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9. Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix

Author

Bellone, Stefania, primary, Jeong, Kyungjo, additional, Halle, Mari Kyllesø, additional, Krakstad, Camilla, additional, McNamara, Blair, additional, Greenman, Michelle, additional, Mutlu, Levent, additional, Demirkiran, Cem, additional, Hartwich, Tobias Max Philipp, additional, Yang-Hartwich, Yang, additional, Zipponi, Margherita, additional, Buza, Natalia, additional, Hui, Pei, additional, Raspagliesi, Francesco, additional, Lopez, Salvatore, additional, Paolini, Biagio, additional, Milione, Massimo, additional, Perrone, Emanuele, additional, Scambia, Giovanni, additional, Altwerger, Gary, additional, Ravaggi, Antonella, additional, Bignotti, Eliana, additional, Huang, Gloria S., additional, Andikyan, Vaagn, additional, Clark, Mitchell, additional, Ratner, Elena, additional, Azodi, Masoud, additional, Schwartz, Peter E., additional, Quick, Charles M., additional, Angioli, Roberto, additional, Terranova, Corrado, additional, Zaidi, Samir, additional, Nandi, Shuvro, additional, Alexandrov, Ludmil B., additional, Siegel, Eric R., additional, Choi, Jungmin, additional, Schlessinger, Joseph, additional, and Santin, Alessandro D., additional

Published
2024
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11. Integrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance

Author

Chakravarthy, Ankur, Reddin, Ian, Henderson, Stephen, Dong, Cindy, Kirkwood, Nerissa, Jeyakumar, Maxmilan, Rodriguez, Daniela Rothschild, Martinez, Natalia Gonzalez, McDermott, Jacqueline, Su, Xiaoping, Egawa, Nagayasau, Fjeldbo, Christina S., Skingen, Vilde Eide, Lyng, Heidi, Halle, Mari Kyllesø, Krakstad, Camilla, Soleiman, Afschin, Sprung, Susanne, Lechner, Matt, Ellis, Peter J. I., Wass, Mark, Michaelis, Martin, Fiegl, Heidi, Salvesen, Helga, Thomas, Gareth J., Doorbar, John, Chester, Kerry, Feber, Andrew, and Fenton, Tim R.

Published
2022
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14. 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

15. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Author

Earp, Madalene, Tyrer, Jonathan P, Winham, Stacey J, Lin, Hui-Yi, Chornokur, Ganna, Dennis, Joe, Aben, Katja KH, Anton‐Culver, Hoda, Antonenkova, Natalia, Bandera, Elisa V, Bean, Yukie T, Beckmann, Matthias W, Bjorge, Line, Bogdanova, Natalia, Brinton, Louise A, Brooks-Wilson, Angela, Bruinsma, Fiona, Bunker, Clareann H, Butzow, Ralf, Campbell, Ian G, Carty, Karen, Chang-Claude, Jenny, Cook, Linda S, Cramer, Daniel W, Cunningham, Julie M, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Easton, Douglas F, Eccles, Diana M, Edwards, Robert P, Ekici, Arif B, Fasching, Peter A, Fridley, Brooke L, Gentry-Maharaj, Aleksandra, Giles, Graham G, Glasspool, Rosalind, Goodman, Marc T, Gronwald, Jacek, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hildebrandt, Michelle AT, Hillemanns, Peter, Hogdall, Claus K, Høgdall, Estrid, Hosono, Satoyo, Iversen, Edwin S, Jakubowska, Anna, Jensen, Allan, Ji, Bu-Tian, Jung, Audrey Y, Karlan, Beth Y, Kellar, Melissa, Kiemeney, Lambertus A, Lim, Boon Kiong, Kjaer, Susanne K, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lele, Shashi, Lester, Jenny, Levine, Douglas A, Li, Zheng, Liang, Dong, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon 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, Odunsi, Kunle, Olson, Sara H, Orlow, Irene, Orsulic, Sandra, Paul, James, Pejovic, Tanja, Pelttari, Liisa M, Permuth, Jenny B, Pike, Malcolm C, Poole, Elizabeth M, Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H, and Runnebaum, Ingo B

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Genetics, Oncology and Carcinogenesis, Biotechnology, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, A Kinase Anchor Proteins, Carcinoma, Ovarian Epithelial, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Monomeric GTP-Binding Proteins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Rho Guanine Nucleotide Exchange Factors, Risk Factors, General Science & Technology
Abstract

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

Published
2018

19. 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, Ovarian Cancer, Rare Diseases, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, 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, 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

20. Hormone Receptor Expression and Activity for Different Tumour Locations in Patients with Advanced and Recurrent Endometrial Carcinoma.

Author

Luijten, Maartje M. W., van Weelden, Willem Jan, Lalisang, Roy I., Bulten, Johan, Lindemann, Kristina, van Beekhuizen, Heleen J., Trum, Hans, Boll, Dorry, Werner, Henrica M. J., van Lonkhuijzen, Luc R. C. W., Yigit, Refika, Krakstad, Camilla, Witteveen, Petronella O., Galaal, Khadra, van Ginkel, Alexandra A., Bignotti, Eliana, Weinberger, Vit, Sweegers, Sanne, Eriksson, Ane Gerda Z., and Keizer, Diederick M.

Subjects
ABDOMINAL physiology, UTERUS physiology, PROGESTERONE, SEX hormones, LYMPH nodes, BIOPSY, RISK assessment, CANCER relapse, PROGESTERONE receptors, RESEARCH funding, ESTROGEN, DESCRIPTIVE statistics, ENDOMETRIAL tumors, METASTASIS, ESTROGEN receptors, MESSENGER RNA, HORMONE therapy, TUMOR classification, CANCER patient psychology, COMPARATIVE studies, CELL receptors, DISEASE progression, DISEASE risk factors, DISEASE complications
Abstract

Simple Summary: Oestrogen and progesterone are two sex hormones that are important in the development of cancer of the inner lining of the uterus and endometrial cancer (EC). Oestrogen binds to the oestrogen receptor (ER) and progesterone to the progesterone receptor (PR). The presence of these receptors is important because the response to hormonal therapy is higher when the receptors are present. However, as EC grows and spreads throughout the body, ER and PR may be lost. In this study, we found that tumours that have spread to other organs throughout the blood and tumours that have spread in the abdomen have a relatively high presence of ER/PR, while tumours located in the lymph nodes have a lower presence of PR. ER/PR-IHC were not lower in tumours that had previously been treated with radiotherapy. This might influence the application of hormonal therapy in the future. Background: Response to hormonal therapy in advanced and recurrent endometrial cancer (EC) can be predicted by oestrogen and progesterone receptor immunohistochemical (ER/PR-IHC) expression, with response rates of 60% in PR-IHC > 50% cases. ER/PR-IHC can vary by tumour location and is frequently lost with tumour progression. Therefore, we explored the relationship between ER/PR-IHC expression and tumour location in EC. Methods: Pre-treatment tumour biopsies from 6 different sites of 80 cases treated with hormonal therapy were analysed for ER/PR-IHC expression and classified into categories 0–10%, 10–50%, and >50%. The ER pathway activity score (ERPAS) was determined based on mRNA levels of ER-related target genes, reflecting the actual activity of the ER receptor. Results: There was a trend towards lower PR-IHC (33% had PR > 50%) and ERPAS (27% had ERPAS > 15) in lymphogenic metastases compared to other locations (p = 0.074). Hematogenous and intra-abdominal metastases appeared to have high ER/PR-IHC and ERPAS (85% and 89% ER-IHC > 50%; 64% and 78% PR-IHC > 50%; 60% and 71% ERPAS > 15, not significant). Tumour grade and previous radiotherapy did not affect ER/PR-IHC or ERPAS. Conclusions: A trend towards lower PR-IHC and ERPAS was observed in lymphogenic sites. Verification in larger cohorts is needed to confirm these findings, which may have implications for the use of hormonal therapy in the future. [ABSTRACT FROM AUTHOR]

Published
2024
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21. Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.

Author

Bellonea, Stefania, Jeongb, Kyungjo, Hallec, Mari Kyllesø, Krakstad, Camilla, McNamara, Blair, Greenman, Michelle, Mutlu, Levent, Demirkiran, Cem, Hartwich, Tobias Max Philipp, Yang Yang-Hartwich, Zipponi, Margherita, Buza, Natalia, Pei Hui, Raspagliesi, Francesco, Lopez, Salvatore, Paolini, Biagio, Milione, Massimo, Perrone, Emanuele, Scambia, Giovanni, and Altwerger, Gary

Subjects
NEUROENDOCRINE tumors, CERVIX uteri, EXCISION repair, HUMAN papillomavirus, GENE fusion, GENETIC counseling
Abstract

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p 22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies. [ABSTRACT FROM AUTHOR]

Published
2024
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23. 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, Prevention, Cancer, Rare Diseases, Ovarian Cancer, Genetics, Genetic Testing, Clinical Research, Endometriosis, 2.1 Biological and endogenous factors, Aetiology, 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

26. 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

27. 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, Clinical Research, Biotechnology, Cancer, Human Genome, Ovarian Cancer, Prevention, Rare Diseases, Genetic Testing, Genetics, Aetiology, 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

28. 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

37. ATAD2 overexpression links to enrichment of B-MYB-translational signatures and development of aggressive endometrial carcinoma

Author

Krakstad, Camilla, Tangen, Ingvild L, Hoivik, Erling A, Halle, Mari K, Berg, Anna, Werner, Henrica M, Ræder, Maria B, Kusonmano, Kanthida, Zou, June X, Øyan, Anne M, Stefansson, Ingunn, Trovik, Jone, Kalland, Karl-Henning, Chen, Hong-Wu, and Salvesen, Helga B

Subjects
Biotechnology, Uterine Cancer, Cancer, Genetics, ATPases Associated with Diverse Cellular Activities, Adenosine Triphosphatases, Biomarkers, Tumor, Cell Cycle Proteins, DNA-Binding Proteins, Endometrial Neoplasms, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Ontology, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Middle Aged, Oligonucleotide Array Sequence Analysis, Outcome Assessment, Health Care, Prognosis, Proportional Hazards Models, Prospective Studies, Trans-Activators, endometrial cancer, ATAD2, biomarker, molecular profiling, Oncology and Carcinogenesis
Abstract

We have explored the potential for clinical implementation of ATAD2 as a biomarker for aggressive endometrial cancer by investigating to what extent immunohistochemical (IHC) staining for ATAD2 is feasible, reflects clinical phenotype and molecular subgroups of endometrial carcinomas. Increased expression of the ATAD2 gene has been implicated in cancer development and progression in a number of tissues, but few studies have investigated ATAD2 expression using IHC. Here we show that high ATAD2 protein expression is significantly associated with established clinical-pathological variables for aggressive endometrial cancer, also in the subset of estrogen receptor α (ERα) positive tumors. Protein and mRNA expression of ATAD2 were highly correlated (P < 0.001), suggesting that IHC staining may represent a more clinically applicable measure of ATAD2 level in routinely collected formalin fixed paraffin embedded specimens. Gene expression alterations in samples with high ATAD2 expression revealed upregulation of several cancer-related genes (B-MYB, CDCs, E2Fs) and gene sets that previously have been linked to aggressive disease and potential for new targeting therapies. Our results support that IHC staining for ATAD2 may be a clinically applicable biomarker reflecting clinical phenotype and targetable alterations in endometrial carcinomas to be further explored in controlled clinical trials.

