait genetics. Most single-nucleotide polymorphisms (SNPs) associated with cancer risk lie in non-protein-coding regions, implicating regulatory DNA elements as functional targets of susceptibility variants. Here, we describe genome-wide annotation of regions of open chromatin and histone modification in fallopian tube and ovarian surface epithelial cells (FTSECs, OSECs), the debated cellular origins of high-grade serous ovarian cancers (HGSOCs) and in endometriosis epithelial cells (EECs), the likely precursor of clear cell ovarian carcinomas (CCOCs). The regulatory architecture of these cell types was compared with normal human mammary epithelial cells and LNCaP prostate cancer cells. We observed similar positional patterns of global enhancer signatures across the three different ovarian cancer precursor cell types, and evidence of tissue-specific regulatory signatures compared to non-gynecological cell types. We found significant enrichment for risk-associated SNPs intersecting regulatory biofeatures at 17 known HGSOC susceptibility loci in FTSECs (P = 3.8 × 10(-30)), OSECs (P = 2.4 × 10(-23)) and HMECs (P = 6.7 × 10(-15)) but not for EECs (P = 0.45) or LNCaP cells (P = 0.88). Hierarchical clustering of risk SNPs conditioned on the six different cell types indicates FTSECs and OSECs are highly related (96% of samples using multi-scale bootstrapping) suggesting both cell types may be precursors of HGSOC. These data represent the first description of regulatory catalogues of normal precursor cells for different ovarian cancer subtypes, and provide unique insights into the tissue specific regulatory variation with respect to the likely functional targets of germline genetic susceptibility variants for ovarian cancer.
Published: 2015

15. Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.

Author: 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, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group, 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 AT, 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 FAG, Kiemeney, Lambertus A, Aben, Katja KH, 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, and Nedergaard, Lotte
Subjects: Australian Cancer Study, Australian Ovarian Cancer Study Group, Humans, Ovarian Neoplasms, Genetic Predisposition to Disease, Gonadotropins, Genetic Markers, Logistic Models, Risk Factors, Case-Control Studies, Signal Transduction, Genotype, Polymorphism, Single Nucleotide, Female, Genome-Wide Association Study, Biomarkers, Tumor, Gene, Genetic variation, Genetics, Ovarian cancer, Polymorphisms, Polymorphism, Single Nucleotide, Biomarkers, Tumor, Ovarian Cancer, Aging, Prevention, Human Genome, Cancer, Biotechnology, Rare Diseases, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine
Abstract: ObjectiveOvarian 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.MethodsGenetic 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.ResultsWe 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).ConclusionsOvarian 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.
Published: 2015

16. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Author: Chornokur, Ganna, Lin, Hui-Yi, Tyrer, Jonathan P, Lawrenson, Kate, Dennis, Joe, Amankwah, Ernest K, Qu, Xiaotao, Tsai, Ya-Yu, Jim, Heather SL, 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, 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 AT, 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 FAG, 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, and Orlow, Irene
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Ovarian Cancer, Cancer, Women's Health, Rare Diseases, 2.1 Biological and endogenous factors, Black or African American, Alleles, Asian, Biological Transport, Carcinoma, Ovarian Epithelial, Carrier Proteins, Case-Control Studies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Humans, Neoplasms, Glandular and Epithelial, Odds Ratio, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk, Georgia Chenevix-Trench, AOCS management group, General Science & Technology
Abstract: BackgroundDefective 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.MethodsIn 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
Published: 2015

17. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

Author: Jim, Heather SL, 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 AT, 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 FAG, 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, and Orsulic, Sandra
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Health Services and Systems, Health Sciences, Oncology and Carcinogenesis, Cancer, Women's Health, Ovarian Cancer, Prevention, Rare Diseases, Sleep Research, Human Genome, Genetic Testing, 2.1 Biological and endogenous factors, Georgia Chenevix-Trench on behalf of the AOCS management group 95, 96
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 BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68-0.90, p = 5.59 × 10-4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
Published: 2015

18. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.

