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1. TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: A non-randomized retrospective study

Author

Markowska Janina, Timorek Agnieszka, Madry Radoslaw, Ziolkowska-Seta Izabela, Kraszewska Ewa, Kupryjanczyk Jolanta, Stelmachow Jerzy, and Bidzinski Mariusz

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Taxane-platinum therapy (TP) has replaced platinum-based therapy (PC or PAC, DNA damaging chemotherapy) in the postoperative treatment of ovarian cancer patients; however, it is not always effective. TP53 protein plays a differential role in response to DNA-damaging agents and taxanes. We sought to define profiles of patients who benefit the most from TP and also of those who can be treated with PC. Methods We compared the effectiveness of PC/PAC (n = 253) and TP (n = 199) with respect to tumor TP53 accumulation in ovarian cancer patients with FIGO stage IIB-IV disease; this was a non-randomized retrospective study. Immunohistochemical analysis was performed on 452 archival tumors; univariate and multivariate analysis by the Cox's and logistic regression models was performed in all patients and in subgroups with [TP53(+)] and without TP53 accumulation [TP53(-)]. Results The advantage of taxane-platinum therapy over platinum-based therapy was seen in the TP53(+), and not in the TP53(-) group. In the TP53(+) group taxane-platinum therapy enhanced the probability of complete remission (p = .018), platinum sensitivity (p = .014), platinum highly sensitive response (p = .038) and longer survival (OS, p = .008). Poor tumor differentiation diminished the advantage from taxane-platinum therapy in the TP53(+) group. In the TP53(-) group PC/PAC was at least equally efficient as taxane-platinum therapy and it enhanced the chance of platinum highly sensitive response (p = .010). However, in the TP53(-) group taxane-platinum therapy possibly diminished the risk of death in patients over 53 yrs (p = .077). Among factors that positively interacted with taxane-platinum therapy in some analyses were endometrioid and clear cell type, FIGO III stage, bulky residual tumor, more advanced age of patient and moderate tumor differentiation. Conclusion Our results suggest that taxane-platinum therapy is particularly justified in patients with TP53(+) tumors or older than 53 years. In the group of patients ≤53 yrs and with TP53(-) tumors platinum-based therapy is possibly equally efficient. We provide hints for planning randomized trials to verify these observations.

Published
2008
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2. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

Author

Ong, Jue-Sheng, Cuellar-Partida, Gabriel, Lu, Yi, Australian Ovarian Cancer Study, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Anne Doherty, Jennifer, Anne Rossing, Mary, Chang-Claude, Jenny, Eilber, Ursula, Rudolph, Anja, Wang-Gohrke, Shan, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Høgdall, Estrid, Høgdall, Claus K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Kjaer, Susanne K, Hildebrandt, Michelle At, Liang, Dong, Lu, Karen H, Wu, Xifeng, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Missmer, Stacey, Bjorge, Line, Salvesen, Helga B, Kopperud, Reidun K, Bischof, Katharina, Aben, Katja Kh, Kiemeney, Lambertus A, Massuger, Leon Fag, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Gilks, C Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Song, Honglin, Tyrer, Jonathan P, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, Lissowska, Jolanta, McLaughlin, John R, Narod, Steven A, Phelan, Catherine, Anton-Culver, Hoda, Ziogas, Argyrios, Eccles, Diana, Campbell, Ian, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Wu, Anna H, Dansonka-Mieszkowska, Agnieszka, Kupryjanczyk, Jolanta, Timorek, Agnieszka, Szafron, Lukasz, Cunningham, Julie M, Fridley, Brooke L, Winham, Stacey J, Bandera, Elisa V, and Poole, Elizabeth M

Subjects
Australian Ovarian Cancer Study, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Genetic Predisposition to Disease, Vitamin D, Odds Ratio, Risk Factors, Polymorphism, Single Nucleotide, Female, Mendelian Randomization Analysis, Carcinoma, Ovarian Epithelial, Neoplasms, Glandular and Epithelial, Polymorphism, Single Nucleotide, Carcinoma, Ovarian Epithelial, Prevention, Rare Diseases, Nutrition, Clinical Research, Cancer, Ovarian Cancer, Statistics, Public Health and Health Services, Epidemiology
Abstract

BackgroundIn vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.MethodsWe employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).ResultsThe odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).ConclusionsGenetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

Published
2016

3. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Author

Cuellar-Partida, Gabriel, Lu, Yi, Dixon, Suzanne C, Australian Ovarian Cancer Study, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Doherty, Jennifer Anne, Rossing, Mary Anne, Chang-Claude, Jenny, Rudolph, Anja, Wang-Gohrke, Shan, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Høgdall, Estrid, Høgdall, Claus, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Kjaer, Susanne K, Hildebrandt, Michelle AT, Liang, Dong, Lu, Karen H, Wu, Xifeng, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Missmer, Stacey, Bjorge, Line, Salvesen, Helga B, Kopperud, Reidun K, Bischof, Katharina, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Blake Gilks, C, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Song, Honglin, Tyrer, Jonathan P, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, Lissowska, Jolanta, McLaughlin, John R, Narod, Steven A, Phelan, Catherine, Anton-Culver, Hoda, Ziogas, Argyrios, Eccles, Diana, Campbell, Ian, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Wu, Anna H, Dansonka-Mieszkowska, Agnieszka, Kupryjanczyk, Jolanta, Timorek, Agnieszka, Szafron, Lukasz, Cunningham, Julie M, Fridley, Brooke L, Winham, Stacey J, Bandera, Elisa V, Poole, Elizabeth M, and Morgan, Terry K

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Obesity, Women's Health, Cancer Genomics, Ovarian Cancer, Cancer, Human Genome, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, Ovarian Epithelial, Female, Genotype, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Pathology, Molecular, Polymorphism, Single Nucleotide, Australian Ovarian Cancer Study, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Published
2016

4. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk.

Author

Kelemen, Linda E, Terry, Kathryn L, Goodman, Marc T, Webb, Penelope M, Bandera, Elisa V, McGuire, Valerie, Rossing, Mary Anne, Wang, Qinggang, Dicks, Ed, Tyrer, Jonathan P, Song, Honglin, Kupryjanczyk, Jolanta, Dansonka-Mieszkowska, Agnieszka, Plisiecka-Halasa, Joanna, Timorek, Agnieszka, Menon, Usha, Gentry-Maharaj, Aleksandra, Gayther, Simon A, Ramus, Susan J, Narod, Steven A, Risch, Harvey A, McLaughlin, John R, Siddiqui, Nadeem, Glasspool, Rosalind, Paul, James, Carty, Karen, Gronwald, Jacek, Lubiński, Jan, Jakubowska, Anna, Cybulski, Cezary, Kiemeney, Lambertus A, Massuger, Leon FAG, van Altena, Anne M, Aben, Katja KH, Olson, Sara H, Orlow, Irene, Cramer, Daniel W, Levine, Douglas A, Bisogna, Maria, Giles, Graham G, Southey, Melissa C, Bruinsma, Fiona, Kjaer, Susanne K, Høgdall, Estrid, Jensen, Allan, Høgdall, Claus K, Lundvall, Lene, Engelholm, Svend-Aage, Heitz, Florian, du Bois, Andreas, Harter, Philipp, Schwaab, Ira, Butzow, Ralf, Nevanlinna, Heli, Pelttari, Liisa M, Leminen, Arto, Thompson, Pamela J, Lurie, Galina, Wilkens, Lynne R, Lambrechts, Diether, Van Nieuwenhuysen, Els, Lambrechts, Sandrina, Vergote, Ignace, Beesley, Jonathan, AOCS Study Group/ACS Investigators, Fasching, Peter A, Beckmann, Matthias W, Hein, Alexander, Ekici, Arif B, Doherty, Jennifer A, Wu, Anna H, Pearce, Celeste L, Pike, Malcolm C, Stram, Daniel, Chang-Claude, Jenny, Rudolph, Anja, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Bogdanova, Natalia, Antonenkova, Natalia, Odunsi, Kunle, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Ness, Roberta B, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Orsulic, Sandra, Fridley, Brooke L, Vierkant, Robert A, Cunningham, Julie M, Wu, Xifeng, Lu, Karen, Liang, Dong, Hildebrandt, Michelle AT, Weber, Rachel Palmieri, and Iversen, Edwin S

Subjects
AOCS Study Group/ACS Investigators, Humans, Carcinoma, Ovarian Neoplasms, Folic Acid Deficiency, Genetic Predisposition to Disease, Folic Acid, Dihydrouracil Dehydrogenase (NADP), Neoplasm Proteins, Diet, Multivariate Analysis, Risk Factors, Case-Control Studies, Energy Intake, Polymorphism, Single Nucleotide, Dietary Supplements, European Continental Ancestry Group, Female, Genome-Wide Association Study, Global Health, Case-control, Dihydropyrimidine dehydrogenase, Folate, Polymorphism, Serine hydroxymethyltransferase 1, Rare Diseases, Cancer, Ovarian Cancer, Genetics, Nutrition, 2.1 Biological and endogenous factors, Nutrition & Dietetics, Food Science, Food Sciences, Nutrition and Dietetics, Public Health and Health Services
Abstract

ScopeWe reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10⁻⁵) and rs828054 (OR = 1.06; p = 1 × 10⁻⁴). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10⁻⁶) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Published
2014

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

Author

Kar, Siddhartha P., primary, Tyrer, Jonathan P., primary, Li, Qiyuan, primary, Lawrenson, Kate, primary, Aben, Katja K.H., primary, Anton-Culver, Hoda, primary, Antonenkova, Natalia, primary, Chenevix-Trench, Georgia, primary, Baker, Helen, primary, Bandera, Elisa V., primary, Bean, Yukie T., primary, Beckmann, Matthias W., primary, Berchuck, Andrew, primary, Bisogna, Maria, primary, Bjørge, Line, primary, Bogdanova, Natalia, primary, Brinton, Louise, primary, Brooks-Wilson, Angela, primary, Butzow, Ralf, primary, Campbell, Ian, primary, Carty, Karen, primary, Chang-Claude, Jenny, primary, Chen, Yian Ann, primary, Chen, Zhihua, primary, Cook, Linda S., primary, Cramer, Daniel, primary, Cunningham, Julie M., primary, Cybulski, Cezary, primary, Dansonka-Mieszkowska, Agnieszka, primary, Dennis, Joe, primary, Dicks, Ed, primary, Doherty, Jennifer A., primary, Dörk, Thilo, primary, du Bois, Andreas, primary, Dürst, Matthias, primary, Eccles, Diana, primary, Easton, Douglas F., primary, Edwards, Robert P., primary, Ekici, Arif B., primary, Fasching, Peter A., primary, Fridley, Brooke L., primary, Gao, Yu-Tang, primary, Gentry-Maharaj, Aleksandra, primary, Giles, Graham G., primary, Glasspool, Rosalind, primary, Goode, Ellen L., primary, Goodman, Marc T., primary, Grownwald, Jacek, primary, Harrington, Patricia, primary, Harter, Philipp, primary, Hein, Alexander, primary, Heitz, Florian, primary, Hildebrandt, Michelle A.T., primary, Hillemanns, Peter, primary, Hogdall, Estrid, primary, Hogdall, Claus K., primary, Hosono, Satoyo, primary, Iversen, Edwin S., primary, Jakubowska, Anna, primary, Paul, James, primary, Jensen, Allan, primary, Ji, Bu-Tian, primary, Karlan, Beth Y., primary, Kjaer, Susanne K., primary, Kelemen, Linda E., primary, Kellar, Melissa, primary, Kelley, Joseph, primary, Kiemeney, Lambertus A., primary, Krakstad, Camilla, primary, Kupryjanczyk, Jolanta, primary, Lambrechts, Diether, primary, Lambrechts, Sandrina, primary, Le, Nhu D., primary, Lee, Alice W., primary, Lele, Shashi, primary, Leminen, Arto, primary, Lester, Jenny, primary, Levine, Douglas A., primary, Liang, Dong, primary, Lissowska, Jolanta, primary, Lu, Karen, primary, Lubinski, Jan, primary, Lundvall, Lene, primary, Massuger, Leon, primary, Matsuo, Keitaro, primary, McGuire, Valerie, primary, McLaughlin, John R., primary, McNeish, Iain A., primary, Menon, Usha, primary, Modugno, Francesmary, primary, Moysich, Kirsten B., primary, Narod, Steven A., primary, Nedergaard, Lotte, primary, Ness, Roberta B., primary, Nevanlinna, Heli, primary, Odunsi, Kunle, primary, Olson, Sara H., primary, Orlow, Irene, primary, Orsulic, Sandra, primary, Weber, Rachel Palmieri, primary, Pearce, Celeste Leigh, primary, Pejovic, Tanja, primary, Pelttari, Liisa M., primary, Permuth-Wey, Jennifer, primary, Phelan, Catherine M., primary, Pike, Malcolm C., primary, Poole, Elizabeth M., primary, Ramus, Susan J., primary, Risch, Harvey A., primary, Rosen, Barry, primary, Rossing, Mary Anne, primary, Rothstein, Joseph H., primary, Rudolph, Anja, primary, Runnebaum, Ingo B., primary, Rzepecka, Iwona K., primary, Salvesen, Helga B., primary, Schildkraut, Joellen M., primary, Schwaab, Ira, primary, Shu, Xiao-Ou, primary, Shvetsov, Yurii B., primary, Siddiqui, Nadeem, primary, Sieh, Weiva, primary, Song, Honglin, primary, Southey, Melissa C., primary, Sucheston-Campbell, Lara E., primary, Tangen, Ingvild L., primary, Teo, Soo-Hwang, primary, Terry, Kathryn L., primary, Thompson, Pamela J., primary, Timorek, Agnieszka, primary, Tsai, Ya-Yu, primary, Tworoger, Shelley S., primary, van Altena, Anne M., primary, Van Nieuwenhuysen, Els, primary, Vergote, Ignace, primary, Vierkant, Robert A., primary, Wang-Gohrke, Shan, primary, Walsh, Christine, primary, Wentzensen, Nicolas, primary, Whittemore, Alice S., primary, Wicklund, Kristine G., primary, Wilkens, Lynne R., primary, Woo, Yin-Ling, primary, Wu, Xifeng, primary, Wu, Anna, primary, Yang, Hannah, primary, Zheng, Wei, primary, Ziogas, Argyrios, primary, Sellers, Thomas A., primary, Monteiro, Alvaro N.A., primary, Freedman, Matthew L., primary, Gayther, Simon A., primary, and Pharoah, Paul D.P., primary

Published
2023
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7. Supplementary Tables S1-6, Figures S1-2 from Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author