Published
2015

38. 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

39. Genome-wide significant risk associations for mucinous ovarian carcinoma (vol 47, pg 888, 2015)

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, Moysich, Kirsten B, Narod, Steven A, and Nedergaard, Lotte

Subjects
Developmental Biology, Medical and Health Sciences, Biological Sciences
Published
2015

40. 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, Prevention, Human Genome, Ovarian Cancer, Biotechnology, Cancer, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, 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

41. 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

42. 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, Cancer, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, 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

43. 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, Orphan Drug, Prevention, Sleep Research, Rare Diseases, Ovarian Cancer, Aetiology, 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

45. 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, for AOCS/ACS group, 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, Lubinski, Jan, Nevanlinna, Heli, Bean, Yukie T, Lurie, Galina, Ziogas, Argyrios, Walsh, Christine, Despierre, Evelyn, Brinton, Louise, Hein, Alexander, Rudolph, Anja, Dansonka-Mieszkowska, Agnieszka, Olson, Sara H, Harter, Philipp, Tyrer, Jonathan, Vitonis, Allison F, Brooks-Wilson, Angela, Aben, Katja K, Pike, Malcolm C, Ramus, Susan J, Wik, Elisabeth, Cybulski, Cezary, Lin, Jie, Sucheston, Lara, Edwards, Robert, McGuire, Valerie, Lester, Jenny, du Bois, Andreas, and Lundvall, Lene

Subjects
for AOCS/ACS group, Humans, Ovarian Neoplasms, NF-kappa B, Risk, Case-Control Studies, Signal Transduction, Polymorphism, Single Nucleotide, Female, TNF-Related Apoptosis-Inducing Ligand, Interleukin-1alpha, Genetic Association Studies, Polymorphism, Single Nucleotide, Prevention, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, Genetics, Clinical Research, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, 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

46. #870 Radiomic profiles improve prognostication and reveal targets for therapy in cervical cancer

Author

Halle, Mari Kyllesø, primary, Hodneland, Erlend, additional, Wagner-Larsen, Kari S, additional, Lura, Njål G, additional, Fasmer, Kristine E, additional, Berg, Hege F, additional, Stokowy, Thomasz, additional, Srivastava, Aashish, additional, Forsse, David, additional, Hoivik, Erling A, additional, Woie, Kathrine, additional, Bertelsen, Bjørn I, additional, Krakstad, Camilla, additional, and Haldorsen, Ingfrid S, additional

Published
2023
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47. #925 Validation of single-cell profiling data from recurrent low stage endometrial cancer; low vimentin is a robust marker for poor prognosis in endometrial cancer, including in low-stage tumors

Author

Lien, Hilde Eide, primary, Hjelmeland, Marta Espevold, additional, Berg, Hege Fredriksen, additional, Halle, Mari Kyllesø, additional, Haldorsen, Ingfrid Salvesen, additional, Trovik, Jone, additional, Akslen, Lars Andreas, additional, and Krakstad, Camilla, additional

Published
2023
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49. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.

Author

Antonenkova, Natalia, Armasu, Sebastian, Baglietto, Laura, Bandera, Elisa, Beckmann, Matthias, Birrer, Michael, Bloom, Greg, Bogdanova, Natalia, Brenton, James, Brinton, Louise, Brooks-Wilson, Angela, Brown, Robert, Butzow, Ralf, Campbell, Ian, Carney, Michael, Carvalho, Renato, Chang-Claude, Jenny, Chen, Y, Chen, Zhihua, Chow, Wong-Ho, Cicek, Mine, Coetzee, Gerhard, Cook, Linda, Cramer, Daniel, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Edwards, Robert, Ekici, Arif, Fasching, Peter, Fenstermacher, David, Flanagan, James, Gao, Yu-Tang, Garcia-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Giles, Graham, Gjyshi, Anxhela, Gore, Martin, Gronwald, Jacek, Guo, Qi, Halle, Mari, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hillemanns, Peter, Hoatlin, Maureen, Høgdall, Estrid, Høgdall, Claus, Hosono, Satoyo, Jakubowska, Anna, Jensen, Allan, Kalli, Kimberly, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu, Lee, Nathan, Lee, Janet, Leminen, Arto, Lim, Boon, Lissowska, Jolanta, Lubiński, Jan, Lundvall, Lene, Lurie, Galina, Massuger, Leon, Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten, Nakanishi, Toru, Narod, Steven, Ness, Roberta, Nevanlinna, Heli, Nickels, Stefan, Noushmehr, Houtan, Odunsi, Kunle, Olson, Sara, Orlow, Irene, Paul, James, Pejovic, Tanja, Pelttari, Liisa, Permuth-Wey, Jenny, Pike, Malcolm, Poole, Elizabeth, Qu, Xiaotao, Risch, Harvey, Rodriguez-Rodriguez, Lorna, Rossing, Mary, Rudolph, Anja, Runnebaum, Ingo, Rzepecka, Iwona, and Salvesen, Helga

Subjects
Case-Control Studies, Cooperative Behavior, Cystadenocarcinoma, Serous, Female, Gene-Environment Interaction, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Neoplasm Invasiveness, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk Factors
Abstract

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

Published
2013

50. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.

Author

Pharoah, Paul DP, Tsai, Ya-Yu, Ramus, Susan J, Phelan, Catherine M, Goode, Ellen L, Lawrenson, Kate, Buckley, Melissa, Fridley, Brooke L, Tyrer, Jonathan P, Shen, Howard, Weber, Rachel, Karevan, Rod, Larson, Melissa C, Song, Honglin, Tessier, Daniel C, Bacot, François, Vincent, Daniel, Cunningham, Julie M, Dennis, Joe, Dicks, Ed, Australian Cancer Study, Australian Ovarian Cancer Study Group, Aben, Katja K, Anton-Culver, Hoda, Antonenkova, Natalia, Armasu, Sebastian M, Baglietto, Laura, Bandera, Elisa V, Beckmann, Matthias W, Birrer, Michael J, Bloom, Greg, Bogdanova, Natalia, Brenton, James D, Brinton, Louise A, Brooks-Wilson, Angela, Brown, Robert, Butzow, Ralf, Campbell, Ian, Carney, Michael E, Carvalho, Renato S, Chang-Claude, Jenny, Chen, Y Anne, Chen, Zhihua, Chow, Wong-Ho, Cicek, Mine S, Coetzee, Gerhard, Cook, Linda S, Cramer, Daniel W, Cybulski, Cezary, Dansonka-Mieszkowska, Agnieszka, Despierre, Evelyn, Doherty, Jennifer A, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Edwards, Robert, Ekici, Arif B, Fasching, Peter A, Fenstermacher, David, Flanagan, James, Gao, Yu-Tang, Garcia-Closas, Montserrat, Gentry-Maharaj, Aleksandra, Giles, Graham, Gjyshi, Anxhela, Gore, Martin, Gronwald, Jacek, Guo, Qi, Halle, Mari K, Harter, Philipp, Hein, Alexander, Heitz, Florian, Hillemanns, Peter, Hoatlin, Maureen, Høgdall, Estrid, Høgdall, Claus K, Hosono, Satoyo, Jakubowska, Anna, Jensen, Allan, Kalli, Kimberly R, Karlan, Beth Y, Kelemen, Linda E, Kiemeney, Lambertus A, Kjaer, Susanne Krüger, Konecny, Gottfried E, Krakstad, Camilla, Kupryjanczyk, Jolanta, Lambrechts, Diether, Lambrechts, Sandrina, Le, Nhu D, Lee, Nathan, Lee, Janet, Leminen, Arto, Lim, Boon Kiong, Lissowska, Jolanta, Lubiński, Jan, Lundvall, Lene, Lurie, Galina, and Massuger, Leon FAG

Subjects
Australian Cancer Study, Australian Ovarian Cancer Study Group, Humans, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Neoplasm Invasiveness, Genetic Predisposition to Disease, Risk Factors, Case-Control Studies, Cooperative Behavior, Genotype, Polymorphism, Single Nucleotide, Female, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, Gene-Environment Interaction, Cancer, Human Genome, Prevention, Genetics, Rare Diseases, Ovarian Cancer, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

Published
2013

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