Author: Hedditch, Ellen L, Gao, Bo, Russell, Amanda J, Lu, Yi, Emmanuel, Catherine, Beesley, Jonathan, Johnatty, Sharon E, Chen, Xiaoqing, Harnett, Paul, George, Joshy, Australian Ovarian Cancer Study Group, Williams, Rebekka T, Flemming, Claudia, Lambrechts, Diether, Despierre, Evelyn, Lambrechts, Sandrina, Vergote, Ignace, Karlan, Beth, Lester, Jenny, Orsulic, Sandra, Walsh, Christine, Fasching, Peter, Beckmann, Matthias W, Ekici, Arif B, Hein, Alexander, Matsuo, Keitaro, Hosono, Satoyo, Nakanishi, Toru, Yatabe, Yasushi, Pejovic, Tanja, Bean, Yukie, Heitz, Florian, Harter, Philipp, du Bois, Andreas, Schwaab, Ira, Hogdall, Estrid, Kjaer, Susan K, Jensen, Allan, Hogdall, Claus, Lundvall, Lene, Engelholm, Svend Aage, Brown, Bob, Flanagan, James, Metcalf, Michelle D, Siddiqui, Nadeem, Sellers, Thomas, Fridley, Brooke, Cunningham, Julie, Schildkraut, Joellen, Iversen, Ed, Weber, Rachel P, Berchuck, Andrew, Goode, Ellen, Bowtell, David D, Chenevix-Trench, Georgia, deFazio, Anna, Norris, Murray D, MacGregor, Stuart, Haber, Michelle, and Henderson, Michelle J
Subjects: Australian Ovarian Cancer Study Group, Humans, Neoplasms, Glandular and Epithelial, Cystadenocarcinoma, Serous, Ovarian Neoplasms, ATP-Binding Cassette Transporters, RNA, Messenger, Cell Movement, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, Female, Neoplastic Stem Cells, Genome-Wide Association Study, Kaplan-Meier Estimate, Real-Time Polymerase Chain Reaction, Neoplasm Grading, ATP Binding Cassette Transporter 1, Carcinoma, Ovarian Epithelial, Ovarian Cancer, Rare Diseases, Biotechnology, Genetics, Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown. The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided. Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration. Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.
Published: 2014

19. Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

Author: Block, Matthew S, Charbonneau, Bridget, Vierkant, Robert A, Fogarty, Zachary, Bamlet, William R, Pharoah, Paul DP, Chenevix-Trench, Georgia, AOCS, for, Group, ACS, 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, and Goode, Ellen L
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Rare Diseases, Genetics, Women's Health, Cancer, Ovarian Cancer, 2.1 Biological and endogenous factors, Adult, Aged, Carcinoma, Ovarian Epithelial, Female, Genotype, Humans, Middle Aged, NF-kappa B, Neoplasm Invasiveness, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Proportional Hazards Models, Signal Transduction, Georgia Chenevix-Trench, for AOCS, /ACS Group, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
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.
Published: 2014

20. Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

Author: 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, Lubiński, 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, group, for the AOCS, and ACS
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Ovarian Cancer, Cancer, Genetics, Clinical Research, Rare Diseases, Women's Health, 2.1 Biological and endogenous factors, Female, Gene Expression, Gene Expression Profiling, Genetic Predisposition to Disease, Genetic Variation, Germ-Line Mutation, Humans, Interleukin-2 Receptor alpha Subunit, Neoplasm Grading, Neoplasm Invasiveness, Ovarian Neoplasms, Patient Outcome Assessment, Polymorphism, Single Nucleotide, Prognosis, T-Lymphocytes, Regulatory, AOCS group, ACS, Pharmacology and Pharmaceutical Sciences, Oncology and carcinogenesis
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.
Published: 2014

21. Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10

Author: 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, group, for AOCS ACS, 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 FAG, Song, Honglin, Doherty, Jennifer A, Krakstad, Camilla, Liang, Dong, Odunsi, Kunle, Berchuck, Andrew, Jensen, Allan, Lubiński, 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, and Lundvall, Lene
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Ovarian Cancer, Cancer, Clinical Research, Rare Diseases, Human Genome, Women's Health, Prevention, 2.1 Biological and endogenous factors, Case-Control Studies, Female, Genetic Association Studies, Humans, Interleukin-1alpha, NF-kappa B, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand, for AOCS/ACS group, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
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.
Published: 2014

22. ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

Author: Johnatty, Sharon E, Beesley, Jonathan, Gao, Bo, Chen, Xiaoqing, Lu, Yi, Law, Matthew H, Henderson, Michelle J, Russell, Amanda J, Hedditch, Ellen L, Emmanuel, Catherine, Fereday, Sian, Webb, Penelope M, Group, Australian Ovarian Cancer Study, Goode, Ellen L, Vierkant, Robert A, Fridley, Brooke L, Cunningham, Julie M, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Hogdall, Estrid, Kjaer, Susanne K, Jensen, Allan, Hogdall, Claus, Brown, Robert, Paul, Jim, Lambrechts, Sandrina, Despierre, Evelyn, Vergote, Ignace, Lester, Jenny, Karlan, Beth Y, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Bean, Yukie, Pejovic, Tanja, Levine, Douglas A, Goodman, Marc T, Camey, Michael E, Thompson, Pamela J, Lurie, Galina, Shildkraut, Joellen, Berchuck, Andrew, Terry, Kathryn L, Cramer, Daniel W, Norris, Murray D, Haber, Michelle, MacGregor, Stuart, deFazio, Anna, and Chenevix-Trench, Georgia
Subjects: Genetics, Ovarian Cancer, Rare Diseases, Human Genome, Cancer, Aetiology, 2.1 Biological and endogenous factors, ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, Antineoplastic Combined Chemotherapy Protocols, Carboplatin, Carcinoma, Ovarian Epithelial, Disease Progression, Disease-Free Survival, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Female, Humans, Kaplan-Meier Estimate, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Paclitaxel, Pharmacogenetics, Polymorphism, Single Nucleotide, Proportional Hazards Models, Ovarian cancer, Polymorphisms, Outcome, Chemotherapy, ABCB1, Australian Ovarian Cancer Study Group, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis
Abstract: ObjectiveABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC).MethodsThe best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n=1158) or any first-line chemotherapy regimen (n=2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients.ResultFine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p=0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours.ConclusionOur study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.
Published: 2013