Kar, Siddhartha P., primary, Tyrer, Jonathan P., primary, Li, Qiyuan, primary, Lawrenson, Kate, primary, Aben, Katja K.H., primary, Anton-Culver, Hoda, primary, Antonenkova, Natalia, primary, Chenevix-Trench, Georgia, primary, Baker, Helen, primary, Bandera, Elisa V., primary, Bean, Yukie T., primary, Beckmann, Matthias W., primary, Berchuck, Andrew, primary, Bisogna, Maria, primary, Bjørge, Line, primary, Bogdanova, Natalia, primary, Brinton, Louise, primary, Brooks-Wilson, Angela, primary, Butzow, Ralf, primary, Campbell, Ian, primary, Carty, Karen, primary, Chang-Claude, Jenny, primary, Chen, Yian Ann, primary, Chen, Zhihua, primary, Cook, Linda S., primary, Cramer, Daniel, primary, Cunningham, Julie M., primary, Cybulski, Cezary, primary, Dansonka-Mieszkowska, Agnieszka, primary, Dennis, Joe, primary, Dicks, Ed, primary, Doherty, Jennifer A., primary, Dörk, Thilo, primary, du Bois, Andreas, primary, Dürst, Matthias, primary, Eccles, Diana, primary, Easton, Douglas F., primary, Edwards, Robert P., primary, Ekici, Arif B., primary, Fasching, Peter A., primary, Fridley, Brooke L., primary, Gao, Yu-Tang, primary, Gentry-Maharaj, Aleksandra, primary, Giles, Graham G., primary, Glasspool, Rosalind, primary, Goode, Ellen L., primary, Goodman, Marc T., primary, Grownwald, Jacek, primary, Harrington, Patricia, primary, Harter, Philipp, primary, Hein, Alexander, primary, Heitz, Florian, primary, Hildebrandt, Michelle A.T., primary, Hillemanns, Peter, primary, Hogdall, Estrid, primary, Hogdall, Claus K., primary, Hosono, Satoyo, primary, Iversen, Edwin S., primary, Jakubowska, Anna, primary, Paul, James, primary, Jensen, Allan, primary, Ji, Bu-Tian, primary, Karlan, Beth Y., primary, Kjaer, Susanne K., primary, Kelemen, Linda E., primary, Kellar, Melissa, primary, Kelley, Joseph, primary, Kiemeney, Lambertus A., primary, Krakstad, Camilla, primary, Kupryjanczyk, Jolanta, primary, Lambrechts, Diether, primary, Lambrechts, Sandrina, primary, Le, Nhu D., primary, Lee, Alice W., primary, Lele, Shashi, primary, Leminen, Arto, primary, Lester, Jenny, primary, Levine, Douglas A., primary, Liang, Dong, primary, Lissowska, Jolanta, primary, Lu, Karen, primary, Lubinski, Jan, primary, Lundvall, Lene, primary, Massuger, Leon, primary, Matsuo, Keitaro, primary, McGuire, Valerie, primary, McLaughlin, John R., primary, McNeish, Iain A., primary, Menon, Usha, primary, Modugno, Francesmary, primary, Moysich, Kirsten B., primary, Narod, Steven A., primary, Nedergaard, Lotte, primary, Ness, Roberta B., primary, Nevanlinna, Heli, primary, Odunsi, Kunle, primary, Olson, Sara H., primary, Orlow, Irene, primary, Orsulic, Sandra, primary, Weber, Rachel Palmieri, primary, Pearce, Celeste Leigh, primary, Pejovic, Tanja, primary, Pelttari, Liisa M., primary, Permuth-Wey, Jennifer, primary, Phelan, Catherine M., primary, Pike, Malcolm C., primary, Poole, Elizabeth M., primary, Ramus, Susan J., primary, Risch, Harvey A., primary, Rosen, Barry, primary, Rossing, Mary Anne, primary, Rothstein, Joseph H., primary, Rudolph, Anja, primary, Runnebaum, Ingo B., primary, Rzepecka, Iwona K., primary, Salvesen, Helga B., primary, Schildkraut, Joellen M., primary, Schwaab, Ira, primary, Shu, Xiao-Ou, primary, Shvetsov, Yurii B., primary, Siddiqui, Nadeem, primary, Sieh, Weiva, primary, Song, Honglin, primary, Southey, Melissa C., primary, Sucheston-Campbell, Lara E., primary, Tangen, Ingvild L., primary, Teo, Soo-Hwang, primary, Terry, Kathryn L., primary, Thompson, Pamela J., primary, Timorek, Agnieszka, primary, Tsai, Ya-Yu, primary, Tworoger, Shelley S., primary, van Altena, Anne M., primary, Van Nieuwenhuysen, Els, primary, Vergote, Ignace, primary, Vierkant, Robert A., primary, Wang-Gohrke, Shan, primary, Walsh, Christine, primary, Wentzensen, Nicolas, primary, Whittemore, Alice S., primary, Wicklund, Kristine G., primary, Wilkens, Lynne R., primary, Woo, Yin-Ling, primary, Wu, Xifeng, primary, Wu, Anna, primary, Yang, Hannah, primary, Zheng, Wei, primary, Ziogas, Argyrios, primary, Sellers, Thomas A., primary, Monteiro, Alvaro N.A., primary, Freedman, Matthew L., primary, Gayther, Simon A., primary, and Pharoah, Paul D.P., primary

Published
2023
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8. Data from Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author

Paul D.P. Pharoah, Simon A. Gayther, Matthew L. Freedman, Alvaro N.A. Monteiro, Thomas A. Sellers, Argyrios Ziogas, Wei Zheng, Hannah Yang, Anna Wu, Xifeng Wu, Yin-Ling Woo, Lynne R. Wilkens, Kristine G. Wicklund, Alice S. Whittemore, Nicolas Wentzensen, Christine Walsh, Shan Wang-Gohrke, Robert A. Vierkant, Ignace Vergote, Els Van Nieuwenhuysen, Anne M. van Altena, Shelley S. Tworoger, Ya-Yu Tsai, Agnieszka Timorek, Pamela J. Thompson, Kathryn L. Terry, Soo-Hwang Teo, Ingvild L. Tangen, Lara E. Sucheston-Campbell, Melissa C. Southey, Honglin Song, Weiva Sieh, Nadeem Siddiqui, Yurii B. Shvetsov, Xiao-Ou Shu, Ira Schwaab, Joellen M. Schildkraut, Helga B. Salvesen, Iwona K. Rzepecka, Ingo B. Runnebaum, Anja Rudolph, Joseph H. Rothstein, Mary Anne Rossing, Barry Rosen, Harvey A. Risch, Susan J. Ramus, Elizabeth M. Poole, Malcolm C. Pike, Catherine M. Phelan, Jennifer Permuth-Wey, Liisa M. Pelttari, Tanja Pejovic, Celeste Leigh Pearce, Rachel Palmieri Weber, Sandra Orsulic, Irene Orlow, Sara H. Olson, Kunle Odunsi, Heli Nevanlinna, Roberta B. Ness, Lotte Nedergaard, Steven A. Narod, Kirsten B. Moysich, Francesmary Modugno, Usha Menon, Iain A. McNeish, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Leon Massuger, Lene Lundvall, Jan Lubinski, Karen Lu, Jolanta Lissowska, Dong Liang, Douglas A. Levine, Jenny Lester, Arto Leminen, Shashi Lele, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Lambertus A. Kiemeney, Joseph Kelley, Melissa Kellar, Linda E. Kelemen, Susanne K. Kjaer, Beth Y. Karlan, Bu-Tian Ji, Allan Jensen, James Paul, Anna Jakubowska, Edwin S. Iversen, Satoyo Hosono, Claus K. Hogdall, Estrid Hogdall, Peter Hillemanns, Michelle A.T. Hildebrandt, Florian Heitz, Alexander Hein, Philipp Harter, Patricia Harrington, Jacek Grownwald, Marc T. Goodman, Ellen L. Goode, Rosalind Glasspool, Graham G. Giles, Aleksandra Gentry-Maharaj, Yu-Tang Gao, Brooke L. Fridley, Peter A. Fasching, Arif B. Ekici, Robert P. Edwards, Douglas F. Easton, Diana Eccles, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A. Doherty, Ed Dicks, Joe Dennis, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Julie M. Cunningham, Daniel Cramer, Linda S. Cook, Zhihua Chen, Yian Ann Chen, Jenny Chang-Claude, Karen Carty, Ian Campbell, Ralf Butzow, Angela Brooks-Wilson, Louise Brinton, Natalia Bogdanova, Line Bjørge, Maria Bisogna, Andrew Berchuck, Matthias W. Beckmann, Yukie T. Bean, Elisa V. Bandera, Helen Baker, Georgia Chenevix-Trench, Natalia Antonenkova, Hoda Anton-Culver, Katja K.H. Aben, Kate Lawrenson, Qiyuan Li, Jonathan P. Tyrer, and Siddhartha P. Kar

Abstract

Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

Published
2023

9. Supplementary Tables S1-6, Figures S1-2 from Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk

Author

Paul D.P. Pharoah, Simon A. Gayther, Matthew L. Freedman, Alvaro N.A. Monteiro, Thomas A. Sellers, Argyrios Ziogas, Wei Zheng, Hannah Yang, Anna Wu, Xifeng Wu, Yin-Ling Woo, Lynne R. Wilkens, Kristine G. Wicklund, Alice S. Whittemore, Nicolas Wentzensen, Christine Walsh, Shan Wang-Gohrke, Robert A. Vierkant, Ignace Vergote, Els Van Nieuwenhuysen, Anne M. van Altena, Shelley S. Tworoger, Ya-Yu Tsai, Agnieszka Timorek, Pamela J. Thompson, Kathryn L. Terry, Soo-Hwang Teo, Ingvild L. Tangen, Lara E. Sucheston-Campbell, Melissa C. Southey, Honglin Song, Weiva Sieh, Nadeem Siddiqui, Yurii B. Shvetsov, Xiao-Ou Shu, Ira Schwaab, Joellen M. Schildkraut, Helga B. Salvesen, Iwona K. Rzepecka, Ingo B. Runnebaum, Anja Rudolph, Joseph H. Rothstein, Mary Anne Rossing, Barry Rosen, Harvey A. Risch, Susan J. Ramus, Elizabeth M. Poole, Malcolm C. Pike, Catherine M. Phelan, Jennifer Permuth-Wey, Liisa M. Pelttari, Tanja Pejovic, Celeste Leigh Pearce, Rachel Palmieri Weber, Sandra Orsulic, Irene Orlow, Sara H. Olson, Kunle Odunsi, Heli Nevanlinna, Roberta B. Ness, Lotte Nedergaard, Steven A. Narod, Kirsten B. Moysich, Francesmary Modugno, Usha Menon, Iain A. McNeish, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Leon Massuger, Lene Lundvall, Jan Lubinski, Karen Lu, Jolanta Lissowska, Dong Liang, Douglas A. Levine, Jenny Lester, Arto Leminen, Shashi Lele, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Lambertus A. Kiemeney, Joseph Kelley, Melissa Kellar, Linda E. Kelemen, Susanne K. Kjaer, Beth Y. Karlan, Bu-Tian Ji, Allan Jensen, James Paul, Anna Jakubowska, Edwin S. Iversen, Satoyo Hosono, Claus K. Hogdall, Estrid Hogdall, Peter Hillemanns, Michelle A.T. Hildebrandt, Florian Heitz, Alexander Hein, Philipp Harter, Patricia Harrington, Jacek Grownwald, Marc T. Goodman, Ellen L. Goode, Rosalind Glasspool, Graham G. Giles, Aleksandra Gentry-Maharaj, Yu-Tang Gao, Brooke L. Fridley, Peter A. Fasching, Arif B. Ekici, Robert P. Edwards, Douglas F. Easton, Diana Eccles, Matthias Dürst, Andreas du Bois, Thilo Dörk, Jennifer A. Doherty, Ed Dicks, Joe Dennis, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Julie M. Cunningham, Daniel Cramer, Linda S. Cook, Zhihua Chen, Yian Ann Chen, Jenny Chang-Claude, Karen Carty, Ian Campbell, Ralf Butzow, Angela Brooks-Wilson, Louise Brinton, Natalia Bogdanova, Line Bjørge, Maria Bisogna, Andrew Berchuck, Matthias W. Beckmann, Yukie T. Bean, Elisa V. Bandera, Helen Baker, Georgia Chenevix-Trench, Natalia Antonenkova, Hoda Anton-Culver, Katja K.H. Aben, Kate Lawrenson, Qiyuan Li, Jonathan P. Tyrer, and Siddhartha P. Kar

Abstract

Supplementary Tables S1-6, Figures S1-2. Supplementary Table S1: Summary of serous EOC GWAS data sets; Supplementary Table S2: Genes in the six significant co-expression networks; Supplementary Table S3: GSEA results after LD-based clumping of SNPs; Supplementary Table S4: GSEA results for the replication data set (COGS); Supplementary Table S5: GSEA results for all networks with > 10 genes; Supplementary Table S6: Number of intragenic SNPs and genes covered by SNPs in the different analyses; Supplementary Figure S1: Q-Q plots of the minimum P-value among all SNPs in each gene with and without the modified Sidak correction; Supplementary Figure S2: Disease Association Protein-Protein Link Evaluator (DAPPLE) protein-protein interaction network

Published
2023

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

Published
2015
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12. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

Author

Lu, Yi, Cuellar-Partida, Gabriel, Painter, Jodie N., Nyholt, Dale R., Morris, Andrew P., Fasching, Peter A., Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W., Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Doherty, Jennifer Anne, Rossing, Mary Anne, Wicklund, Kristine G., Chang-Claude, Jenny, Eilber, Ursula, Rudolph, Anja, Wang-Gohrke, Shan, Goodman, Marc T., Bogdanova, Natalia, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B., Antonenkova, Natalia, Butzow, Ralf, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M., Edwards, Robert P., Kelley, Joseph L., Modugno, Francesmary, Moysich, Kirsten B., Ness, Roberta B., Cannioto, Rikki, Høgdall, Estrid, Jensen, Allan, Giles, Graham G., Bruinsma, Fiona, Kjaer, Susanne K., Hildebrandt, Michelle A.T., Liang, Dong, Lu, Karen H., Wu, Xifeng, Bisogna, Maria, Dao, Fanny, Levine, Douglas A., Cramer, Daniel W., Terry, Kathryn L., Tworoger, Shelley S., Missmer, Stacey, Bjorge, Line, Salvesen, Helga B., Kopperud, Reidun K., Bischof, Katharina, Aben, Katja K.H., Kiemeney, Lambertus A., Massuger, Leon F.A.G., Brooks-Wilson, Angela, Olson, Sara H., McGuire, Valerie, Rothstein, Joseph H., Sieh, Weiva, Whittemore, Alice S., Cook, Linda S., Le, Nhu D., Gilks, C. Blake, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Gawełko, Jan, Song, Honglin, Tyrer, Jonathan P., Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, Lissowska, Jolanta, Mclaughlin, John R., Narod, Steven A., Phelan, Catherine, Anton-Culver, Hoda, Ziogas, Argyrios, Eccles, Diana, Gayther, Simon A., Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J., Wu, Anna H., Dansonka-Mieszkowska, Agnieszka, Kupryjanczyk, Jolanta, Timorek, Agnieszka, Szafron, Lukasz, Cunningham, Julie M., Fridley, Brooke L., Winham, Stacey J., Bandera, Elisa V., Poole, Elizabeth M., Morgan, Terry K., Risch, Harvey A., Goode, Ellen L., Schildkraut, Joellen M., Webb, Penelope M., Pearce, Celeste L., Berchuck, Andrew, Pharoah, Paul D.P., Montgomery, Grant W., Zondervan, Krina T., Chenevix-Trench, Georgia, MacGregor, Stuart, Anderson, Carl A., Gordon, Scott D., Guo, Qun, Henders, Anjali K., Lambert, Ann, Lee, Sang Hong, Kraft, Peter, Kennedy, Stephen H., Macgregor, Stuart, Martin, Nicholas G., Missmer, Stacey A., Montgomery, Grant W., Morris, Andrew P., Nyholt, Dale R., Painter, Jodie N., Roseman, Fenella, Treloar, Susan A., Visscher, Peter M., Wallace, Leanne, and Zondervan, Krina T.

Published
2015
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13. 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., Couch, Fergus J., Offit, Kenneth, Chenevix-Trench, Georgia, Monteiro, Alvaro N.A., Antoniou, Antonis, Freedman, Matthew, Coetzee, Gerhard A., Pharoah, Paul D.P., Noushmehr, Houtan, Gayther, Simon A., Tyrer, Jonathan, 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, Bois, Andreas du, 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 A.T., 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, Lissowska, Jolanta, Lu, Karen, Lubinski, Jan, Lundvall, Lene, Massuger, Leon F.A.G., Matsuo, Keitaro, McGuire, Valerie, McLaughlin, John R., McNeish, Ian, Menon, Usha, Modugno, Francesmary, Moysich, Kirsten B., Narod, Steven A., Nedergaard, Lotte, Ness, Roberta B., Azmi, Mat Adenan Noor, Odunsi, Kunle, Olson, Sara H., Orlow, Irene, Orsulic, Sandra, Weber, Rachel Palmieri, Pearce, Celeste L., Pejovic, Tanja, Pelttari, Liisa M., Permuth-Wey, Jennifer, Phelan, Catherine M., Pike, Malcolm C., Poole, Elizabeth M., Risch, Harvey A., Rosen, Barry, Rossing, Mary Anne, Rothstein, Joseph H., Rudolph, Anja, Runnebaum, Ingo B., Rzepecka, Iwona K., Salvesen, Helga B., Schildkraut, Joellen M., Schwaab, Ira, Sellers, Thomas A., Shu, Xiao-Ou, Shvetsov, Yurii B, Siddiqui, Nadeem, Sieh, Weiva, Song, Honglin, Southey, Melissa C., Sucheston, Lara, Tangen, Ingvild L., Teo, Soo-Hwang, Terry, Kathryn L., Thompson, Pamela J., Timorek, Agnieszka, Tsai, Ya-Yu, Tworoger, Shelley S., Tyrer, Jonathan, van Altena, Anne M., Van Nieuwenhuysen, Els, Vergote, Ignace, Vierkant, Robert A., Wang-Gohrke, Shan, Walsh, Christine, Wentzensen, Nicolas, Whittemore, Alice S., Wicklund, Kristine G., Wilkens, Lynne R., Woo, Yin-Ling, Wu, Xifeng, Wu, Anna H., Yang, Hannah, Zheng, Wei, and Ziogas, Argyrios

Published
2015
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14. Recommendations of the Polish Gynecological Oncology Society for the diagnosis and treatment of ovarian cancer

Author

Mariusz Bidziński, Paweł Blecharz, Antoni Basta, Łukasz Wicherek, Robert Jach, Marcin Misiek, Jacek J. Sznurkowski, Paweł Knapp, Włodzimierz Sawicki, Zbigniew Kojs, Andrzej Bieńkiewicz, Jan Bahyrycz, Lubomir Bodnar, Jan Kotarski, Agnieszka Timorek-Lemieszczuk, Janina Markowska, and Radosław Mądry

Subjects
Gynecology, medicine.medical_specialty, Gynecological oncology, business.industry, Endocrinology, Diabetes and Metabolism, General surgery, Endometrial cancer, Obstetrics and Gynecology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, medicine, 030212 general & internal medicine, business
Published
2017

15. Prognosis of patients with BRCA1 -associated ovarian carcinomas depends on TP53 accumulation status in tumor cells

Author

Lukasz Szafron, Agnieszka Stys, Piotr Sobiczewski, Barbara Pienkowska-Grela, Agnieszka Podgorska, Iwona K. Rzepecka, Agnieszka Timorek, Anna Felisiak-Golabek, Jolanta Kupryjanczyk, and Mona El-Bahrawy

Subjects
0301 basic medicine, Oncology, endocrine system diseases, FEATURES, Genes, BRCA2, Genes, BRCA1, Logistic regression, Tp53 mutation, 0302 clinical medicine, 1114 Paediatrics And Reproductive Medicine, PLATINUM, Ovarian Neoplasms, Confounding, Obstetrics & Gynecology, Obstetrics and Gynecology, BRCA1/2 MUTATIONS, Middle Aged, Prognosis, 030220 oncology & carcinogenesis, SURVIVAL, GROWTH, Ovarian carcinomas, Female, Life Sciences & Biomedicine, EXPRESSION, Adult, medicine.medical_specialty, Tumor cells, 03 medical and health sciences, Germline mutation, stomatognathic system, Ovarian cancer, Internal medicine, medicine, BREAST-CANCER, Humans, Clinical significance, CANCER PATIENTS, Oncology & Carcinogenesis, CLINICAL-SIGNIFICANCE, neoplasms, Aged, P53, Science & Technology, business.industry, BRCA1, medicine.disease, 030104 developmental biology, Mutation, Tumor Suppressor Protein p53, TP53 accumulation, business, 1112 Oncology And Carcinogenesis
Abstract

Objective TP53 mutation is the most frequent molecular event in BRCA1 -associated ovarian carcinomas. TP53 status may be a confounding factor in the evaluation of clinical importance of other proteins. We aimed to evaluate the clinical significance of BRCA1 mutations with respect to the TP53 accumulation status in 159 high-grade ovarian carcinomas. Methods Statistical analyses were done with the Kaplan-Meier method, log-rank test, the Cox's and logistic regression models for all patients, and in subgroups with and without TP53 accumulation (TP53+ and TP53−, respectively). Results Forty of 159 ovarian carcinomas (25.2%) were diagnosed in patients with BRCA1 germline mutations; 102 tumors (64.2%) were TP53+ and 57 (37.8%) were TP53−. Among patients with TP53+ carcinomas, BRCA1 carriers had increased odds of recurrence compared with sporadic cases (HR 2.25, P =0.003; median disease-free survival time 7.7 vs. 18.4months, respectively). In the smaller TP53− subgroup, BRCA1 mutation reduced the risk of death by 46% (HR 0.54, P =0.099, median overall survival time 42.7 vs. 28.1months), but beyond the border of significance. When the TP53 status was not taken into account, BRCA1 mutations did not show any significance, however, there was a trend toward increased odds of complete remission for women with BRCA1 mutations compared to non-carriers (OR 2.47, P =0.064). Taxane-platinum therapy showed advantage over the platinum-cyclophosphamide one in the entire group of patients and in the TP53+ subgroup. Conclusions Our results suggest that the TP53 accumulation status determines the prognosis of BRCA1 mutation carriers with high-grade ovarian carcinomas.

Published
2017

16. EP804 Prognostic role of second-line platinum-based therapy in recurrent platinum resistant ovarian cancer patients – data from real-world clinical practice in poland

Author

Jacek J. Sznurkowski, A. Gąsowska-Bodnar, Radosław Mądry, A. Ptak-Chmielewska, Robert Jach, P Blecharz, Paweł Knapp, M. Sikorska, L Bodnar, and A. Timorek

Subjects
Chemotherapy, medicine.medical_specialty, business.industry, medicine.medical_treatment, chemistry.chemical_element, medicine.disease, Debulking, Clinical Practice, chemistry.chemical_compound, Second line, Paclitaxel, chemistry, Internal medicine, medicine, Ovarian cancer, Platinum, business, Platinum resistant
Abstract

Introduction/Background Strategy of treatment in patients with recurrent ovarian cancer (OC) dependents on platinum-free interval (PFI). We aimed to compare survival in ‘platinum resistant’ OC patients who received platinum-based or non-platinum chemotherapy at first relapse in real world practice based. Methodology Data of OC patients treated with primary debulking surgery and standard chemotherapy (paclitaxel/platinum analogs) between January 1, 2011 and December 31, 2011 were extracted from Polish National Health Fund Database. Further overall survival (OS) was compared between patients who received any type of chemotherapy up to 6 months PFI. Results 17% (227/1369) patients classified as ‘platinum-resistant’ by the 6-month threshold of PFI and 29% (66/227) of those group, were treated with Pt-based chemotherapy at second line. Median OS after platinum-based 2-nd line chemotherapy was significantly longer compared to non- platinum chemotherapy group (median OS was 28.1 months, 95% CI: 23.3–42.0 vs. 16.4 months, 95% CI: 13.1–21.0; HR=0.71, 95% CI, 0.51–0.99; P=0.049). This effect was seen, among patients with PFI of 3–6 months (median OS was, 28.1 months, 95% CI: 23.1–42.0 vs 14.3 months, 95% CI: 10.4–40.5, respectively; HR=0.61, 95%CI, 0.39–0.96; P=0.0336). but not in PFI Conclusion Our results from real world data based on nationwide population cohort study shows that six-months PFI as an arbitrary threshold for subsequent Pt-based chemotherapy is questionable. Biomarkers of platinum sensitivity are needed to identify potential responders, especially in group of patients with PFI 3–6 months. Disclosure Nothing to disclose.

Published
2019

17. P21WAF1, P27KIP1, TP53 and C-MYC analysis in 204 ovarian carcinomas treated with platinum-based regimens

Author

Plisiecka-Halasa, J., Karpinska, G., Szymanska, T., Ziólkowska, I., Madry, R., Timorek, A., Debniak, J., Ulanska, M., Jedryka, M., Chudecka-Glaz, A., Klimek, M., Rembiszewska, A., Kraszewska, E., Dybowski, B., Markowska, J., Emerich, J., Pluzanska, A., Goluda, M., Rzepka-Górska, I., Urbanski, K., Zielinski, J., Stelmachów, J., Chrabowska, M., and Kupryjanczyk, J.

Published
2003

18. The significance of c.690G>T polymorphism (rs34529039) and expression of the CEBPA gene in ovarian cancer outcome

Author

Agnieszka Podgorska, Agnieszka Timorek, Jolanta Kupryjanczyk, Agnieszka Dansonka-Mieszkowska, Beata Spiewankiewicz, Ewa Kwiatkowska, Lukasz Szafron, Anna Stachurska, Barbara Pienkowska-Grela, Martyna Lukasik, Anna Balcerak, Aleksandra Zolocinska, Mona El-Bahrawy, and Bozena Konopka

Subjects
0301 basic medicine, Oncology, Adult, medicine.medical_specialty, Cyclophosphamide, Genotype, medicine.medical_treatment, Gynecologic oncology, Kaplan-Meier Estimate, Polymorphism, Single Nucleotide, Disease-Free Survival, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, DNA-damaging chemotherapy, CEBPA, Antineoplastic Combined Chemotherapy Protocols, medicine, synonymous polymorphism, Humans, Genotyping, Aged, Proportional Hazards Models, Gynecology, Ovarian Neoplasms, Chemotherapy, Taxane, business.industry, Middle Aged, medicine.disease, Prognosis, Chemotherapy regimen, 030104 developmental biology, ovarian cancer, Treatment Outcome, 030220 oncology & carcinogenesis, gene expression, CCAAT-Enhancer-Binding Proteins, Female, business, Ovarian cancer, medicine.drug, Research Paper
Abstract

// Bozena Konopka 1, * , Lukasz Michal Szafron 1, * , Ewa Kwiatkowska 2 , Agnieszka Podgorska 1 , Aleksandra Zolocinska 3 , Barbara Pienkowska-Grela 1 , Agnieszka Dansonka-Mieszkowska 1 , Anna Balcerak 3 , Martyna Lukasik 1 , Anna Stachurska 1, 4 , Agnieszka Timorek 5 , Beata Spiewankiewicz 6 , Mona El-Bahrawy 7 , Jolanta Kupryjanczyk 1 1 Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 2 Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 3 Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 4 Department of Applied Pharmacy and Bioengineering, Medical University of Warsaw, Warsaw, Poland 5 Department of Obstetrics, Gynecology and Oncology, 2nd Faculty of Medicine, Medical University of Warsaw and Brodnowski Hospital, Warsaw, Poland 6 Department of Gynecologic Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland 7 Department of Histopathology, Imperial College London, UK * These authors have contributed equally to this study Correspondence to: Lukasz Michal Szafron, email: lukszafron@gmail.com Keywords: ovarian cancer, CEBPA, synonymous polymorphism, gene expression, DNA-damaging chemotherapy Received: May 18, 2016 Accepted: August 25, 2016 Published: September 02, 2016 ABSTRACT The CEBPA gene is known to be mutated or abnormally expressed in several cancers. This is the first study assessing the clinical impact of CEBPA gene status and expression on the ovarian cancer outcome. The CEBPA gene sequence was analyzed in 118 ovarian cancer patients (44 platinum/cyclophosphamide (PC)-treated and 74 taxane/platinum (TP)-treated), both in tumors and blood samples, and in blood from 236 healthy women, using PCR-Sanger sequencing and Real-Time quantitative PCR (qPCR)-based genotyping methods, respectively. The CEBPA mRNA level was examined with Reverse Transcription quantitative PCR (RT-qPCR). The results were correlated to different clinicopathological parameters. Thirty of 118 (25.4%) tumors harbored the CEBPA synonymous c.690G>T polymorphism (rs34529039), that we showed to be related to up-regulation of CEBPA mRNA levels (p=0.0059). The presence of the polymorphism was significantly associated with poor prognosis (p=0.005) and poor response to the PC chemotherapy regimen (p=0.024). In accordance, elevated CEBPA mRNA levels negatively affected patient survival (p T, p.(Thr230Thr) (rs34529039) polymorphism of the CEBPA gene, together with up-regulation of its mRNA expression, are negative factors worsening ovarian cancer outcome. Their adverse clinical effect depends on a therapeutic regimen used, which might make them potential prognostic and predictive biomarkers for response to DNA-damaging chemotherapy.

Published
2016

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

Author

Ellen L. Goode, Andreas du Bois, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Joe Dennis, Celeste Leigh Pearce, Kristine G. Wicklund, Lynne R. Wilkens, Rosalind Glasspool, Diana Eccles, Susanne K. Kjaer, Roberta B. Ness, James Paul, Matthias Dürst, Camilla Krakstad, Irene Orlow, Rachel Palmieri Weber, Jonathan Tyrer, Valerie McGuire, Matthias W. Beckmann, Thomas A. Sellers, Elizabeth M. Poole, Ian G. Campbell, Arif B. Ekici, Steven A. Narod, Lotte Nedergaard, Shan Wang-Gohrke, Estrid Høgdall, Yurii B. Shvetsov, Douglas F. Easton, Sandrina Lambrechts, Linda E. Kelemen, Zhihua Chen, Karen Lu, Elisa V. Bandera, Qiyuan Li, Joellen M. Schildkraut, Agnieszka Dansonka-Mieszkowska, Liisa M. Pelttari, Kate Lawrenson, Sandra Orsulic, Ed Dicks, Kirsten B. Moysich, Melissa C. Southey, Christine Walsh, Louise A. Brinton, Argyrios Ziogas, Yukie Bean, Julie M. Cunningham, Patricia Harrington, Philipp Harter, Sara H. Olson, Keitaro Matsuo, Alvaro N.A. Monteiro, Claus Høgdall, Anne M. van Altena, Jenny Lester, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Yu-Tang Gao, Shelley S. Tworoger, Maria Bisogna, Michelle A.T. Hildebrandt, Yian Ann Chen, Iain A. McNeish, Allan Jensen, Diether Lambrechts, Usha Menon, Satoyo Hosono, Pamela J. Thompson, Yin Ling Woo, Jennifer Permuth-Wey, Francesmary Modugno, Matthew L. Freedman, Linda S. Cook, Harvey A. Risch, Ya-Yu Tsai, Marc T. Goodman, Dong Liang, Kathryn L. Terry, Soo Hwang Teo, Lara E. Sucheston-Campbell, Ira Schwaab, Robert A. Vierkant, Georgia Chenevix-Trench, Ralf Bützow, Siddhartha Kar, Wei Zheng, Nhu D. Le, Andrew Berchuck, Brooke L. Fridley, Edwin S. Iversen, Robert P. Edwards, Peter Hillemanns, Daniel W. Cramer, Mary Anne Rossing, Thilo Dörk, Malcolm C. Pike, Jolanta Kupryjanczyk, Anja Rudolph, Joseph H. Rothstein, Douglas A. Levine, Xiao-Ou Shu, Nicolas Wentzensen, Hannah P. Yang, Graham G. Giles, Hoda Anton-Culver, Line Bjørge, Peter A. Fasching, Catherine M. Phelan, Simon A. Gayther, Ignace Vergote, Alexander Hein, Cezary Cybulski, Ingvild L. Tangen, Els Van Nieuwenhuysen, Joseph L. Kelley, Honglin Song, Helen Baker, Alice S. Whittemore, Melissa Kellar, Kunle Odunsi, Bu Tian Ji, Heli Nevanlinna, Jolanta Lissowska, Shashi Lele, Barry P. Rosen, Katja K.H. Aben, Karen Carty, Leon F.A.G. Massuger, Iwona K. Rzepecka, Susan J. Ramus, Angela Brooks-Wilson, Xifeng Wu, Ingo B. Runnebaum, Lene Lundvall, Natalia Bogdanova, Helga B. Salvesen, Alice W. Lee, Jan Lubinski, Agnieszka Timorek, Nadeem Siddiqui, Anna H. Wu, Natalia Antonenkova, Weiva Sieh, Tanja Pejovic, John R. McLaughlin, Arto Leminen, Jennifer A. Doherty, Florian Heitz, Beth Y. Karlan, and Jacek Grownwald

Subjects
endocrine system diseases, Microarray, Epidemiology, Genome-wide association study, Global Health, Bioinformatics, Medical and Health Sciences, Risk Factors, 2.1 Biological and endogenous factors, Aetiology, Hox gene, Cancer, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Nuclear Proteins, DNA, Neoplasm, female genital diseases and pregnancy complications, Ovarian Cancer, Gene Expression Regulation, Neoplastic, Serous fluid, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Biotechnology, Australian Ovarian Cancer Study Group, Genotype, Population, Cystadenocarcinoma, Single-nucleotide polymorphism, Computational biology, Biology, Article, Rare Diseases, Australian Cancer Study, Genetics, Humans, Genetic Predisposition to Disease, education, Gene, Genetic association, Neoplastic, Prevention, Human Genome, Serous, DNA, Cystadenocarcinoma, Serous, Gene Expression Regulation, Neoplasm, Morbidity, Transcription Factors, Genome-Wide Association Study
Abstract

Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

Published
2015

20. Recommendations of the Polish Gynecological Oncology Society for the diagnosis and treatment of ovarian cancer

Author

Basta, Antoni, Bidziński, Mariusz, Bieńkiewicz, Andrzej, Blecharz, Paweł, Bodnar, Lubomir, Jach, Robert, Knapp, Paweł, Kojs, Zbigniew, Kotarski, Jan, Markowska, Janina, Misiek, Marcin, Jan Sznurkowski, Jacek, Wicherek, Łukasz, Sawicki, Włodzimierz, Timorek-Lemieszczuk, Agnieszka, Bahyrycz, Jan, and Mądry, Radosław

Subjects
endocrine system, endocrine system diseases, female genital diseases and pregnancy complications, humanities, eye diseases
Abstract

Recommendations of the Polish Gynecological Oncology Society for the diagnosis and treatment of ovarian cancer

Published
2017

21. Treatment Patterns, Health Care Utilization, and Costs of Ovarian Cancer in Central and Eastern Europe Using a Delphi Panel Based on a Retrospective Chart Review

Author

S. Vasovic, Rodoslaw Madry, Emma Hernlund, Imre Pete, Nahila Justo, Lubomir Bodnar, Kun Kim, Tomáš Minárik, Tatjana Bozanovic, Agnieszka Timorek–Lemieszczuk, Lýdia Heľpianska, Zorica Tomasevic, Milica Zivaljevic, Hana Garanová, Vladimir Pazin, A. Szánthó, János Révész, and Zoltán Hernádi

Subjects
Slovakia, medicine.medical_specialty, Palliative care, Total cost, Cost-Benefit Analysis, Delphi method, Tertiary Care Centers, Health care, medicine, Humans, Intensive care medicine, Disease burden, Retrospective Studies, Ovarian Neoplasms, Hungary, Cost–benefit analysis, business.industry, Palliative Care, Obstetrics and Gynecology, Retrospective cohort study, Health Care Costs, Health Services, Prognosis, Combined Modality Therapy, Markov Chains, Oncology, Telephone interview, Family medicine, Female, Poland, business, Serbia, Follow-Up Studies
Abstract

ObjectiveDespite the considerable disease burden of ovarian cancer, there were no cost studies in Central and Eastern Europe. This study aimed to describe treatment patterns, health care utilization, and costs associated with treating ovarian cancer in Hungary, Poland, Serbia, and Slovakia.MethodOverall clinical practice for management of epithelial ovarian cancer was investigated through a 3-round Delphi panel. Experts completed a survey based on the chart review (n = 1542). The survey was developed based on clinical guidelines and the International Federation of Gynecology and Obstetrics Annual Report. Means, ranges, and outlier values were discussed with the experts during a telephone interview. Finally, consensus estimates were obtained in face-to-face workshops. Based on these results, overall cost of ovarian cancer was estimated using a Markov model.ResultsThe patients included in the chart review were followed up from presurgical diagnosis and in each phase of treatment, that is, surgical staging and primary surgery, chemotherapy and chemotherapy monitoring, follow-up, and palliative care. The 5-year overall cost per patient was €14,100 to €16,300 in Hungary, €14,600 to €15,800 in Poland, €7600 to €8100 in Serbia, and €12,400 to €14,500 in Slovakia. The main components were chemotherapy-associated costs (68%–74% of the total cost), followed by cost of primary treatment with surgery (15%–21%) and palliative care (3%–10%).ConclusionsPatients with ovarian cancer consume considerable health care resources and incur substantial costs in Central and Eastern Europe. These findings may prove useful for clinicians and decision makers in understanding the economic implications of managing ovarian cancer in Central and Eastern Europe and the need for innovative therapies.

Published
2013

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

Author

Francesmary Modugno, Alice S. Whittemore, Kunle Odunsi, Heli Nevanlinna, Fiona Bruinsma, Iwona K. Rzepecka, Jolanta Lissowska, Malcolm C. Pike, Bu-Tian Ji, Michelle A.T. Hildebrandt, Warren Davis, Agnieszka Dansonka-Mieszkowska, Line Bjørge, Roberta B. Ness, James Paul, Katja K.H. Aben, Nonna Kolomeyevskaya, Melissa C. Southey, Bridget Kruszka, Daniel W. Cramer, Shashikant Lele, Edwin S. Iversen, Kristina Schmitt, Julie M. Cunningham, Xifeng Wu, Celeste Leigh Pearce, Keitaro Matsuo, Cezary Cybulski, Linda E. Kelemen, Kirsten B. Moysich, Kristine G. Wicklund, Ralf Bützow, Shelley S. Tworoger, Grace Friel, Robert P. Edwards, Agnieszka Timorek, Leah Preus, Anna Jakubowska, Paul D.P. Pharoah, Karen Lu, Lambertus A. Kiemeney, Allan Jensen, Elisa V. Bandera, Steven A. Narod, Soo-Hwang Teo, Susanne K. Kjaer, Jonathan Tyrer, Joseph H. Rothstein, Irene Orlow, Rachel Palmieri Weber, Janine M. Joseph, Anna M. van Altena, Mary Nesline, Rüdiger Klapdor, Hannah P. Yang, Graham G. Giles, Pamela J. Thompson, Christine Walsh, Jolanta Kupryjanczyk, Wei Zheng, Nicolas Wentzensen, Angela Brooks-Wilson, Arto Leminen, Philipp Harter, Nadeem Siddiqui, Joanna Moes-Sosnowska, Yin Ling Woo, Anja Rudolph, John R. McLaughlin, Louise A. Brinton, Ingo B. Runnebaum, Shalaka S. Hampras, Linda S. Cook, Lotte Nedergaard, Lara E. Sucheston-Campbell, Natalia Bogdanova, Alexander Hein, Joseph L. Kelley, Claus Høgdall, Matthias Dürst, Jennifer A. Doherty, Ignace Vergote, Argyrios Ziogas, Ian G. Campbell, Prashant Singh, Hoda Anton-Culver, Shan Wang-Gohrke, Helga B. Salvesen, Stefan Nickels, Ingvild L. Tangen, Joe Dennis, Georgia Chenevix-Trench, Eva S. Schernhammer, Paul K. Wallace, Leon F.A.G. Massuger, Lynne R. Wilkens, Ed Dicks, Yukie Bean, Alice W. Lee, Ian McNeish, Evelyn Despierre, Patricia Harrington, Kevin H. Eng, Maria Bisogna, Nhu D. Le, Sandrina Lambrechts, Andrew Berchuck, Honglin Song, Hanis Nazihah Hasmad, Nils Schoof, Diana Eccles, Harvey A. Risch, Xiao-Ou Shu, Rosalind Glasspool, Peter Hillemanns, Jenny Permuth-Wey, Chi-Chen Hong, Catherine M. Phelan, Marc T. Goodman, Peter A. Fasching, Matthias W. Beckmann, Helen Baker, Doug Easton, Robert A. Vierkant, Barbara Perkins, Lene Lundvall, Elizabeth M. Poole, Joanna Plisiecka-Halasa, Arif B. Ekici, Melissa Kellar, Jan Lubinski, Alyssa Clay, Diether Lambrechts, Jacek Gronwald, Keith L. Knutson, Karen Carty, Camilla Krakstad, Jenny Lester, Simon A. Gayther, Ya-Yu Tsai, Rikki Cannioto, Kathryn L. Terry, Ira Schwaab, Susan J. Ramus, Andreas du Bois, Thomas A. Sellers, Estrid Høgdall, Valeria McGuire, Yurii B. Shvetsov, Joellen M. Schildkraut, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Sara H. Olson, Ellen L. Goode, Song Liu, Usha Menon, Dong Liang, Tanja Pejovic, Yu-Tang Gao, Florian Heitz, Beth Y. Karlan, Brooke L. Fridley, Mary Anne Rossing, Thilo Dörk, Douglas A. Levine, Weiva Sieh, Liisa M. Pelttari, Anna H. Wu, Natalia Antonenkova, Satoyo Hosono, Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Easton, Douglas [0000-0003-2444-3247], Song, Honglin [0000-0001-5076-7371], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, endocrine system diseases, Carcinoma, Ovarian Epithelial, T-Lymphocytes, Regulatory, 0302 clinical medicine, STAGE, Gene Frequency, Risk Factors, Genotype, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], immunosuppression, Middle Aged, Protein-Serine-Threonine Kinases, female genital diseases and pregnancy complications, 3. Good health, TGFBR2, Gene Expression Regulation, Neoplastic, Serous fluid, ovarian cancer, Oncology, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Adenocarcinoma, Female, Life Sciences & Biomedicine, EXPRESSION, Adult, CARCINOMA, Population, chemical and pharmacologic phenomena, Single-nucleotide polymorphism, FCGR2B, Protein Serine-Threonine Kinases, PERIPHERAL-BLOOD, Biology, DENDRITIC CELLS, Polymorphism, Single Nucleotide, 03 medical and health sciences, LUNG-CANCER, medicine, BREAST-CANCER, Humans, Genetic Predisposition to Disease, REGULATORY T-CELLS, education, Aged, Science & Technology, RECEPTOR, Receptor, Transforming Growth Factor-beta Type II, biomarkers, Cell Biology, medicine.disease, 030104 developmental biology, FC-GAMMA-RIIB, Immunology, genetic variation, Cancer research, Ovarian cancer, Receptors, Transforming Growth Factor beta, Clear cell, Priority Research Paper, Adenocarcinoma, Clear Cell
Abstract

Contains fulltext : 167177.pdf (Publisher’s version ) (Open Access) BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016

23. The role of mathematical models and scoring systems in detecting dysgerminoma in a young patient

Author

Agnieszka Timorek, Joanna Winiarek, Nabil Abdalla, Krzysztof Cendrowski, and Włodzimierz Sawicki

Subjects
Ovarian Neoplasms, medicine.medical_specialty, Models, Statistical, Mathematical model, business.industry, Obstetrics and Gynecology, Dysgerminoma, medicine.disease, Young Adult, medicine, Humans, Medical physics, Female, business, Neoplasm Staging
Published
2016

24. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Author

Joseph L. Kelley, Michelle A.T. Hildebrandt, Diana Eccles, Karen Lu, Elisa V. Bandera, Steven A. Narod, Linda S. Cook, Matthias W. Beckmann, John R. McLaughlin, Liisa M. Pelttari, Elizabeth M. Poole, Arto Leminen, Jennifer A. Doherty, Argyrios Ziogas, Weiva Sieh, Maria Bisogna, Stuart MacGregor, Andrew Berchuck, Agnieszka Timorek, Ralf Bützow, Hoda Anton-Culver, Robert P. Edwards, Peter Hillemanns, Anja Rudolph, Joseph H. Rothstein, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Ignace Vergote, Louise A. Brinton, Meir J. Stampfer, Honglin Song, Jenny Chang-Claude, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Graham G. Giles, Valerie McGuire, Reidun K. Kopperud, Daniel W. Cramer, Alice S. Whittemore, Jacek Gronwald, Gabriel Cuellar-Partida, Georgia Chenevix-Trench, Ellen L. Goode, Stacey J. Winham, Julie M. Cunningham, Estrid Høgdall, Adriaan Vanderstichele, Jan Lubinski, Lukasz Szafron, Peter A. Fasching, Jonathan Tyrer, Alexander Hein, Harvey A. Risch, Ian G. Campbell, Joellen M. Schildkraut, Shelley S. Tworoger, C. Blake Gilks, Allan Jensen, Natalia Bogdanova, Helga B. Salvesen, Rikki Cannioto, Shan Wang-Gohrke, Terry K. Morgan, Susan J. Ramus, Catherine M. Phelan, Kirsten B. Moysich, Usha Menon, Penelope M. Webb, Angela Brooks-Wilson, Ingo B. Runnebaum, Anna H. Wu, Celeste Leigh Pearce, Suzanne C. Dixon, Dong Liang, Yi Lu, Natalia Antonenkova, Diether Lambrechts, Stacey A. Missmer, Brooke L. Fridley, Roberta B. Ness, Mary Anne Rossing, Thilo Dörk, Stefanie Burghaus, Douglas A. Levine, Marc T. Goodman, Susanne K. Kjaer, Britton Trabert, Kathryn L. Terry, Claus Høgdall, Tomasz Kluz, Heli Nevanlinna, Line Bjørge, Francesmary Modugno, Jolanta Lissowska, Fanny Dao, Simon A. Gayther, Katja K.H. Aben, Leon F.A.G. Massuger, Fiona Bruinsma, Xifeng Wu, Matthias Dürst, Jolanta Kupryjanczyk, Nicolas Wentzensen, Katharina Bischof, Els Van Nieuwenhuysen, Nhu D. Le, and Sara H. Olson

Subjects
0301 basic medicine, endocrine system diseases, Genome-wide association study, Australian Ovarian Cancer Study, Carcinoma, Ovarian Epithelial, 0302 clinical medicine, Neoplasms, Ovarian Epithelial, Genotype, Pathology, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, Pathology, Molecular, Aetiology, Genetics (clinical), Cancer, Genetics, Ovarian Neoplasms, Genetics & Heredity, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Glandular and Epithelial, Single Nucleotide, female genital diseases and pregnancy complications, 3. Good health, Ovarian Cancer, Serous fluid, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Clear cell carcinoma, Female, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Paediatrics and Reproductive Medicine, 03 medical and health sciences, Rare Diseases, Complementary and Alternative Medicine, medicine, Humans, Polymorphism, Carcinoma, Human Genome, Molecular, Heritability, medicine.disease, Genetic architecture, 030104 developmental biology, Ovarian cancer
Abstract

Contains fulltext : 171782.pdf (Publisher’s version ) (Closed access) Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 +/- 1.1 %), endometrioid ([Formula: see text] = 3.2 +/- 1.6 %), clear cell ([Formula: see text] = 6.7 +/- 3.3 %) and all EOC ([Formula: see text] = 5.6 +/- 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Published
2016

25. Evaluation of urgent multivisceral resections due to complications resulting from an advanced ovarian cancer

Author

Witold Woźniak, Tomasz Miłek, Agnieszka Timorek, Piotr Porzycki, Piotr Ciostek, Krzysztof Cendrowski, Włodzimierz Sawicki, and Alkalayla Habib

Subjects
Adult, medicine.medical_specialty, Gastrointestinal bleeding, Ovariectomy, Perforation (oil well), Abdominal cavity, Enteral administration, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Aged, Neoplasm Staging, Retrospective Studies, Aged, 80 and over, Ovarian Neoplasms, Postoperative Care, business.industry, Mortality rate, General surgery, Carcinoma, Obstetrics and Gynecology, Perioperative, Middle Aged, medicine.disease, Survival Analysis, Surgery, medicine.anatomical_structure, Treatment Outcome, Respiratory failure, Chemotherapy, Adjuvant, Female, Ovarian cancer, business
Abstract

Background: Unlike other solid tumors (i.e. pancreas, gallbladder, stomach), an ovarian cancer is responsive to a systemic treatment with platinum derivates in 80% of patients. This apparent chemosensitivity justifies a broader surgical approach. A cytoreductive, ”tumor-debulking” surgery is defined as an attempt to remove in a maximum degree all visible and detect­able lesions. Despite treatment, the advancement of the disease very often leads to complications defined as “surgical” and life-threatening. Objectives: The aim was to evaluate the efficacy and safety of palliative surgery in advanced ovarian cancer implicating acute surgical diseases of the abdominal cavity. Material and methods: Between years 2005 and 2014 were operated 118 patients with an advanced ovarian cancer (FIGO III-IV) implicating acute and directly life-threatening diseases of the abdominal cavity, involving 132 surgical operations. The causes of these operations were: obstruction of the gastrointestinal tract — 91 patients; perforation of the gastrointestinal tract — 15; gastrointestinal bleeding — 9; intussusceptions — 3. Results: Retrospective data for the 118 patients were analyzed. Safety and the perioperative mortality rate were assessed. Serious postoperative complications were recorded in 31 patients (anastomotic stoma — 9; bleeding requiring repeated surgery —3; recurring gastrointestinal obstruction — 16; liver failure after partial hepatic resection — 3). Systemic compli­cations in the form of respiratory failure and cardiovascular disorders requiring cardiological treatment — 21. All patients required clinical nutrition, both parenteral and enteral. Deaths recorded — 3. 39 patients were rehospitalized within 30 days of surgery. 7 deaths were recorded in this group. Conclusions: Combining lifesaving surgery with cytoreduction allows further adjuvant treatment. Early rehospitalization occurring within less than 30 days is linked to increased mortality.

Published
2016

26. Using our own developed stent in the palliative treatment of obstruction in the left half of the colon due to ovarian cancer

Author

Konrad Pasek, Krzysztof Cendrowski, Agnieszka Timorek, Włodzimierz Sawicki, Habib Alkalaya, Piotr Ciostek, and Tomasz Miłek

Subjects
medicine.medical_specialty, Decompression, medicine.medical_treatment, Self Expandable Metallic Stents, Rectum, Colonic Diseases, Stoma (medicine), Ovarian carcinoma, Medicine, Humans, cardiovascular diseases, Neoplasm Metastasis, Left half, Ovarian Neoplasms, Gastrointestinal tract, business.industry, Carcinoma, Palliative Care, Obstetrics and Gynecology, Stent, Colonoscopy, Equipment Design, equipment and supplies, medicine.disease, Surgery, Colon, Descending, surgical procedures, operative, medicine.anatomical_structure, Treatment Outcome, Female, Radiology, business, Ovarian cancer, Intestinal Obstruction
Abstract

Objectives: An assessment of implantation efficacy and safety of self-developed self-expanding stent in patients with an ovarian cancer induced by intestinal obstruction. Material and methods: The study of the stenting efficacy and safety was realized prospectively. The group consisted of 13 patients with left half colon obstruction due to an inoperable metastatic ovarian carcinoma. All the patients had a histopathologically diagnosed ovarian carcinoma and were treated in the past both surgically and systemically. Stenting was preceded by a Computed Tomography (CT) scan confirming and locating the obstruction. Patients with a multilevel intestinal obstruction were disqualified. Results: Nine stents were implanted in the rectosigmoid; 4 stents were implanted in an externally compressed rectum. One migration of implanted stent was observed. In one case 2 stents were implanted due to an insufficient coverage of the stricture. The decompression of the obstruction of the gastrointestinal tract was achieved in 11 patients (85%). Conclusions: 1) The implantation of our own developed, self-expanding stent is effective and safe. 2) The implantation of the stent in patients with an inoperable ovarian cancer causing an obstruction of the gastrointestinal tract is an effective procedure limiting postoperative complications and improving life comfort by avoiding stoma.

Published
2016

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

Subjects
endocrine system diseases, female genital diseases and pregnancy complications
Abstract

Background: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.\ud Methods: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.\ud Results: The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively).\ud Conclusions: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016

28. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study

Author

Liisa M. Pelttari, Joseph L. Kelley, Adriaan Vanderstichele, Jue-Sheng Ong, Jonathan Tyrer, Linda S. Cook, Sara H. Olson, Agnieszka Dansonka-Mieszkowska, Ellen L. Goode, Fiona Bruinsma, Roberta B. Ness, Daniel W. Cramer, Francesmary Modugno, Penelope M. Webb, C. Blake Gilks, Britton Trabert, Jacek Gronwald, Diana Eccles, Georgia Chenevix-Trench, Fanny Dao, Michelle A.T. Hildebrandt, Graham G. Giles, Gabriel Cuellar-Partida, Julie M. Cunningham, Puya Gharahkhani, Celeste Leigh Pearce, Usha Menon, Maria Bisogna, Estrid Høgdall, Shelley S. Tworoger, Allan Jensen, Alexander Hein, Matthias W. Beckmann, Anna Jakubowska, Paul D.P. Pharoah, Xifeng Wu, Valerie McGuire, Dong Liang, Robert P. Edwards, Joellen M. Schildkraut, Catherine M. Phelan, John R. McLaughlin, Arto Leminen, Heli Nevanlinna, Stacey A. Missmer, Brooke L. Fridley, Angela Brooks-Wilson, Ingo B. Runnebaum, Lambertus A. Kiemeney, Elizabeth M. Poole, Yi-chen Lu, Jolanta Lissowska, Jennifer A. Doherty, Ian G. Campbell, Susanne K. Kjaer, Mary Anne Rossing, Stuart MacGregor, Argyrios Ziogas, Thilo Dörk, Stefanie Burghaus, Douglas A. Levine, Claus Høgdall, Jolanta Kupryjanczyk, Kirsten B. Moysich, Nicolas Wentzensen, Katja K.H. Aben, Shan Wang-Gohrke, Katharina Bischof, Reidun K. Kopperud, Alice S. Whittemore, Hoda Anton-Culver, Ursula Eilber, Karen Lu, Elisa V. Bandera, Line Bjørge, Simon A. Gayther, Rikki Cannioto, Honglin Song, Els Van Nieuwenhuysen, Susan J. Ramus, Louise A. Brinton, Steven A. Narod, Meir J. Stampfer, Anja Rudolph, Ignace Vergote, Matthias Dürst, Andrew Berchuck, Peter Hillemanns, Rachel E. Neale, Aleksandra Gentry-Maharaj, Lukasz Szafron, Harvey A. Risch, Jenny Chang-Claude, Terry K. Morgan, Marc T. Goodman, Natalia Bogdanova, Helga B. Salvesen, Weiva Sieh, Ralf Bützow, Peter A. Fasching, Joseph H. Rothstein, Agnieszka Timorek, Nhu D. Le, Diether Lambrechts, Anna H. Wu, Natalia Antonenkova, Stacey J. Winham, Jan Lubinski, Kathryn L. Terry, Tomasz Kluz, and Leon F.A.G. Massuger

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Single-nucleotide polymorphism, Australian Ovarian Cancer Study, Carcinoma, Ovarian Epithelial, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Mendelian Randomization, Risk Factors, Internal medicine, Mendelian randomization, medicine, Vitamin D and neurology, Odds Ratio, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, Vitamin D, Ovarian Neoplasms, Cancer prevention, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], business.industry, Confounding, Statistics, Cancer, General Medicine, Odds ratio, Mendelian Randomization Analysis, medicine.disease, 3. Good health, 030104 developmental biology, Endocrinology, 030220 oncology & carcinogenesis, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Public Health and Health Services, Female, business, Ovarian cancer
Abstract

Contains fulltext : 171904.pdf (Publisher’s version ) (Closed access) BACKGROUND: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. METHODS: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). RESULTS: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). CONCLUSIONS: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

Published
2016

29. Recommendations of the Polish Gynecological Oncology Society for the diagnosis and treatment of ovarian cancer

Author

Basta, Antoni, primary, Bidziński, Mariusz, additional, Bieńkiewicz, Andrzej, additional, Blecharz, Paweł, additional, Bodnar, Lubomir, additional, Jach, Robert, additional, Knapp, Paweł, additional, Kojs, Zbigniew, additional, Kotarski, Jan, additional, Markowska, Janina, additional, Misiek, Marcin, additional, Sznurkowski, Jacek Jan, additional, Wicherek, Łukasz, additional, Sawicki, Włodzimierz, additional, Timorek-Lemieszczuk, Agnieszka, additional, Bahyrycz, Jan, additional, and Mądry, Radosław, additional

Published
2017
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32. Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Author

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

Subjects
Cancer Research, endocrine system diseases, Genome-wide association study, Carcinoma, Ovarian Epithelial, Risk Factors, Neoplasms, Ovarian Epithelial, 2.1 Biological and endogenous factors, Neoplasms, Glandular and Epithelial, Aetiology, skin and connective tissue diseases, Cancer, Genetics, Ovarian Neoplasms, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Glandular and Epithelial, General Medicine, Single Nucleotide, female genital diseases and pregnancy complications, Ovarian Cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Biotechnology, Australian Ovarian Cancer Study Group, Quantitative Trait Loci, Oncology and Carcinogenesis, Locus (genetics), Single-nucleotide polymorphism, Original Manuscript, Biology, Polymorphism, Single Nucleotide, Rare Diseases, Clinical Research, Australian Cancer Study, SNP, Humans, Genetic Predisposition to Disease, Genetic Testing, Oncology & Carcinogenesis, 1000 Genomes Project, Polymorphism, CHEK2, Genetic association, Prevention, Carcinoma, Human Genome, Checkpoint Kinase 2, Genetic Loci, Case-Control Studies, Cancer research, Imputation (genetics), Genome-Wide Association Study
Abstract

Contains fulltext : 152042.pdf (Publisher’s version ) (Closed access) 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

Published
2015

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

Author

Rosalind Glasspool, Lynne R. Wilkens, Camilla Krakstad, Diana Eccles, Liisa M. Pelttari, Thomas A. Sellers, Anja Rudolph, Estrid Høgdall, Yurii B. Shvetsov, Matthias W. Beckmann, Ignace Vergote, Angela Brooks-Wilson, Ingo B. Runnebaum, Joellen M. Schildkraut, Joe Dennis, Ingvild L. Tangen, Elizabeth M. Poole, Arif B. Ekici, Xiao-Ou Shu, Alice S. Whittemore, Valerie McGuire, Kunle Odunsi, Agnieszka Dansonka-Mieszkowska, Melissa C. Southey, Keitaro Matsuo, Anna Jakubowska, Paul D.P. Pharoah, Lambertus A. Kiemeney, Douglas T. Easton, Simon A. Gayther, Anna deFazio, Ian G. Campbell, Hanis Nazihah Hasmad, Shashi Lele, Maria Bisogna, Zhihua Chen, Usha Menon, Jenny Lester, Ursula Eilber, Iwona K. Rzepecka, Shan Wang-Gohrke, Steven A. Narod, Qiyuan Li, Dong Liang, Jonathan Tyrer, Kate Lawrenson, Hoda Anton-Culver, Alvaro N.A. Monteiro, Ed Dicks, Lene Lundvall, Sandra Orsulic, Brooke L. Fridley, Ellen L. Goode, Linda E. Kelemen, Edwin S. Iversen, Ya Yu Tsai, Mary Anne Rossing, Karen Carty, Thilo Dörk, Penelope M. Webb, Yukie Bean, Matthias Dürst, Soo Hwang Teo, Claus Høgdall, Robert P. Edwards, Alison M. Karst, Yu-Tang Gao, Harvey A. Risch, Patricia Harrington, Daniel W. Cramer, Ji-Heui Seo, Douglas A. Levine, Christine Walsh, Karen Lu, Elisa V. Bandera, Louise A. Brinton, Satoyo Hosono, Hannah P. Yang, Graham G. Giles, Robert A. Vierkant, Argyrios Ziogas, Honglin Song, Ian McNeish, Anne M. van Altena, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Kirsten B. Moysich, Philipp Harter, Joseph L. Kelley, Andrew Berchuck, Paul A. James, Peter Hillemanns, Susan J. Ramus, Jacek Grownwald, Celeste Leigh Pearce, Ronny Drapkin, Kristine G. Wicklund, Mat Adenan Noor Azmi, Lara Sucheston, Alexander Hein, Jolanta Kupryjanczyk, Ralf Bützow, Georgia Chenevix-Trench, Michelle A.T. Hildebrandt, Francesmary Modugno, John R. McLaughlin, Arto Leminen, Nicolas Wentzensen, Siddhartha Kar, Sara H. Olson, Susanne K. Kjaer, Barry P. Rosen, Andreas du Bois, Linda S. Cook, Jennifer A. Doherty, Joseph H. Rothstein, Aleksandra Gentry-Maharaj, Julie M. Cunningham, Leon F.A.G. Massuger, Irene Orlow, Rachel Palmieri Weber, Pamela J. Thompson, Tassja J. Spindler, Jenny Chang-Claude, Jennifer Permuth-Wey, Catherine M. Phelan, Yi-Bu Chen, Bu Tian Ji, Heli Nevanlinna, Roberta B. Ness, Shelley S. Tworoger, Allan Jensen, Anna H. Wu, Malcolm C. Pike, Fiona Bruinsma, Line Bjørge, Jolanta Lissowska, Natalia Antonenkova, Cezary Cybulski, Wei Zheng, Lotte Nedergaard, Els Van Nieuwenhuysen, Anne Chen, Janet M. Lee, David D.L. Bowtell, Helen Baker, Katja K.H. Aben, Xifeng Wu, Melissa Kellar, Weiva Sieh, Nhu D. Le, Marc T. Goodman, Matthew L. Freedman, Yin Ling Woo, Sandrina Lambrechts, Peter A. Fasching, Diether Lambrechts, Kathryn L. Terry, Ira Schwaab, Jan Lubinski, Natalia Bogdanova, Helga B. Salvesen, Alice W. Lee, Agnieszka Timorek, Nadeem Siddiqui, Department of Pathology, Medicum, Department of Obstetrics and Gynecology, Clinicum, and HUS Gynecology and Obstetrics

Subjects
EXPRESSION, Quantitative Trait Loci, General Physics and Astronomy, Locus (genetics), Genome-wide association study, Quantitative trait locus, Biology, Carcinoma, Ovarian Epithelial, VARIANTS, ANALYSES REVEAL, BREAST, General Biochemistry, Genetics and Molecular Biology, Article, Nuchal Cord, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Cell Line, Tumor, Genetic predisposition, SNP, Humans, Genetic Predisposition to Disease, Neoplasms, Glandular and Epithelial, GENOME-WIDE ASSOCIATION, Genetic Association Studies, 030304 developmental biology, Genetic association, Genetics, Homeodomain Proteins, Ovarian Neoplasms, 0303 health sciences, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, LONG-RANGE INTERACTION, IDENTIFICATION, General Chemistry, RISK LOCI, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, FALLOPIAN-TUBE, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Expression quantitative trait loci, Female, 3111 Biomedicine, HOX GENES, Protein Binding
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, Genome-wide association studies have identified regions which confer risk of high-grade serous epithelial ovarian cancer. Here the authors use expression quantitative train locus analysis to identify candidate genes and functionally characterise them, identifying a role for HOXD9 in ovarian cancer.

Published
2015

34. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

Author

C B Gilks, Anna H. Wu, Natalia Antonenkova, Weiva Sieh, Angela Brooks-Wilson, Liisa M. Pelttari, Ingo B. Runnebaum, Argyrios Ziogas, John R. McLaughlin, Arto Leminen, Jennifer A. Doherty, Aben Kkh., Jacek Gronwald, Diana Eccles, Kirsten B. Moysich, Jonathan Tyrer, Valerie McGuire, Julie M. Cunningham, Georgia Chenevix-Trench, Agnieszka Timorek, Penelope M. Webb, Estrid Høgdall, Shelley S. Tworoger, Allan Jensen, Stuart MacGregor, Line Bjørge, Matthias W. Beckmann, Joellen M. Schildkraut, Sara H. Olson, Adriaan Vanderstichele, Shan Wang-Gohrke, Jan Gawełko, Elizabeth M. Poole, Anja Rudolph, Francesmary Modugno, Marc T. Goodman, Usha Menon, Hoda Anton-Culver, Celeste Leigh Pearce, Kristine G. Wicklund, Hildebrandt Mat., Karen Lu, Elisa V. Bandera, Ignace Vergote, Peter A. Fasching, Susanne K. Kjaer, Honglin Song, Catherine M. Phelan, Pharoah Pdp., Simon A. Gayther, Fanny Dao, Maria Bisogna, Dong Liang, Massuger Lfag., Linda S. Cook, Steven A. Narod, Andrew Berchuck, Lukasz Szafron, Harvey A. Risch, Robert P. Edwards, Peter Hillemanns, Diether Lambrechts, Matthias Dürst, Stacey J. Winham, Rikki Cannioto, Alice S. Whittemore, Stacey A. Missmer, Jan Lubinski, Jolanta Kupryjanczyk, Susan J. Ramus, Jodie N. Painter, Nicolas Wentzensen, Brooke L. Fridley, Katharina Bischof, Agnieszka Dansonka-Mieszkowska, Mary Anne Rossing, Thilo Dörk, Natalia Bogdanova, Reidun K. Kopperud, Helga B. Salvesen, Nhu D. Le, Yi Lu, Britton Trabert, Terry K. Morgan, Stefanie Burghaus, Douglas A. Levine, Graham G. Giles, Kathryn L. Terry, Roberta B. Ness, Anna Jakubowska, Dale R. Nyholt, E Van Nieuwenhuysen, Gabriel Cuellar-Partida, Lambertus A. Kiemeney, Fiona Bruinsma, Ralf Bützow, Louise A. Brinton, Grant W. Montgomery, Alexander Hein, Xifeng Wu, Daniel W. Cramer, Joseph H. Rothstein, Andrew P. Morris, Joseph L. Kelley, Heli Nevanlinna, Jolanta Lissowska, Ellen L. Goode, Krina T. Zondervan, Ursula Eilber, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Lu, Yi, Cuellar-Partida, Gabriel, Painter, Jodie N, Nyholt, Dale R, MacGregor, Stuart, Lee, Sang Hong, Australian Ovarian Cancer Study, and International Endogene Consortium (IEC)

Subjects
endometriosis, Oncology, Risk, medicine.medical_specialty, endocrine system diseases, genetic association studies, Serous carcinoma, Endometriosis, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Medizinische Fakultät, Internal medicine, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, ddc:610, Molecular Biology, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, Genetic association, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, 0303 health sciences, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Association Studies Articles, General Medicine, ovarian neoplasms, medicine.disease, 3. Good health, Serous fluid, ovarian cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Clear cell carcinoma, Female, Ovarian cancer, genetic predisposition
Abstract

Contains fulltext : 153959.pdf (Publisher’s version ) (Closed access) Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.

Published
2015

36. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

Author

Cuellar-Partida, G., Lu, Y., Dixon, S.C., Fasching, P.A., Hein, A., Burghaus, S., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Vanderstichele, A., Doherty, J.A., Rossing, M.A., Chang-Claude, J., Rudolph, A., Wang-Gohrke, S., Goodman, M.T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Hogdall, C., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A.T., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Stampfer, M., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Gilks, C. Blake, Gronwald, J., Jakubowska, A., Lubinski, J., Kluz, T., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Campbell, I., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., Morgan, T.K., Goode, E.L., Cuellar-Partida, G., Lu, Y., Dixon, S.C., Fasching, P.A., Hein, A., Burghaus, S., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Vanderstichele, A., Doherty, J.A., Rossing, M.A., Chang-Claude, J., Rudolph, A., Wang-Gohrke, S., Goodman, M.T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Hogdall, C., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A.T., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Stampfer, M., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Gilks, C. Blake, Gronwald, J., Jakubowska, A., Lubinski, J., Kluz, T., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Campbell, I., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., Morgan, T.K., and Goode, E.L.

Abstract

Contains fulltext : 171782.pdf (publisher's version ) (Closed access), Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 +/- 1.1 %), endometrioid ([Formula: see text] = 3.2 +/- 1.6 %), clear cell ([Formula: see text] = 6.7 +/- 3.3 %) and all EOC ([Formula: see text] = 5.6 +/- 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

Published
2016

37. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study

Author

Ong, J.S., Cuellar-Partida, G., Lu, Y., Fasching, P.A., Hein, A., Burghaus, S., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Vanderstichele, A., Doherty, J., Rossing, M. Anne, Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M.T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Hogdall, C.K., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A.T., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Stampfer, M., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Gilks, C.B., Gronwald, J., Jakubowska, A., Lubinski, J., Kluz, T., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Campbell, I., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., Morgan, T.K., Ong, J.S., Cuellar-Partida, G., Lu, Y., Fasching, P.A., Hein, A., Burghaus, S., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Vanderstichele, A., Doherty, J., Rossing, M. Anne, Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M.T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Hogdall, C.K., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A.T., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Stampfer, M., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Gilks, C.B., Gronwald, J., Jakubowska, A., Lubinski, J., Kluz, T., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Campbell, I., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., and Morgan, T.K.

Abstract

Contains fulltext : 171904.pdf (publisher's version ) (Closed access), BACKGROUND: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. METHODS: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). RESULTS: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). CONCLUSIONS: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

Published
2016

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

Author

Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Doerk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, C-C, Friel, G, Davis, W, Nesline, M, Pearce, CL, Kelemen, LE, Goodman, MT, Bandera, EV, Terry, KL, Schoof, N, Eng, KH, Clay, A, Singh, PK, Joseph, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Despierre, E, Dicks, E, Doherty, JA, du Bois, A, Duerst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hogdall, C, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Klapdor, R, Kolomeyevskaya, N, Krakstad, C, Kjaer, SK, Kruszka, B, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Liu, S, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Moes-Sosnowska, J, Narod, SA, Nedergaard, L, Nevanlinna, H, Nickels, S, Olson, SH, Orlow, I, Weber, RP, Paul, J, Pejovic, T, Pelttari, LM, Perkins, B, Permuth-Wey, J, Pike, MC, Plisiecka-Halasa, J, Poole, EM, Risch, HA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schmitt, K, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Tangen, IL, Teo, S-H, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Tyrer, J, van Altena, AM, Vergote, I, Vierkant, RA, Walsh, C, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Gayther, SA, Ramus, SJ, Sellers, TA, Schildkraut, JM, Phelan, CM, Berchuck, A, Chenevix-Trench, G, Cunningham, JM, Pharoah, PP, Ness, RB, Odunsi, K, Goode, EL, Moysich, KB, Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Doerk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, C-C, Friel, G, Davis, W, Nesline, M, Pearce, CL, Kelemen, LE, Goodman, MT, Bandera, EV, Terry, KL, Schoof, N, Eng, KH, Clay, A, Singh, PK, Joseph, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Despierre, E, Dicks, E, Doherty, JA, du Bois, A, Duerst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hogdall, C, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Klapdor, R, Kolomeyevskaya, N, Krakstad, C, Kjaer, SK, Kruszka, B, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Liu, S, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Moes-Sosnowska, J, Narod, SA, Nedergaard, L, Nevanlinna, H, Nickels, S, Olson, SH, Orlow, I, Weber, RP, Paul, J, Pejovic, T, Pelttari, LM, Perkins, B, Permuth-Wey, J, Pike, MC, Plisiecka-Halasa, J, Poole, EM, Risch, HA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schmitt, K, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Tangen, IL, Teo, S-H, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Tyrer, J, van Altena, AM, Vergote, I, Vierkant, RA, Walsh, C, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Gayther, SA, Ramus, SJ, Sellers, TA, Schildkraut, JM, Phelan, CM, Berchuck, A, Chenevix-Trench, G, Cunningham, JM, Pharoah, PP, Ness, RB, Odunsi, K, Goode, EL, and Moysich, KB

Abstract

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016

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

Abstract

BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively).CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.

Published
2016

40. Association of vitamin D levels and risk of ovarian cancer:a Mendelian randomization study

Author

Ong, Jue-Sheng, Cuellar-Partida, Gabriel, Lu, Yi, Ovarian Cancer Study, Australian, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Anne Doherty, Jennifer, Anne Rossing, Mary, Chang-Claude, Jenny, Eilber, Ursula, Rudolph, Anja, Wang-Gohrke, Shan, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Høgdall, Estrid, Høgdall, Claus K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Kjaer, Susanne K, Hildebrandt, Michelle At, Liang, Dong, Lu, Karen H, Wu, Xifeng, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Missmer, Stacey, Bjorge, Line, Salvesen, Helga B, Kopperud, Reidun K, Bischof, Katharina, Aben, Katja Kh, Kiemeney, Lambertus A, Massuger, Leon Fag, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Blake Gilks, C, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Song, Honglin, Tyrer, Jonathan P, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, Lissowska, Jolanta, McLaughlin, John R, Narod, Steven A, Phelan, Catherine, Anton-Culver, Hoda, Ziogas, Argyrios, Eccles, Diana, Campbell, Ian, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Wu, Anna H, Dansonka-Mieszkowska, Agnieszka, Kupryjanczyk, Jolanta, Timorek, Agnieszka, Szafron, Lukasz, Cunningham, Julie M, Fridley, Brooke L, Winham, Stacey J, Bandera, Elisa V, Poole, Elizabeth M, Morgan, Terry K, Risch, Harvey A, Goode, Ellen L, Schildkraut, Joellen M, Pearce, Celeste L, Berchuck, Andrew, Pharoah, Paul Dp, Chenevix-Trench, Georgia, Gharahkhani, Puya, Neale, Rachel E, Webb, Penelope M, MacGregor, Stuart, Ong, Jue-Sheng, Cuellar-Partida, Gabriel, Lu, Yi, Ovarian Cancer Study, Australian, Fasching, Peter A, Hein, Alexander, Burghaus, Stefanie, Beckmann, Matthias W, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Vanderstichele, Adriaan, Anne Doherty, Jennifer, Anne Rossing, Mary, Chang-Claude, Jenny, Eilber, Ursula, Rudolph, Anja, Wang-Gohrke, Shan, Goodman, Marc T, Bogdanova, Natalia, Dörk, Thilo, Dürst, Matthias, Hillemanns, Peter, Runnebaum, Ingo B, Antonenkova, Natalia, Butzow, Ralf, Leminen, Arto, Nevanlinna, Heli, Pelttari, Liisa M, Edwards, Robert P, Kelley, Joseph L, Modugno, Francesmary, Moysich, Kirsten B, Ness, Roberta B, Cannioto, Rikki, Høgdall, Estrid, Høgdall, Claus K, Jensen, Allan, Giles, Graham G, Bruinsma, Fiona, Kjaer, Susanne K, Hildebrandt, Michelle At, Liang, Dong, Lu, Karen H, Wu, Xifeng, Bisogna, Maria, Dao, Fanny, Levine, Douglas A, Cramer, Daniel W, Terry, Kathryn L, Tworoger, Shelley S, Stampfer, Meir, Missmer, Stacey, Bjorge, Line, Salvesen, Helga B, Kopperud, Reidun K, Bischof, Katharina, Aben, Katja Kh, Kiemeney, Lambertus A, Massuger, Leon Fag, Brooks-Wilson, Angela, Olson, Sara H, McGuire, Valerie, Rothstein, Joseph H, Sieh, Weiva, Whittemore, Alice S, Cook, Linda S, Le, Nhu D, Blake Gilks, C, Gronwald, Jacek, Jakubowska, Anna, Lubiński, Jan, Kluz, Tomasz, Song, Honglin, Tyrer, Jonathan P, Wentzensen, Nicolas, Brinton, Louise, Trabert, Britton, Lissowska, Jolanta, McLaughlin, John R, Narod, Steven A, Phelan, Catherine, Anton-Culver, Hoda, Ziogas, Argyrios, Eccles, Diana, Campbell, Ian, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Menon, Usha, Ramus, Susan J, Wu, Anna H, Dansonka-Mieszkowska, Agnieszka, Kupryjanczyk, Jolanta, Timorek, Agnieszka, Szafron, Lukasz, Cunningham, Julie M, Fridley, Brooke L, Winham, Stacey J, Bandera, Elisa V, Poole, Elizabeth M, Morgan, Terry K, Risch, Harvey A, Goode, Ellen L, Schildkraut, Joellen M, Pearce, Celeste L, Berchuck, Andrew, Pharoah, Paul Dp, Chenevix-Trench, Georgia, Gharahkhani, Puya, Neale, Rachel E, Webb, Penelope M, and MacGregor, Stuart

Abstract

BACKGROUND: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.METHODS: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).RESULTS: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).CONCLUSIONS: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.

Published
2016

41. TP53 status determines clinical significance of ERBB2 expression in ovarian cancer

Author

I Ziółkowska, J Emerich, Agnieszka Timorek, Jerzy Stelmachów, K Urbański, Radoslaw Madry, J Bar, Ewa Kraszewska, Marcin Jędryka, Janina Markowska, A. Pluzanska, Jolanta Kupryjanczyk, J Zieliński, I Rzepka-Górska, and Joanna Plisiecka-Halasa

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, Organoplatinum Compounds, endocrine system diseases, Receptor, ErbB-2, medicine.medical_treatment, Biology, Epitopes, Trastuzumab, Internal medicine, Ovarian carcinoma, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Clinical significance, TP53, Stage (cooking), ERBB2, skin and connective tissue diseases, neoplasms, Aged, Neoplasm Staging, Ovarian Neoplasms, Chemotherapy, Molecular and Cellular Pathology, Antibodies, Monoclonal, Middle Aged, Prognosis, medicine.disease, Gene Expression Regulation, Neoplastic, ovarian cancer, Drug Resistance, Neoplasm, Monoclonal, Cancer research, Immunohistochemistry, Female, Tumor Suppressor Protein p53, Ovarian cancer, medicine.drug
Abstract

ERBB2 expression has been found in 19 to 44% of ovarian carcinomas; however, its predictive value has not been demonstrated, and trastuzumab has not found clinical application in ovarian cancer patients. We evaluated clinical significance of ERBB2 expression in relation to TP53 accumulation in ovarian carcinoma patients treated with platinum-based regimens. Immunohistochemical analysis with CB11 and a novel NCL-CBE356 antibody (against the internal and external domains of ERBB2, respectively) was performed on 233 tumours (FIGO stage IIB-IV); the US Food and Drug Administration-approved grading system with 0 to 3+ scale was used for evaluation, and the results were analysed by the Cox and logistic regression models. In all, 42% of the tumours expressed (category 1+, 2+ or 3+) either CB11 or CBE356 or both (CB11/CBE356 parameter). Associations between ERBB2 expression and clinical factors were observed only if tumours with staining category 1+ were grouped together with tumours showing staining categories 2+ and 3+. CB11/CBE356 parameter had a better predictive value than CB11 alone. CB11/CBE356 expression was negatively associated with platinum sensitivity (PS) in the TP53(-) group (P=0.022) and with disease-free survival (DFS) in the TP53(+) group (P=0.009). Our results may suggest that trastuzumab should be given postoperatively to patients with TP53(-)/ERBB2(+) ovarian carcinomas to enhance PS, and after completion of chemotherapy to patients with complete remission and TP53(+)/ERBB2(+) carcinomas to extend DFS time (in total to 30.4% of all patients analysed). Thus, novel criteria for ovarian cancer patient inclusion for clinical trials with trastuzumab should be considered and tested.

Published
2004

42. Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen

Author

G Karpińska, A. Pluzanska, Janina Markowska, T Szymańska, Agnieszka Timorek, Marcin Jędryka, M. Goluda, Ewa Kraszewska, K Urbański, I Rzepka-Górska, J Emerich, Jerzy Stelmachów, I Ziółkowska, J. Dębniak, Alina Rembiszewska, J Bręborowicz, J Zieliński, Jolanta Kupryjanczyk, M. Klimek, R. Mądry, M. Ulanska, and Anita Chudecka-Głaz

Subjects
Cancer Research, endocrine system diseases, medicine.medical_treatment, MAP Kinase Kinase 1, Antineoplastic Combined Chemotherapy Protocols, TP53, bcl-2-Associated X Protein, Ovarian Neoplasms, Middle Aged, Prognosis, Immunohistochemistry, MEK, female genital diseases and pregnancy complications, Gene Expression Regulation, Neoplastic, ovarian cancer, Treatment Outcome, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Oncology, Predictive value of tests, Regression Analysis, Female, medicine.drug, Adult, BCL-2, Ovary, Protein Serine-Threonine Kinases, Biology, Disease-Free Survival, Bcl-2-associated X protein, Predictive Value of Tests, Proto-Oncogene Proteins, Biomarkers, Tumor, Carcinoma, medicine, Humans, Clinical significance, neoplasms, Aged, Neoplasm Staging, Mitogen-Activated Protein Kinase Kinases, Cisplatin, Chemotherapy, Molecular and Cellular Pathology, medicine.disease, BAX, biology.protein, Cancer research, Tumor Suppressor Protein p53, Ovarian cancer
Abstract

In cell line studies, BCL-2, BAX, as well as novel MEK1 protein levels have strong influence on ovarian cancer response to cisplatin-based chemotherapy. However, such associations have not been demonstrated clinically. We evaluated prognostic/predictive significance of these proteins with regard to TP53 status. Immunohistochemical analysis was performed on 229 ovarian carcinomas FIGO stage IIB-IV treated with platinum-based chemotherapy; the results were analysed by the Cox and logistic regression models. Clinical parameters (residual tumour size, patient age, FIGO stage) were the only indicators of overall survival (OS) and the strongest predictors of complete remission (CR). On the other hand, BAX expression was the strongest (P=0.005) or the only (in FIGO IIIC, P=0.02) prognostic indicator of disease-free survival (DFS) in the TP53(+) group. TP53(+) and TP53(-) ovarian carcinomas differed in clinical and molecular prognostic and predictive factors. Another novel finding is that CR was negatively influenced by high BAX expression in all patients group (P=0.047) and by BCL2 expression in the TP53(-) group (P=0.05). High MEK1 expression was associated with endometrioid and clear cell carcinomas (P=0.049); its loss was found with advancing FIGO stage (P=0.002). Our results suggest that binomial TP53 status divides ovarian carcinomas into two biologically distinct groups. BAX expression is an important factor of DFS in the TP53(+) group. BCL-2 and BAX, but not MEK1 expressions have predictive value in ovarian cancer patients treated with platinum-based chemotherapy.

Published
2003

43. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

Author

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

Subjects
Purine, Folate, Genome-wide association study, Global Health, chemistry.chemical_compound, 0302 clinical medicine, Polymorphism (computer science), Risk Factors, AOCS Study Group/ACS Investigators, 2.1 Biological and endogenous factors, Aetiology, Purine metabolism, Cancer, Genetics, Ovarian Neoplasms, 0303 health sciences, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Nutrition and Dietetics, Single Nucleotide, Case-control, Neoplasm Proteins, Ovarian Cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, Pyrimidine metabolism, Public Health and Health Services, Female, Dihydropyrimidine dehydrogenase, Biotechnology, medicine.medical_specialty, European Continental Ancestry Group, Biology, Folic Acid Deficiency, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Folic Acid, Rare Diseases, Food Sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, Dihydrouracil Dehydrogenase (NADP), 030304 developmental biology, Nutrition, Nutrition & Dietetics, Carcinoma, Case-control study, Diet, Endocrinology, chemistry, Case-Control Studies, Multivariate Analysis, Dietary Supplements, DPYD, Serine hydroxymethyltransferase 1, Energy Intake, Genome-Wide Association Study, Food Science
Abstract

Contains fulltext : 137688.pdf (Publisher’s version ) (Closed access) SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 x 10(-5)) and rs828054 (OR = 1.06; p = 1 x 10(-4)). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 x 10(-6)) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (p(interaction) = 0.03-0.006). CONCLUSION: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Published
2014

44. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

Author

Kelemen, LE, Terry, KL, Goodman, MT, Webb, PM, Bandera, EV, McGuire, V, Anne Rossing, M, Wang, Q, Dicks, E, Tyrer, JP, Song, H, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Timorek, A, Menon, U, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Narod, SA, Risch, HA, McLaughlin, JR, Siddiqui, N, Glasspool, R, Paul, J, Carty, K, Gronwald, J, Lubiński, J, Jakubowska, A, Cybulski, C, Kiemeney, LA, Massuger, LFAG, van Altena, AM, Aben, KKH, Olson, SH, Orlow, I, Cramer, DW, Levine, DA, Bisogna, M, Giles, GG, Southey, MC, Bruinsma, F, Kjær, SK, Høgdall, E, Jensen, A, Høgdall, CK, Lundvall, L, Engelholm, SA, Heitz, F, du Bois, A, Harter, P, Schwaab, I, Butzow, R, Nevanlinna, H, Pelttari, LM, Leminen, A, Thompson, PJ, Lurie, G, Wilkens, LR, Lambrechts, D, Van Nieuwenhuysen, E, Lambrechts, S, Vergote, I, Beesley, J, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Doherty, JA, Wu, AH, Pearce, CL, Pike, MC, Stram, D, Chang-Claude, J, Rudolph, A, Dörk, T, Dürst, M, Hillemanns, P, Runnebaum, IB, and Bogdanova, N

Subjects
Folate, Serine hydroxymethyltransferase 1 (soluble), Case-control, Polymorphism, Dihydropyrimidine dehydrogenase
Abstract

© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Scope: We reevaluated previously reported associations between variants in pathways of onecarbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. Methods and results: Odds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10-5) and rs828054 (OR = 1.06; p = 1 × 10-4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10-6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction= 0.03-0.006). Conclusion: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Published
2014

47. The significance of c.690G>T polymorphism (rs34529039) and expression of the CEBPA gene in ovarian cancer outcome

Author

Konopka, Bozena, primary, Szafron, Lukasz Michal, additional, Kwiatkowska, Ewa, additional, Podgorska, Agnieszka, additional, Zolocinska, Aleksandra, additional, Pienkowska-Grela, Barbara, additional, Dansonka-Mieszkowska, Agnieszka, additional, Balcerak, Anna, additional, Lukasik, Martyna, additional, Stachurska, Anna, additional, Timorek, Agnieszka, additional, Spiewankiewicz, Beata, additional, El-Bahrawy, Mona, additional, and Kupryjanczyk, Jolanta, additional

Published
2016
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48. Shared genetics underlying epidemiological association between endometriosis and ovarian cancer

Author

Lu, Y., Cuellar-Partida, G., Painter, J.N., Nyholt, D.R., Morris, A.P., Fasching, P.A., Hein, A., Burghaus, S., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Vanderstichele, A., Doherty, J.A., Rossing, M.A., Wicklund, K.G., Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M.T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Gilks, C.B., Gronwald, J., Jakubowska, A., Lubinski, J., Gawelko, J., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., Morgan, T.K., et al., Lu, Y., Cuellar-Partida, G., Painter, J.N., Nyholt, D.R., Morris, A.P., Fasching, P.A., Hein, A., Burghaus, S., Beckmann, M.W., Lambrechts, D., Nieuwenhuysen, E. Van, Vergote, I., Vanderstichele, A., Doherty, J.A., Rossing, M.A., Wicklund, K.G., Chang-Claude, J., Eilber, U., Rudolph, A., Wang-Gohrke, S., Goodman, M.T., Bogdanova, N., Dork, T., Durst, M., Hillemanns, P., Runnebaum, I.B., Antonenkova, N., Butzow, R., Leminen, A., Nevanlinna, H., Pelttari, L.M., Edwards, R.P., Kelley, J.L., Modugno, F., Moysich, K.B., Ness, R.B., Cannioto, R., Hogdall, E., Jensen, A., Giles, G.G., Bruinsma, F., Kjaer, S.K., Hildebrandt, M.A., Liang, D., Lu, K.H., Wu, X., Bisogna, M., Dao, F., Levine, D.A., Cramer, D.W, Terry, K.L., Tworoger, S.S., Missmer, S., Bjorge, L., Salvesen, H.B., Kopperud, R.K., Bischof, K., Aben, K.K.H., Kiemeney, L.A.L.M., Massuger, L.F.A.G., Brooks-Wilson, A., Olson, S.H., McGuire, V., Rothstein, J.H., Sieh, W., Whittemore, A.S., Cook, L.S., Le, N.D., Gilks, C.B., Gronwald, J., Jakubowska, A., Lubinski, J., Gawelko, J., Song, H., Tyrer, J.P., Wentzensen, N., Brinton, L., Trabert, B., Lissowska, J., McLaughlin, J.R., Narod, S.A., Phelan, C., Anton-Culver, H., Ziogas, A., Eccles, D., Gayther, S.A., Gentry-Maharaj, A., Menon, U., Ramus, S.J., Wu, A.H., Dansonka-Mieszkowska, A., Kupryjanczyk, J., Timorek, A., Szafron, L., Cunningham, J.M., Fridley, B.L., Winham, S.J., Bandera, E.V., Poole, E.M., Morgan, T.K., and et al.

Abstract

Contains fulltext : 153959.pdf (publisher's version ) (Closed access), Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.

Published
2015

49. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Author

Kuchenbaecker, Karoline B., Ramus, Susan J., Tyrer, Jonathan, Lee, Andrew, Shen, Howard C., Beesley, Jonathan, Lawrenson, Kate, McGuffog, Lesley, Healey, Sue, Lee, Janet M., Spindler, Tassja J., Lin, Yvonne G., Pejovic, Tanja, Bean, Yukie, Li, Qiyuan, Coetzee, Simon, Hazelett, Dennis, Miron, Alexander, Southey, Melissa, Terry, Mary Beth, Goldgar, David E., Buys, Saundra S., Janavicius, Ramunas, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Neuhausen, Susan L., Ding, Yuan Chun, Hansen, Thomas V. O., Jonson, Lars, Gerdes, Anne-Marie, Ejlertsen, Bent, Barrowdale, Daniel, Dennis, Joe, Benitez, Javier, Osorio, Ana, Garcia, Maria Jose, Komenaka, Ian, Weitzel, Jeffrey N., Ganschow, Pamela, Peterlongo, Paolo, Bernard, Loris, Viel, Alessandra, Bonanni, Bernardo, Peissel, Bernard, Manoukian, Siranoush, Radice, Paolo, Papi, Laura, Ottini, Laura, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Frost, Debra, Perkins, Jo, Platte, Radka, Ellis, Steve, Godwin, Andrew K., Schmutzler, Rita Katharina, Meindl, Alfons, Engel, Christoph, Sutter, Christian, Sinilnikova, Olga M., Damiola, Francesca, Mazoyer, Sylvie, Stoppa-Lyonnet, Dominique, Claes, Kathleen, De Leeneer, Kim, Kirk, Judy, Rodriguez, Gustavo C., Piedmonte, Marion, O'Malley, David M., de la Hoya, Miguel, Caldes, Trinidad, Aittomaeki, Kristiina, Nevanlinna, Heli, Collee, J. Margriet, Rookus, Matti A., Oosterwijk, Jan C., Tihomirova, Laima, Tung, Nadine, Hamann, Ute, Isaccs, Claudine, Tischkowitz, Marc, Imyanitov, Evgeny N., Caligo, Maria A., Campbell, Ian G., Hogervorst, Frans B. L., Olah, Edith, Diez, Orland, Blanco, Ignacio, Brunet, Joan, Lazaroso, Conxi, Angel Pujana, Miguel, Jakubowska, Anna, Gronwald, Jacek, Lubinski, Jan, Sukiennicki, Grzegorz, Barkardottir, Rosa B., Plante, Marie, Simard, Jacques, Soucy, Penny, Montagna, Marco, Tognazzo, Silvia, Teixeira, Manuel R., Pankratz, Vernon S., Wang, Xianshu, Lindor, Noralane, Szabo, Csilla I., Kauff, Noah, Vijai, Joseph, Aghajanian, Carol A., Pfeiler, Georg, Berger, Andreas, Singer, Christian F., Tea, Muy-Kheng, Phelan, Catherine M., Greene, Mark H., Mai, Phuong L., Rennert, Gad, Mulligan, Anna Marie, Tchatchou, Sandrine, Andrulis, Irene L., Glendon, Gord, Toland, Amanda Ewart, Jensen, Uffe Birk, Kruse, Torben A., Thomassen, Mads, Bojesen, Anders, Zidan, Jamal, Friedman, Eitan, Laitman, Yael, Soller, Maria, Liljegren, Annelie, Arver, Brita, Einbeigi, Zakaria, Stenmark-Askmalm, Marie, Olopade, Olufunmilayo I., Nussbaum, Robert L., Rebbeck, Timothy R., Nathanson, Katherine L., Domchek, Susan M., Lu, Karen H., Karlan, Beth Y., Walsh, Christine, Lester, Jenny, Hein, Alexander, Ekici, Arif B., Beckmann, Matthias W., Fasching, Peter A., Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambrechts, Sandrina, Dicks, Ed, Doherty, Jennifer A., Wicklund, Kristine G., Rossing, Mary Anne, Rudolph, Anja, Chang-Claude, Jenny, Wang-Gohrke, Shan, Eilber, Ursula, Moysich, Kirsten B., Odunsi, Kunle, Sucheston, Lara, Lele, Shashi, Wilkens, Lynne R., Goodman, Marc T., Thompson, Pamela J., Shvetsov, Yurii B., Runnebaum, Ingo B., Duerst, Matthias, Hillemanns, Peter, Doerk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Leminen, Arto, Pelttari, Liisa M., Butzow, Ralf, Modugno, Francesmary, Kelley, Joseph L., Edwards, Robert P., Ness, Roberta B., du Bois, Andreas, Heitz, Florian, Schwaab, Ira, Harter, Philipp, Matsuo, Keitaro, Hosono, Satoyo, Orsulic, Sandra, Jensen, Allan, Kjaer, Susanne Kruger, Hogdall, Estrid, Hasmad, Hanis Nazihah, Azmi, Mat Adenan Noor, Teo, Soo-Hwang, Woo, Yin-Ling, Fridley, Brooke L., Goode, Ellen L., Cunningham, Julie M., Vierkant, Robert A., Bruinsma, Fiona, Giles, Graham G., Liang, Dong, Hildebrandt, Michelle A. T., Wu, Xifeng, Levine, Douglas A., Bisogna, Maria, Berchuck, Andrew, Iversen, Edwin S., Schildkraut, Joellen M., Concannon, Patrick, Weber, Rachel Palmieri, Cramer, Daniel W., Terry, Kathryn L., Poole, Elizabeth M., Tworoger, Shelley S., Bandera, Elisa V., Orlow, Irene, Olson, Sara H., Krakstad, Camilla, Salvesen, Helga B., Tangen, Ingvild L., Bjorge, Line, van Altena, Anne M., Aben, Katja K. H., Kiemeney, Lambertus A., Massuger, Leon F. A. G., Kellar, Melissa, Brooks-Wilson, Angela, Kelemen, Linda E., Cook, Linda S., Le, Nhu D., Cybulski, Cezary, Yang, Hannah, Lissowska, Jolanta, Brinton, Louise A., Wentzensen, Nicolas, Hogdall, Claus, Lundvall, Lene, Nedergaard, Lotte, Baker, Helen, Song, Honglin, Eccles, Diana, McNeish, Ian, Paul, James, Carty, Karen, Siddiqui, Nadeem, Glasspool, Rosalind, Whittemore, Alice S., Rothstein, Joseph H., McGuire, Valerie, Sieh, Weiva, Ji, Bu-Tian, Zheng, Wei, Shu, Xiao-Ou, Gao, Yu-Tang, Rosen, Barry, Risch, Harvey A., McLaughlin, John R., Narod, Steven A., Monteiro, Alvaro N., Chen, Ann, Lin, Hui-Yi, Permuth-Wey, Jenny, Sellers, Thomas A., Tsai, Ya-Yu, Chen, Zhihua, Ziogas, Argyrios, Anton-Culver, Hoda, Gentry-Maharaj, Aleksandra, Menon, Usha, Harrington, Patricia, Lee, Alice W., Wu, Anna H., Pearce, Celeste L., Coetzee, Gerry, Pike, Malcolm C., Dansonka-Mieszkowska, Agnieszka, Timorek, Agnieszka, Rzepecka, Iwona K., Kupryjanczyk, Jolanta, Freedman, Matt, Noushmehr, Houtan, Easton, Douglas F., Offit, Kenneth, Couch, Fergus J., Gayther, Simon, Pharoah, Paul P., Antoniou, Antonis C., Chenevix-Trench, Georgia, Kuchenbaecker, Karoline B., Ramus, Susan J., Tyrer, Jonathan, Lee, Andrew, Shen, Howard C., Beesley, Jonathan, Lawrenson, Kate, McGuffog, Lesley, Healey, Sue, Lee, Janet M., Spindler, Tassja J., Lin, Yvonne G., Pejovic, Tanja, Bean, Yukie, Li, Qiyuan, Coetzee, Simon, Hazelett, Dennis, Miron, Alexander, Southey, Melissa, Terry, Mary Beth, Goldgar, David E., Buys, Saundra S., Janavicius, Ramunas, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Neuhausen, Susan L., Ding, Yuan Chun, Hansen, Thomas V. O., Jonson, Lars, Gerdes, Anne-Marie, Ejlertsen, Bent, Barrowdale, Daniel, Dennis, Joe, Benitez, Javier, Osorio, Ana, Garcia, Maria Jose, Komenaka, Ian, Weitzel, Jeffrey N., Ganschow, Pamela, Peterlongo, Paolo, Bernard, Loris, Viel, Alessandra, Bonanni, Bernardo, Peissel, Bernard, Manoukian, Siranoush, Radice, Paolo, Papi, Laura, Ottini, Laura, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Frost, Debra, Perkins, Jo, Platte, Radka, Ellis, Steve, Godwin, Andrew K., Schmutzler, Rita Katharina, Meindl, Alfons, Engel, Christoph, Sutter, Christian, Sinilnikova, Olga M., Damiola, Francesca, Mazoyer, Sylvie, Stoppa-Lyonnet, Dominique, Claes, Kathleen, De Leeneer, Kim, Kirk, Judy, Rodriguez, Gustavo C., Piedmonte, Marion, O'Malley, David M., de la Hoya, Miguel, Caldes, Trinidad, Aittomaeki, Kristiina, Nevanlinna, Heli, Collee, J. Margriet, Rookus, Matti A., Oosterwijk, Jan C., Tihomirova, Laima, Tung, Nadine, Hamann, Ute, Isaccs, Claudine, Tischkowitz, Marc, Imyanitov, Evgeny N., Caligo, Maria A., Campbell, Ian G., Hogervorst, Frans B. L., Olah, Edith, Diez, Orland, Blanco, Ignacio, Brunet, Joan, Lazaroso, Conxi, Angel Pujana, Miguel, Jakubowska, Anna, Gronwald, Jacek, Lubinski, Jan, Sukiennicki, Grzegorz, Barkardottir, Rosa B., Plante, Marie, Simard, Jacques, Soucy, Penny, Montagna, Marco, Tognazzo, Silvia, Teixeira, Manuel R., Pankratz, Vernon S., Wang, Xianshu, Lindor, Noralane, Szabo, Csilla I., Kauff, Noah, Vijai, Joseph, Aghajanian, Carol A., Pfeiler, Georg, Berger, Andreas, Singer, Christian F., Tea, Muy-Kheng, Phelan, Catherine M., Greene, Mark H., Mai, Phuong L., Rennert, Gad, Mulligan, Anna Marie, Tchatchou, Sandrine, Andrulis, Irene L., Glendon, Gord, Toland, Amanda Ewart, Jensen, Uffe Birk, Kruse, Torben A., Thomassen, Mads, Bojesen, Anders, Zidan, Jamal, Friedman, Eitan, Laitman, Yael, Soller, Maria, Liljegren, Annelie, Arver, Brita, Einbeigi, Zakaria, Stenmark-Askmalm, Marie, Olopade, Olufunmilayo I., Nussbaum, Robert L., Rebbeck, Timothy R., Nathanson, Katherine L., Domchek, Susan M., Lu, Karen H., Karlan, Beth Y., Walsh, Christine, Lester, Jenny, Hein, Alexander, Ekici, Arif B., Beckmann, Matthias W., Fasching, Peter A., Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambrechts, Sandrina, Dicks, Ed, Doherty, Jennifer A., Wicklund, Kristine G., Rossing, Mary Anne, Rudolph, Anja, Chang-Claude, Jenny, Wang-Gohrke, Shan, Eilber, Ursula, Moysich, Kirsten B., Odunsi, Kunle, Sucheston, Lara, Lele, Shashi, Wilkens, Lynne R., Goodman, Marc T., Thompson, Pamela J., Shvetsov, Yurii B., Runnebaum, Ingo B., Duerst, Matthias, Hillemanns, Peter, Doerk, Thilo, Antonenkova, Natalia, Bogdanova, Natalia, Leminen, Arto, Pelttari, Liisa M., Butzow, Ralf, Modugno, Francesmary, Kelley, Joseph L., Edwards, Robert P., Ness, Roberta B., du Bois, Andreas, Heitz, Florian, Schwaab, Ira, Harter, Philipp, Matsuo, Keitaro, Hosono, Satoyo, Orsulic, Sandra, Jensen, Allan, Kjaer, Susanne Kruger, Hogdall, Estrid, Hasmad, Hanis Nazihah, Azmi, Mat Adenan Noor, Teo, Soo-Hwang, Woo, Yin-Ling, Fridley, Brooke L., Goode, Ellen L., Cunningham, Julie M., Vierkant, Robert A., Bruinsma, Fiona, Giles, Graham G., Liang, Dong, Hildebrandt, Michelle A. T., Wu, Xifeng, Levine, Douglas A., Bisogna, Maria, Berchuck, Andrew, Iversen, Edwin S., Schildkraut, Joellen M., Concannon, Patrick, Weber, Rachel Palmieri, Cramer, Daniel W., Terry, Kathryn L., Poole, Elizabeth M., Tworoger, Shelley S., Bandera, Elisa V., Orlow, Irene, Olson, Sara H., Krakstad, Camilla, Salvesen, Helga B., Tangen, Ingvild L., Bjorge, Line, van Altena, Anne M., Aben, Katja K. H., Kiemeney, Lambertus A., Massuger, Leon F. A. G., Kellar, Melissa, Brooks-Wilson, Angela, Kelemen, Linda E., Cook, Linda S., Le, Nhu D., Cybulski, Cezary, Yang, Hannah, Lissowska, Jolanta, Brinton, Louise A., Wentzensen, Nicolas, Hogdall, Claus, Lundvall, Lene, Nedergaard, Lotte, Baker, Helen, Song, Honglin, Eccles, Diana, McNeish, Ian, Paul, James, Carty, Karen, Siddiqui, Nadeem, Glasspool, Rosalind, Whittemore, Alice S., Rothstein, Joseph H., McGuire, Valerie, Sieh, Weiva, Ji, Bu-Tian, Zheng, Wei, Shu, Xiao-Ou, Gao, Yu-Tang, Rosen, Barry, Risch, Harvey A., McLaughlin, John R., Narod, Steven A., Monteiro, Alvaro N., Chen, Ann, Lin, Hui-Yi, Permuth-Wey, Jenny, Sellers, Thomas A., Tsai, Ya-Yu, Chen, Zhihua, Ziogas, Argyrios, Anton-Culver, Hoda, Gentry-Maharaj, Aleksandra, Menon, Usha, Harrington, Patricia, Lee, Alice W., Wu, Anna H., Pearce, Celeste L., Coetzee, Gerry, Pike, Malcolm C., Dansonka-Mieszkowska, Agnieszka, Timorek, Agnieszka, Rzepecka, Iwona K., Kupryjanczyk, Jolanta, Freedman, Matt, Noushmehr, Houtan, Easton, Douglas F., Offit, Kenneth, Couch, Fergus J., Gayther, Simon, Pharoah, Paul P., Antoniou, Antonis C., and Chenevix-Trench, Georgia

Abstract

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

Published
2015

50. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Author

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

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

Published
2015

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