23. Common variants at 19p13 are associated with susceptibility to ovarian cancer.

Author: Bolton, Kelly L, Tyrer, Jonathan, Song, Honglin, Ramus, Susan J, Notaridou, Maria, Jones, Chris, Sher, Tanya, Gentry-Maharaj, Aleksandra, Wozniak, Eva, Tsai, Ya-Yu, Weidhaas, Joanne, Paik, Daniel, Van Den Berg, David J, Stram, Daniel O, Pearce, Celeste Leigh, Wu, Anna H, Brewster, Wendy, Anton-Culver, Hoda, Ziogas, Argyrios, Narod, Steven A, Levine, Douglas A, Kaye, Stanley B, Brown, Robert, Paul, Jim, Flanagan, James, Sieh, Weiva, McGuire, Valerie, Whittemore, Alice S, Campbell, Ian, Gore, Martin E, Lissowska, Jolanta, Yang, Hanna P, Medrek, Krzysztof, Gronwald, Jacek, Lubinski, Jan, Jakubowska, Anna, Le, Nhu D, Cook, Linda S, Kelemen, Linda E, Brooks-Wilson, Angela, Massuger, Leon FAG, Kiemeney, Lambertus A, Aben, Katja KH, van Altena, Anne M, Houlston, Richard, Tomlinson, Ian, Palmieri, Rachel T, Moorman, Patricia G, Schildkraut, Joellen, Iversen, Edwin S, Phelan, Catherine, Vierkant, Robert A, Cunningham, Julie M, Goode, Ellen L, Fridley, Brooke L, Kruger-Kjaer, Susan, Blaeker, Jan, Hogdall, Estrid, Hogdall, Claus, Gross, Jenny, Karlan, Beth Y, Ness, Roberta B, Edwards, Robert P, Odunsi, Kunle, Moyisch, Kirsten B, Baker, Julie A, Modugno, Francesmary, Heikkinenen, Tuomas, Butzow, Ralf, Nevanlinna, Heli, Leminen, Arto, Bogdanova, Natalia, Antonenkova, Natalia, Doerk, Thilo, Hillemanns, Peter, Dürst, Matthias, Runnebaum, Ingo, Thompson, Pamela J, Carney, Michael E, Goodman, Marc T, Lurie, Galina, Wang-Gohrke, Shan, Hein, Rebecca, Chang-Claude, Jenny, Rossing, Mary Anne, Cushing-Haugen, Kara L, Doherty, Jennifer, Chen, Chu, Rafnar, Thorunn, Besenbacher, Soren, Sulem, Patrick, Stefansson, Kari, Birrer, Michael J, Terry, Kathryn L, Hernandez, Dena, Cramer, Daniel W, Vergote, Ignace, Amant, Frederic, Lambrechts, Diether, and Despierre, Evelyn
Subjects: Australian Ovarian Cancer Study Group, Australian Cancer Study, Ovarian Cancer Association Consortium, Ovary, Tumor Cells, Cultured, Chromosomes, Human, Pair 19, Humans, Adenocarcinoma, Clear Cell, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Endometrial Neoplasms, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Oligonucleotide Array Sequence Analysis, Case-Control Studies, Gene Expression Profiling, Genotype, Polymorphism, Single Nucleotide, Genome, Human, Middle Aged, Female, Genome-Wide Association Study, Biomarkers, Tumor, Tumor Cells, Cultured, Chromosomes, Human, Pair 19, Adenocarcinoma, Clear Cell, Mucinous, Cystadenocarcinoma, Serous, Adaptor Proteins, Signal Transducing, Polymorphism, Single Nucleotide, Genome, Biomarkers, Tumor, Cancer, Human Genome, Genetics, Ovarian Cancer, Orphan Drug, Rare Diseases, 2.1 Biological and endogenous factors, Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract: Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
Published: 2010

24. Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study

Author: Song, Honglin, Ramus, Susan J, Kjaer, Susanne Krüger, DiCioccio, Richard A, Chenevix-Trench, Georgia, Pearce, Celeste Leigh, Hogdall, Estrid, Whittemore, Alice S, McGuire, Valerie, Hogdall, Claus, Blaakaer, Jan, Wu, Anna H, Van Den Berg, David J, Stram, Daniel O, Menon, Usha, Gentry-Maharaj, Aleksandra, Jacobs, Ian J, Webb, Penny M, Beesley, Jonathan, Chen, Xiaoqing, Rossing, Mary Anne, Doherty, Jennifer A, Chang-Claude, Jenny, Wang-Gohrke, Shan, Goodman, Marc T, Lurie, Galina, Thompson, Pamela J, Carney, Michael E, Ness, Roberta B, Moysich, Kirsten, Goode, Ellen L, Vierkant, Robert A, Cunningham, Julie M, Anderson, Stephanie, Schildkraut, Joellen M, Berchuck, Andrew, Iversen, Edwin S, Moorman, Patricia G, Garcia-Closas, Montserrat, Chanock, Stephen, Lissowska, Jolanta, Brinton, Louise, Anton-Culver, Hoda, Ziogas, Argyrios, Brewster, Wendy R, Ponder, Bruce AJ, Easton, Douglas F, Gayther, Simon A, and Pharoah, Paul DP
Subjects: Biological Sciences, Genetics, Prevention, Human Genome, Ovarian Cancer, Clinical Research, Cancer, Breast Cancer, Aging, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glycoproteins, Humans, Neuropeptides, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors, White People, Australian Cancer (Ovarian) Study, Australian Ovarian Cancer Study Group, Ovarian Cancer Association Consortium, Medical and Health Sciences, Genetics & Heredity
Abstract: Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, we evaluated 11 of the most significant hits (six with confirmed associations with breast cancer) from the breast cancer genome-wide association study for association with invasive ovarian cancer. Eleven SNPs were initially genotyped in 2927 invasive ovarian cancer cases and 4143 controls from six ovarian cancer case-control studies. Genotype frequencies in cases and controls were compared using a likelihood ratio test in a logistic regression model stratified by study. Initially, three SNPs (rs2107425 in MRPL23, rs7313833 in PTHLH, rs3803662 in TNRC9) were weakly associated with ovarian cancer risk and one SNP (rs4954956 in NXPH2) was associated with serous ovarian cancer in non-Hispanic white subjects (P-trend < 0.1). These four SNPs were then genotyped in an additional 4060 cases and 6308 controls from eight independent studies. Only rs4954956 was significantly associated with ovarian cancer risk both in the replication study and in combined analyses. This association was stronger for the serous histological subtype [per minor allele odds ratio (OR) 1.07 95% CI 1.01-1.13, P-trend = 0.02 for all types of ovarian cancer and OR 1.14 95% CI 1.07-1.22, P-trend = 0.00017 for serous ovarian cancer]. In conclusion, we found that rs4954956 was associated with increased ovarian cancer risk, particularly for serous ovarian cancer. However, none of the six confirmed breast cancer susceptibility variants we tested was associated with ovarian cancer risk. Further work will be needed to identify the causal variant associated with rs4954956 or elucidate its function.
Published: 2009

25. Identification of a genetic variant associated with treatment outcome in ovarian cancer: the potential role of cholesterol metabolism as a determinant of response to chemotherapy

Author: Chenevix-Trench Georgia, Lu Yi, Johnatty Sharon, Gamazon Eric, Beesley Jonathan, Chen Xiaoqing, Gao Bo, Harnett Paul, Stephanie Huang R, Despierre Evelyn, Heitz Florian, Hogdall Estrid, Hogdall Claus, Brown Robert, Moyisch Kirsten, Fasching Peter, Goode Ellen, Russell Amanda, Henderson Michelle, Haber Michelle, Dolan Eileen, Macgregor Stuart, and deFazio Anna
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Genetics, QH426-470
Published: 2012
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources

Refine your results

25 results on '"Hogdall, Estrid"'

1. Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

2. rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology.

3. Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

4. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

5. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

6. Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk

7. Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer

8. Evidence of a genetic link between endometriosis and ovarian cancer

9. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk.

10. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

11. Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk.

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

13. Genome-wide significant risk associations for mucinous ovarian carcinoma

14. Cell-type-specific enrichment of risk-associated regulatory elements at ovarian cancer susceptibility loci

15. Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.

16. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

17. Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC)

18. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer.

19. Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

20. Large-Scale Evaluation of Common Variation in Regulatory T Cell–Related Genes and Ovarian Cancer Outcome

21. Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10

22. ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

23. Common variants at 19p13 are associated with susceptibility to ovarian cancer.

24. Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study

25. Identification of a genetic variant associated with treatment outcome in ovarian cancer: the potential role of cholesterol metabolism as a determinant of response to chemotherapy

Catalog

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

25 results on '"Hogdall, Estrid"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources