22 results on '"Maria P. Intermaggio"'
Search Results
2. Data from Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition
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Kylie L. Gorringe, Ian G. Campbell, Kaylene J. Simpson, Richard B. Pearson, David G. Huntsman, David D.L. Bowtell, Susan J. Ramus, Felix Hilpert, Andreas du Bois, Jacobus Pfisterer, Stefan Kommoss, Anna Wu, Malcolm C. Pike, Celeste Leigh Pearce, Jacek Gronwald, Jan Lubinski, Aleksandra Gentry-Maharaj, Usha Menon, Maria P. Intermaggio, Sian Fereday, Nadia Traficante, Joshy George, Michael S. Anglesio, Karen E. Sheppard, and Sally J. Davis
- Abstract
Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of amplified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling. Mol Cancer Ther; 14(6); 1495–503. ©2015 AACR.
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- 2023
3. Supplementary Table 1 from Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition
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Kylie L. Gorringe, Ian G. Campbell, Kaylene J. Simpson, Richard B. Pearson, David G. Huntsman, David D.L. Bowtell, Susan J. Ramus, Felix Hilpert, Andreas du Bois, Jacobus Pfisterer, Stefan Kommoss, Anna Wu, Malcolm C. Pike, Celeste Leigh Pearce, Jacek Gronwald, Jan Lubinski, Aleksandra Gentry-Maharaj, Usha Menon, Maria P. Intermaggio, Sian Fereday, Nadia Traficante, Joshy George, Michael S. Anglesio, Karen E. Sheppard, and Sally J. Davis
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Nanostring data including clinical information
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- 2023
4. Supplementary Figures and Tables from Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition
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Kylie L. Gorringe, Ian G. Campbell, Kaylene J. Simpson, Richard B. Pearson, David G. Huntsman, David D.L. Bowtell, Susan J. Ramus, Felix Hilpert, Andreas du Bois, Jacobus Pfisterer, Stefan Kommoss, Anna Wu, Malcolm C. Pike, Celeste Leigh Pearce, Jacek Gronwald, Jan Lubinski, Aleksandra Gentry-Maharaj, Usha Menon, Maria P. Intermaggio, Sian Fereday, Nadia Traficante, Joshy George, Michael S. Anglesio, Karen E. Sheppard, and Sally J. Davis
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Supplementary Figures S1 (Nanostring data and combined PFS for BMP8B and ATP13A4), S2 (Nanostring expression histograms), S3 (GAB2 survival by cohort), S4 (BMP8B and ATP13A4 survival by cohort), S5 (Metacore network maps); Supplementary Tables S2 (Cell line information), S3 (Univariate survival analysis results), S4 (Step-wise AIC results) and S6 (association of GAB2 expression with PRAS40).
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- 2023
5. Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)
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Sven Mahner, Robertson Mackenzie, Aline Talhouk, Linda E. Kelemen, Gottfried E. Konecny, Jennifer Alsop, Rosalind Glasspool, Chiu-Chen Tseng, Joy Hendley, Dennis J. Slamon, Jennifer A. Doherty, Andrew Berchuck, Anna H. Wu, Anna M. Piskorz, Chen Wang, Cristina Rodríguez-Antona, D.G.H. de Silva, Valerie Rhenius, Peter A. Fasching, Stacey J. Winham, Gary L. Keeney, Teodora Goranova, Joshy George, Jan Lubinski, Michelle J. Henderson, Rex C. Bentley, Jenny Lester, Sabine Behrens, Joellen M. Schildkraut, Michael E. Carney, Timothy Budden, David G. Huntsman, Oleg Oszurek, Michael S. Anglesio, Jacek Gronwald, Ruby Yun-Ju Huang, Martin Köbel, Javier Benitez, Martin Widschwendter, Melissa C. Larson, Raghwa Sharma, Clara Bodelon, Usha Menon, Janusz Menkiszak, Blake Gilks, María Josefa Mosteiro García, Jesús García-Donas, Wafaa Elatre, Scott H. Kaufmann, Paul Haluska, Pamela J. Thompson, Boris Winterhoff, Susan J. Ramus, Louise A. Brinton, Simon A. Gayther, Mary Anne Rossing, Georgia Chenevix-Trench, Hugh Luk, Jolanta Lissowska, Marc T. Goodman, Billy Chen, Beth Y. Karlan, Naveena Singh, Sian Fereday, Mark E. Sherman, Ana Osorio, Lynne R. Wilkens, Maria P. Intermaggio, Brenda Y. Hernandez, Britton Trabert, Esther Herpel, Mercedes Jimenez-Linan, Janine Senz, Geyi Liu, Celeste Leigh Pearce, Samuel C Y Leong, Iain A. McNeish, Isabelle Ray-Coquard, Susana Banerjee, Malcolm C. Pike, Liz-Anne Lewsley, Helen Steed, Honglin Song, Samantha Hinsley, David D.L. Bowtell, James D. Brenton, Holly R. Harris, Tuan Zea Tan, Cezary Cybulski, Alicia Beeghly-Fadiel, A. Toloczko, Nikilyn Nevins, Robert S. Brown, Darren Ennis, Stephanie Chen, Euan A. Stronach, José Palacios, Sandra Orsulic, Anna deFazio, Geoff Macintyre, Kara L. Cushing-Haugen, Mila Volchek, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Paul D.P. Pharoah, Hanwei Sudderuddin, Stefan Kommoss, Derek S. Chiu, Huei San Leong, Peter Sinn, Catherine J. Kennedy, Chloe Karpinskyj, Alison Brand, Amy Lum, Veronica Chow, Nicolas Wentzensen, Tayyebeh M. Nazeran, Nadia Traficante, Dustin Johnson, Yoke-Eng Chiew, Casey S. Greene, Jennifer M Koziak, Renée T. Fortner, Imperial College Healthcare NHS Trust- BRC Funding, Cancer Research UK, Ovarian Cancer Action, Talhouk, Aline [0000-0001-7760-410X], George, Joshy [0000-0001-8510-8229], Wang, Chen [0000-0003-2638-3081], Tan, Tuan Zea [0000-0001-6624-1593], Behrens, Sabine [0000-0002-9714-104X], Bodelon, Clara [0000-0002-6578-2678], Brinton, Louise [0000-0003-3853-8562], Fortner, Renée T [0000-0002-1426-8505], García-Donas, Jesús [0000-0001-7731-3601], Gentry-Maharaj, Aleksandra [0000-0001-7270-9762], Glasspool, Rosalind [0000-0002-5000-1680], Greene, Casey S [0000-0001-8713-9213], Harris, Holly R [0000-0002-2572-6727], Kaufmann, Scott H [0000-0002-4900-7145], Kennedy, Catherine J [0000-0002-4465-5784], Köbel, Martin [0000-0002-6615-2037], Koziak, Jennifer M [0000-0001-5830-0397], Lissowska, Jolanta [0000-0003-2695-5799], McNeish, Iain A [0000-0002-9387-7586], Menkiszak, Janusz [0000-0001-8279-7196], Hinsley, Samantha [0000-0001-6903-4688], Pike, Malcolm C [0000-0003-4891-1199], Rodriguez-Antona, Cristina [0000-0001-8750-7338], Sinn, Peter [0000-0003-2836-6699], Trabert, Britton [0000-0002-1539-6090], Widschwendter, Martin [0000-0002-7778-8380], Winham, Stacey J [0000-0002-8492-9102], Brenton, James D [0000-0002-5738-6683], Brown, Robert [0000-0001-7960-5755], Chang-Claude, Jenny [0000-0001-8919-1971], deFazio, Anna [0000-0003-0057-4744], Fasching, Peter A [0000-0003-4885-8471], Kelemen, Linda E [0000-0003-4362-9784], Menon, Usha [0000-0003-3708-1732], Pharoah, Paul DP [0000-0001-8494-732X], Ramus, Susan J [0000-0003-0005-7798], Doherty, Jennifer A [0000-0002-1454-8187], Anglesio, Michael S [0000-0003-1639-5003], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Bevacizumab ,03 medical and health sciences ,Ovarian tumor ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Ovarian carcinoma ,Internal medicine ,medicine ,Humans ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Stage (cooking) ,Aged ,Ovarian Neoplasms ,business.industry ,Cystadenoma, Serous ,Cancer ,Middle Aged ,Precision medicine ,Omics ,medicine.disease ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Serous fluid ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,Neoplasm Grading ,Transcriptome ,business ,Algorithms ,medicine.drug - Abstract
Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271
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- 2020
6. Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium
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Scott H. Kaufmann, Daniel Guimarães Tiezzi, Valerie Rhenius, Gary L. Keeney, Alexander Hein, Dominique-Laurent Couturier, Florin Andrei Taran, Robert Edwards, Aline Talhouk, Stacey J. Winham, Christiani Bisinoto de Sousa, Nadja Pejovic, Andreas D. Hartkopf, Ramona Erber, Brenda Y. Hernandez, Jenny Lester, Teri A. Longacre, Anna L. Paterson, Peter Sinn, Robin Crawford, Lene Lundvall, Hugh Luk, Roberta B. Ness, Adekunle Odunsi, Suha Deen, Javier Benitez, Alice S. Whittemore, Anna Fischer, Anthony N. Karnezis, Christine Chow, Ana Osorio, Ellen L. Goode, Stefan Kommoss, Angela Brooks-Wilson, Linda E. Kelemen, Tanja Pejovic, Simon A. Gayther, Peter A. Fasching, Beth Y. Karlan, Jurandyr Moreira de Andrade, Samuel Leung, David D.L. Bowtell, James D. Brenton, Aleksandra Vrvilo, Marc T. Goodman, Paul D.P. Pharoah, Sara Y. Brucker, Honglin Song, Jennifer M Koziak, Robert A. Vierkant, Naveena Singh, Valerie McGuire, Chloe Karpinskyj, Mercedes Jimenez-Linan, Aleksandra Gentry-Maharaj, Anna deFazio, Jenny Chang-Claude, Linda S. Cook, Francesmary Modugno, Filipe C. Martins, Estrid Høgdall, Prafull Ghatage, Marie Lyne Alcaraz, Susan J. Ramus, Annette Staebler, Jennifer Alsop, David G. Huntsman, Joseph H. Rothstein, Tayyebeh M. Nazeran, Cristina Rodríguez-Antona, Luis Robles-Díaz, Bryan M. McCauley, María Jesús Gómez García, Michael E. Carney, Michael S. Anglesio, Yurii B. Shvetsov, Claus Høgdall, Sian Fereday, Martin Köbel, Maria P. Intermaggio, Sandra Orsulic, Luis Paz-Ares, Mary Anne Brett, Weiva Sieh, Matthias W. Beckmann, Helen Steed, Arndt Hartmann, Michael Schneider, Lynne R. Wilkens, Esther Herpel, Jacek Gronwald, Francisco José Candido dos Reis, Nhu D. Le, Gregg Nelson, Kirsten B. Moysich, Nadia Traficante, Usha Menon, Candido Dos Reis, Francisco J [0000-0001-5758-5917], Brenton, James D [0000-0002-5738-6683], Apollo - University of Cambridge Repository, Candido dos Reis, Francisco J. [0000-0001-5758-5917], and Brenton, James D. [0000-0002-5738-6683]
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Oncology ,Cancer Research ,692/4028/67/1517/1709 ,Carcinoma, Ovarian Epithelial ,Clear Cell ,Androgen ,ESTUDOS PROSPECTIVOS ,Cohort Studies ,Gene Knockout Techniques ,0302 clinical medicine ,Ovarian carcinoma ,Ovarian Epithelial ,Receptors ,Prospective Studies ,Progesterone ,Cancer ,Ovarian Neoplasms ,0303 health sciences ,Tumor ,Molecular medicine ,biology ,Hazard ratio ,article ,Age Factors ,Middle Aged ,Ovarian Cancer ,Serous fluid ,Receptors, Estrogen ,Receptors, Androgen ,030220 oncology & carcinogenesis ,Public Health and Health Services ,Biomarker (medicine) ,Female ,Receptors, Progesterone ,medicine.medical_specialty ,Oncology and Carcinogenesis ,Down-Regulation ,Adenocarcinoma ,03 medical and health sciences ,Rare Diseases ,Ovarian cancer ,Internal medicine ,Progesterone receptor ,medicine ,Biomarkers, Tumor ,PTEN ,Humans ,Oncology & Carcinogenesis ,030304 developmental biology ,Neoplasm Staging ,business.industry ,Tumor Suppressor Proteins ,Carcinoma ,PTEN Phosphohydrolase ,medicine.disease ,Estrogen ,692/4017 ,Androgen receptor ,Tissue Array Analysis ,biology.protein ,business ,Biomarkers ,Adenocarcinoma, Clear Cell - Abstract
Background PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
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- 2020
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7. Population based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high grade serous ovarian cancer
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Jonathan Tyrer, Georgia Chenevix-Trench, Jenny Lester, Penelope M. Webb, Jacek Gronwald, Julie M. Cunningham, Usha Menon, Cezary Cybulski, Anna de Fazio, Allan Jensen, Maria P. Intermaggio, Karen Hosking, Donghui Li, Ellen L. Goode, Anna H. Wu, Jennifer Alsop, Celeste Leigh Pearce, Mary Anne Rossing, Thilo Dörk, Chad D. Huff, Jennifer B. Permuth, Estrid Høgdall, Joellen M. Schildkraut, Susanne K. Kjaer, Douglas A. Levine, Anna Jakubowska, Paul D.P. Pharoah, Beth Y. Karlan, Ed Dicks, Stacey J. Winham, Andrew Berchuck, Yao Yu, Jan Lubinski, David D.L. Bowtell, Holly R. Harris, James D. Brenton, Patricia Harrington, Isaac H Y Chan, Ian G. Campbell, Miquel Angel Pujana, Kirsten B. Moysich, Jennifer A. Doherty, Francesmary Modugno, Susan J. Ramus, Natalia Bogdanova, Anna M. Piskorz, Catherine J. Kennedy, Roberta B. Ness, Robert A. Vierkant, Elke Van Oudenhove, Nadia Traficante, Simon A. Gayther, Conxi Lázaro, Honglin Song, Matthias Dürst, Michelle A.T. Hildebrandt, Xifeng Wu, Teodora Goranova, Marjorie J. Riggan, and Kunle Odunsi
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Oncology ,0303 health sciences ,medicine.medical_specialty ,Candidate gene ,endocrine system diseases ,business.industry ,PALB2 ,Odds ratio ,Disease ,medicine.disease ,Germline ,female genital diseases and pregnancy complications ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Coding region ,Ovarian cancer ,business ,Gene ,030304 developmental biology - Abstract
PurposeThe known EOC susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases verses controls were further examined in an independent set of 14,146 EOC cases and 28,661 controls from the ovarian cancer association consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe odds ratios (OR) associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 – 5.68; P = 0.00068), 1.99 for POLK (95% CI 1.15 – 3.43; P = 0.014), and 4.07 for SLX4 (95% CI 1.34-12.4; P = 0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 −1.00, P=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
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- 2019
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8. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer
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Matthew S. Block, Robert A. Vierkant, Peter F. Rambau, Stacey J. Winham, Philipp Wagner, Nadia Traficante, Aleksandra Tołoczko, Daniel G. Tiezzi, Florin Andrei Taran, Peter Sinn, Weiva Sieh, Raghwa Sharma, Joseph H. Rothstein, Teresa Ramón y Cajal, Luis Paz-Ares, Oleg Oszurek, Sandra Orsulic, Roberta B. Ness, Gregg Nelson, Francesmary Modugno, Janusz Menkiszak, Valerie McGuire, Bryan M. McCauley, Marie Mack, Jan Lubiński, Teri A. Longacre, Zheng Li, Jenny Lester, Catherine J. Kennedy, Kimberly R. Kalli, Audrey Y. Jung, Sharon E. Johnatty, Mercedes Jimenez-Linan, Allan Jensen, Maria P. Intermaggio, Jillian Hung, Esther Herpel, Brenda Y. Hernandez, Andreas D. Hartkopf, Paul R. Harnett, Prafull Ghatage, José M. García-Bueno, Bo Gao, Sian Fereday, Ursula Eilber, Robert P. Edwards, Christiani B. de Sousa, Jurandyr M. de Andrade, Anita Chudecka-Głaz, Georgia Chenevix-Trench, Alicia Cazorla, Sara Y. Brucker, Jennifer Alsop, Alice S. Whittemore, Helen Steed, Annette Staebler, Kirsten B. Moysich, Usha Menon, Jennifer M. Koziak, Stefan Kommoss, Susanne K. Kjaer, Linda E. Kelemen, Beth Y. Karlan, David G. Huntsman, Estrid Høgdall, Jacek Gronwald, Marc T. Goodman, Blake Gilks, María José García, Peter A. Fasching, Anna de Fazio, Suha Deen, Jenny Chang-Claude, Francisco J. Candido dos Reis, Ian G. Campbell, James D. Brenton, David D. Bowtell, Javier Benítez, Paul D.P. Pharoah, Martin Köbel, Susan J. Ramus, Ellen L. Goode, D. Bowtell, G. Chenevix-Trench, A. Green, P. Webb, A. DeFazio, D. Gertig, N. Traficante, S. Fereday, S. Moore, J. Hung, K. Harrap, T. Sadkowsky, N. Pandeya, M. Malt, A. Mellon, R. Robertson, T. Vanden Bergh, M. Jones, P. Mackenzie, J. Maidens, K. Nattress, Y.E. Chiew, A. Stenlake, H. Sullivan, B. Alexander, P. Ashover, S. Brown, T. Corrish, L. Green, L. Jackman, K. Ferguson, K. Martin, A. Martyn, B. Ranieri, J. White, V. Jayde, P. Mamers, L. Bowes, L. Galletta, D. Giles, J. Hendley, K. Alsop, T. Schmidt, H. Shirley, C. Ball, C. Young, S. Viduka, Hoa Tran, Sanela Bilic, Lydia Glavinas, Julia Brooks, R. Stuart-Harris, F. Kirsten, J. Rutovitz, P. Clingan, A. Glasgow, A. Proietto, S. Braye, G. Otton, J. Shannon, T. Bonaventura, J. Stewart, S. Begbie, M. Friedlander, D. Bell, S. Baron-Hay, A. Ferrier, G. Gard, D. Nevell, N. Pavlakis, S. Valmadre, B. Young, C. Camaris, R. Crouch, L. Edwards, N. Hacker, D. Marsden, G. Robertson, P. Beale, J. Beith, J. Carter, C. Dalrymple, R. Houghton, P. Russell, M. Links, J. Grygiel, J. Hill, A. Brand, K. Byth, R. Jaworski, P. Harnett, R. Sharma, G. Wain, B. Ward, D. Papadimos, A. Crandon, M. Cummings, K. Horwood, A. Obermair, L. Perrin, D. Wyld, J. Nicklin, M. Davy, M.K. Oehler, C. Hall, T. Dodd, T. Healy, K. Pittman, D. Henderson, J. Miller, J. Pierdes, P. Blomfield, D. Challis, R. McIntosh, A. Parker, B. Brown, R. Rome, D. Allen, P. Grant, S. Hyde, R. Laurie, M. Robbie, D. Healy, T. Jobling, T. Manolitsas, J. McNealage, P. Rogers, B. Susil, E. Sumithran, I. Simpson, K. Phillips, D. Rischin, S. Fox, D. Johnson, S. Lade, M. Loughrey, N. O'Callaghan, W. Murray, P. Waring, V. Billson, J. Pyman, D. Neesham, M. Quinn, C. Underhill, R. Bell, L.F. Ng, R. Blum, V. Ganju, I. Hammond, Y. Leung, A. McCartney, M. Buck, I. Haviv, D. Purdie, D. Whiteman, and N. Zeps
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Carcinoma, Ovarian Epithelial/metabolism ,Adult ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Myeloid Differentiation Factor 88/metabolism ,Carcinoma, Ovarian Epithelial ,Article ,03 medical and health sciences ,Ovarian tumor ,0302 clinical medicine ,Internal medicine ,Immunohistochemistry/methods ,Biomarkers, Tumor ,medicine ,Carcinoma ,Humans ,Clear-cell ovarian carcinoma ,Tissue Array Analysis/methods ,Survival analysis ,Aged ,Ovarian Neoplasms ,Tissue microarray ,business.industry ,Hazard ratio ,General Medicine ,Middle Aged ,Ovarian Neoplasms/metabolism ,medicine.disease ,ANÁLISE DE SOBREVIVÊNCIA ,Immunohistochemistry ,Survival Analysis ,3. Good health ,Toll-Like Receptor 4 ,Serous fluid ,Toll-Like Receptor 4/metabolism ,030104 developmental biology ,Tissue Array Analysis ,Biomarkers, Tumor/metabolism ,030220 oncology & carcinogenesis ,Myeloid Differentiation Factor 88 ,Female ,business ,Ovarian cancer - Abstract
Objective: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. Patients and Methods: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). Results: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P
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- 2018
9. A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases
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Christine Chow, Hugh Luk, Jennifer Alsop, Aleksandra Tołoczko-Grabarek, Qin Wang, Nicola S. Meagher, Janusz Menkiszak, Stacey J. Winham, Jan Lubinski, Bonnie Zhang, Simon A. Gayther, Gary L. Keeney, Rhonda Farrell, Tomasz Kluz, Constantina Mateoiu, Mona El-Bahrawy, Raghwa Sharma, Montserrat Garcia-Closas, Adeline Tan, Brenda Y. Hernandez, Minouk J. Schoemaker, Maria P. Intermaggio, Marc T. Goodman, Robert A. Vierkant, Björg Kristjansdottir, Chloe Karpinskyj, Penny Coulson, Parham Minoo, Kylie L. Gorringe, Aline Talhouk, Oliver F. Bathe, Anthony J. Swerdlow, Michael E. Carney, James D. Brenton, Robert P. Edwards, John Lewis Etter, Kirsten B. Moysich, Colin J.R. Stewart, Jennifer M Koziak, Mercedes Jimenez-Linan, Yee Leung, Kunle Odunsi, Peter F Rambau, Sabine Behrens, Linda S. Cook, Michael S. Anglesio, Lynne R. Wilkens, Karin Sundfeldt, Esther Herpel, Martin Köbel, Sanela Bilic, Jacek Gronwald, Paul R. Harnett, Helen Steed, Katrina Tang, Susan J. Ramus, Paul A. Cohen, Xianyong Gui, Frances Daley, Ellen L. Goode, Anna deFazio, Ian G. Campbell, Paul D.P. Pharoah, Peter Sinn, Paul Klonowski, Yanina Natanzon, Linyuan Wang, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Catherine J. Kennedy, Roberta B. Ness, Linda E. Kelemen, Oleg Oszurek, Usha Menon, Mitul Shah, Martin Widschwendter, Melissa C. Larson, Gregory Robertson, Francesmary Modugno, David G. Huntsman, Audrey Y. Jung, and Neil Lambie
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0301 basic medicine ,Male ,Pathology ,0302 clinical medicine ,Medicine ,Neoplasm Metastasis ,11 Medical and Health Sciences ,Ovarian Neoplasms ,Tissue microarray ,SERIES ,Adenocarcinoma, Mucinous ,Immunohistochemistry ,Appendiceal Neoplasms ,030220 oncology & carcinogenesis ,Cohort ,SURVIVAL ,Adenocarcinoma ,Female ,Colorectal Neoplasms ,Life Sciences & Biomedicine ,NEOPLASMS ,EXPRESSION ,medicine.medical_specialty ,CARCINOMA ,CANCERS ,Sensitivity and Specificity ,Article ,Pathology and Forensic Medicine ,Diagnosis, Differential ,03 medical and health sciences ,DISTINCTION ,Carcinoma ,Biomarkers, Tumor ,Humans ,Science & Technology ,business.industry ,Keratin-7 ,Histology ,ADENOCARCINOMA ,PROFILES ,Matrix Attachment Region Binding Proteins ,medicine.disease ,030104 developmental biology ,CDX2 ,Keratin 7 ,business ,PAX8 ,Transcription Factors - Abstract
Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.
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- 2019
10. Abstract B37: Germline mutations in new susceptibility genes for non-high-grade serous ovarian cancer
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Mark Pinese, Adelyn Bolithon, Ed Dicks, Honglin Song, Anna deFazio, Ian G. Campbell, Kunle Odunsi, Deepak Subramanian, Peter A. Fasching, Francesmary Modugno, Penelope M. Webb, Jennifer A. Doherty, Ellen L. Goode, Anna H. Wu, Amir Ariff, Susanne K. Kjaer, Paul D.P. Pharoah, David D.L. Bowtell, Marina Pavanello, Susan J. Ramus, Simon A. Gayther, Maria P. Intermaggio, Kirsten B. Moysich, and Paul A. James
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Cancer Research ,Germline mutation ,Oncology ,Cancer research ,Serous ovarian cancer ,Susceptibility gene ,Biology - Abstract
Improving risk prediction and prevention strategies through identifying new susceptibility genes for non-high-grade serous ovarian cancer (non-HGS) would represent an important advance in reducing incidence and mortality. Epithelial ovarian cancer (EOC) has five main histotypes that have distinct pathologies, molecular changes, clinical characteristics, and tissues of origin. They are classified as high-grade serous (HGS), low-grade serous (LGS), clear-cell (CCC), endometrioid (END), and mucinous (MUC). A family history of breast or ovarian cancer is the strongest single risk factor for EOC. Germline mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2 confer EOC risks of 44% and 17% by age 80, respectively. Only 40% of the excess familial risk is known, suggesting there are many other susceptibility genes yet unidentified. The non-HGS histotypes are poorly studied due to limited sample size within individual studies. Thus, families of cases with non-HGS tumors have few risk prediction options. Whole-exome sequencing (WES) analysis was performed on 251 non-HGS cases (56 LGS, 55 CCC, 117 END, 23 MUC). Cases were screened negative for BRCA1/2 mutations and selected for a family history of ovarian or breast cancer, or young onset ( Citation Format: Marina Pavanello, Ed Dicks, Honglin Song, Amir Ariff, Adelyn Bolithon, Maria P. Intermaggio, Mark Pinese, Kirsten Moysich, Kunle O. Odunsi, Ellen Goode, David D. Bowtell, Peter Fasching, Jennifer A. Doherty, Francesmary Modugno, Susanne K. Kjær, Penelope M. Webb, Anna Wu, Anna deFazio, Ovarian Cancer Association Consortium, Paul James, Deepak Subramanian, Ian Campbell, Simon A. Gayther, Paul D.P. Pharoah, Susan J. Ramus. Germline mutations in new susceptibility genes for non-high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B37.
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- 2020
11. Dose-Response Relationship of CD8+ Tumor Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer
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Valerie McGuire, Mercedes Jimenez-Linan, Usha Menon, Anna deFazio, Ana Osorio, Joseph L. Kelley, Robert P. Edwards, Martin Köbel, Ian G. Campbell, Jennifer Alsop, Brooke L. Fridley, Beth Y. Karlan, Florin Andrei Taran, Susan J. Ramus, Javier Benitez, Luis Robles-Díaz, Linda E. Kelemen, Annette Staebler, Bryan M. McCauley, Arndt Hartmann, Paul R. Harnett, Janusz Menkiszak, Joseph H. Rothstein, Christiani Bisinoto de Sousa, Linda S. Cook, Oleg Oszurek, Raghwa Sharma, Naveena Singh, Jenny Lester, Matthew S. Block, Philipp Wagner, Matthias Ruebner, Andy Ryan, Jesús García-Donas, Martin Widschwendter, Helen Steed, Teri A. Longacre, Blake Gilks, Suha Deen, Jill Nation, Yanina Natanzon, Weiva Sieh, Marc T. Goodman, Daniel Guimarães Tiezzi, Maria P. Intermaggio, Chloe Karpinskyj, Anita Chudecka-Głaz, Maria J. Garcia, Chen Wang, Susanne K. Kjaer, Jillian Hung, Estrid Høgdall, Peter A. Fasching, Georgia Chenevix-Trench, Alexander Hein, Prafull Ghatage, A. Toloczko, Peter F Rambau, Catherine J. Kennedy, Aleksandra Gentry-Maharaj, Stacey J. Winham, Kimberly R. Kalli, Allan Jensen, Roberta B. Ness, Audrey Y. Jung, Jurandyr Moreira de Andrade, Wenqian Chen, Matthias W. Beckmann, Gregg Nelson, Jenny Chang-Claude, Jan Lubinski, Jennifer M Koziak, Paul D.P. Pharoah, Brenda Y. Hernandez, Jacek Gronwald, José Palacios, Alice S. Whittemore, Andreas D. Hartkopf, Sandra Orsulic, David L. Wachter, Sara Y. Brucker, Francesmary Modugno, Aliecia L. Bouligny, Peter Sinn, David G. Huntsman, Robert A. Vierkant, Zachary C. Fogarty, David D.L. Bowtell, James D. Brenton, Ursula Eilber, Ellen L. Goode, Stefan Kommoss, Kirsten B. Moysich, Sharon E. Johnatty, Anthony M. Magliocco, Francisco José Candido dos Reis, Bo Gao, Zheng Li, and Esther Herpel
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,CD8 Antigens ,chemical and pharmacologic phenomena ,Carcinoma, Ovarian Epithelial ,Article ,Cohort Studies ,03 medical and health sciences ,Ovarian tumor ,0302 clinical medicine ,Breast cancer ,Lymphocytes, Tumor-Infiltrating ,Internal medicine ,Medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Survival analysis ,BRCA2 Protein ,Ovarian Neoplasms ,business.industry ,Tumor-infiltrating lymphocytes ,hemic and immune systems ,Middle Aged ,Debulking ,medicine.disease ,Survival Analysis ,Cystadenocarcinoma, Serous ,Serous fluid ,030104 developmental biology ,Treatment Outcome ,CITOTOXICIDADE IMUNOLÓGICA ,030220 oncology & carcinogenesis ,Mutation ,Female ,Neoplasm Grading ,business ,Ovarian cancer - Abstract
Importance Cytotoxic CD8+tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+TILs by histotype and in relation to other clinical factors. Objective To define the prognostic role of CD8+TILs in epithelial ovarian cancer. Design, Setting, and Participants This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years. Exposures Following immunohistochemical analysis, CD8+TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines. Main Outcomes and Measures Overall survival time. Results The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+TILs, respectively (Pvalue for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germlineBRCA1pathogenic mutation, but were not prognostic forBRCA2mutation carriers. Evaluation of uncategorized CD8+TIL counts showed a near-log-linear functional form. Conclusions and Relevance This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.
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- 2017
12. Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study
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Bruce R. Rosen, A. Hartmann, Bo Gao, Georgia Chenevix-Trench, Gregg Nelson, Marcus Q. Bernardini, Carl Morrison, Mercedes Jimenez-Linan, Usha Menon, C Ewanowich, E Benjamin, Joshy George, S Liu, Blaise Clarke, Sian Fereday, Brooke L. Fridley, Allan Jensen, A Gentry-Maharaj, Peter A. Fasching, Suha Deen, Zachary C. Fogarty, Kunle Odunsi, David L. Wachter, Falk Thiel, Simon A. Gayther, Anna deFazio, Shashikant Lele, David D.L. Bowtell, Lara Sucheston, Kristy Driver, James D. Brenton, Michael S. Anglesio, Gary L. Keeney, Helen Steed, Ellen L. Goode, Martin Köbel, Robert A. Vierkant, Alexander Hein, Helen J. Mackay, Linda E. Kelemen, Paul D.P. Pharoah, David G. Huntsman, Sharon E. Johnatty, Amit M. Oza, S.K. Kjaer, S Cho, Martin Widschwendter, Maria P. Intermaggio, Claus Høgdall, Marie Mack, J Madore, Kimberly R. Kalli, Jennifer M Koziak, M. W. Beckmann, Prafull Ghatage, P Shaw, Jennifer Alsop, Estrid Høgdall, Susan J. Ramus, K. Moysich, Wiam Bshara, and Laura Galletta
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Oncology ,endocrine system ,Cancer Research ,medicine.medical_specialty ,Pathology ,endocrine system diseases ,medicine.medical_treatment ,Biology ,Carcinoma, Ovarian Epithelial ,Disease-Free Survival ,folate receptor alpha ,chemistry.chemical_compound ,Ovarian carcinoma ,Internal medicine ,Carcinoma ,medicine ,Biomarkers, Tumor ,Humans ,Folate Receptor 1 ,Neoplasms, Glandular and Epithelial ,Survival analysis ,Ovarian Neoplasms ,Chemotherapy ,Farletuzumab ,FRA ,TCGA ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Survival Analysis ,female genital diseases and pregnancy complications ,3. Good health ,ovarian cancer ,chemistry ,Tissue Array Analysis ,Female ,Folate receptor 1 ,prognosis ,Ovarian cancer ,Translational Therapeutics - Abstract
Background: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. Methods: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. Results: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20–0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10–3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25–0.94). Conclusions: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.
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- 2014
13. Germline whole exome sequencing and large-scale replication identifies
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Ed, Dicks, Honglin, Song, Susan J, Ramus, Elke Van, Oudenhove, Jonathan P, Tyrer, Maria P, Intermaggio, Siddhartha, Kar, Patricia, Harrington, David D, Bowtell, Aocs Study, Group, Mine S, Cicek, Julie M, Cunningham, Brooke L, Fridley, Jennifer, Alsop, Mercedes, Jimenez-Linan, Anna, Piskorz, Teodora, Goranova, Emma, Kent, Nadeem, Siddiqui, James, Paul, Robin, Crawford, Samantha, Poblete, Shashi, Lele, Lara, Sucheston-Campbell, Kirsten B, Moysich, Weiva, Sieh, Valerie, McGuire, Jenny, Lester, Kunle, Odunsi, Alice S, Whittemore, Natalia, Bogdanova, Matthias, Dürst, Peter, Hillemanns, Beth Y, Karlan, Aleksandra, Gentry-Maharaj, Usha, Menon, Marc, Tischkowitz, Douglas, Levine, James D, Brenton, Thilo, Dörk, Ellen L, Goode, Simon A, Gayther, and D P Paul, Pharoah
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next generation sequencing ,ovarian cancer ,DNA repair ,susceptibility genes ,Research Paper - Abstract
We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8×10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 – were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2, where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 – 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.
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- 2016
14. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer
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Usha Menon, Mine S. Cicek, David V. Conti, Maria P. Intermaggio, Valerie McGuire, Weiva Sieh, Gillian Mitchell, Ed Dicks, Brooke L. Fridley, Thilo Dörk, Honglin Song, Antonis C. Antoniou, Jenny Lester, David D.L. Bowtell, Matthias Dürst, Natalia Bogdanova, Aleksandra Gentry-Maharaj, Lara E. Sucheston-Campbell, Adam N. Rosenthal, Ian Jacobs, Peter Hillemanns, Julie M. Cunningham, Paul D.P. Pharoah, Patricia Harrington, Jonathan Tyrer, Kathryn Alsop, Mercedes Jimenez-Linan, Beth Y. Karlan, Christopher Anderson, Samantha Poblete, Kirsten B. Moysich, Jennifer Alsop, Daniel Barrowdale, Alice S. Whittemore, Kunle Odunsi, Shashi Lele, Jane Hayward, Susan Philpott, Simon A. Gayther, Christopher K. Edlund, Lindsay Fraser, Susan J. Ramus, and Ellen L. Goode
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Adult ,Risk ,Oncology ,Cancer Research ,medicine.medical_specialty ,Ubiquitin-Protein Ligases ,PALB2 ,Population ,Mutation, Missense ,Cell Cycle Proteins ,Carcinoma, Ovarian Epithelial ,Biology ,Bioinformatics ,White People ,Germline ,Germline mutation ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Neoplasms, Glandular and Epithelial ,education ,Germ-Line Mutation ,Aged ,Ovarian Neoplasms ,education.field_of_study ,Cancer prevention ,Tumor Suppressor Proteins ,High-Throughput Nucleotide Sequencing ,Nuclear Proteins ,Middle Aged ,medicine.disease ,Penetrance ,Fanconi Anemia Complementation Group Proteins ,United States ,DNA-Binding Proteins ,Relative risk ,Female ,Fanconi Anemia Complementation Group N Protein ,Ovarian cancer ,RNA Helicases - Abstract
BACKGROUND: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality. METHODS: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes—BRIP1, BARD1, PALB2 and NBN—in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided. RESULTS: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10–4 and 8 x 10–4, respectively), but no differences for BARD1 (P = .39), NBN1 (P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10–4). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10–4) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10–5). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10–7). CONCLUSIONS: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.
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- 2015
15. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population
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Jacek Gronwald, Anna Jakubowska, Paul D.P. Pharoah, Susanne K. Kjaer, Mercedes Jimenez-Linan, Aleksandra Gentry-Maharaj, Julie M. Cunningham, Allan Jensen, Kathryn Alsop, Tomasz Huzarski, Estrid Høgdall, Lindsay Fraser, Ian Jacobs, Christopher K. Edlund, Usha Menon, Kunle Odunsi, Claus Høgdall, Ed Dicks, Honglin Song, Shashi Lele, Brooke L. Fridley, Jan Lubinski, Susan Philpott, Simon A. Gayther, Jennifer Alsop, Christopher Anderson, Samantha Poblete, Jane Hayward, Kirsten B. Moysich, Ellen L. Goode, Adam N. Rosenthal, Patricia Harrington, Jonathan P. Tyrer, David D.L. Bowtell, David V. Conti, Lara E. Sucheston-Campbell, Maria P. Intermaggio, Mine S. Cicek, and Susan J. Ramus
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Oncology ,Adult ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,Population ,Genes, BRCA2 ,Genes, BRCA1 ,Genome-wide association study ,Carcinoma, Ovarian Epithelial ,Germline ,Germline mutation ,Internal medicine ,Carcinoma ,Medicine ,Humans ,Genetic Predisposition to Disease ,Neoplasms, Glandular and Epithelial ,education ,Germ-Line Mutation ,Aged ,Genetics ,Ovarian Neoplasms ,education.field_of_study ,business.industry ,Odds ratio ,ORIGINAL REPORTS ,Middle Aged ,medicine.disease ,DNA-Binding Proteins ,RAD51C ,Female ,business ,Ovarian cancer - Abstract
Purpose The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. Patients and Methods The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis. Results In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). Conclusion These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.
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- 2015
16. Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition
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Maria P. Intermaggio, Richard B. Pearson, Kaylene J. Simpson, Anna H. Wu, Usha Menon, Jacobus Pfisterer, Andreas du Bois, David G. Huntsman, Aleksandra Gentry-Maharaj, Sian Fereday, Ian G. Campbell, Nadia Traficante, Jacek Gronwald, David D.L. Bowtell, Kylie L. Gorringe, Jan Lubinski, Joshy George, Karen E. Sheppard, Malcolm C. Pike, Stefan Kommoss, Celeste Leigh Pearce, Susan J. Ramus, Felix Hilpert, Michael S. Anglesio, and Sally J. Davis
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Adult ,Cancer Research ,DNA Copy Number Variations ,Cell Survival ,Pyridones ,Kaplan-Meier Estimate ,Biology ,Disease-Free Survival ,Metastasis ,Ovarian tumor ,Young Adult ,Ovarian carcinoma ,Cell Line, Tumor ,medicine ,Carcinoma ,Humans ,Gene Regulatory Networks ,Adaptor Proteins, Signal Transducing ,Aged ,Phosphoinositide-3 Kinase Inhibitors ,Aged, 80 and over ,Ovarian Neoplasms ,Oncogene ,Gene Expression Profiling ,Gene Amplification ,Middle Aged ,medicine.disease ,Cystadenocarcinoma, Serous ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,Serous fluid ,Pyrimidines ,Oncology ,Multivariate Analysis ,Cancer research ,Female ,Neoplasm Grading ,Ovarian cancer - Abstract
Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of amplified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling. Mol Cancer Ther; 14(6); 1495–503. ©2015 AACR.
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- 2015
17. The sex hormone system in carriers of BRCA1/2 mutations: a case-control study
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Martin, Widschwendter, Adam N, Rosenthal, Sue, Philpott, Ivana, Rizzuto, Lindsay, Fraser, Jane, Hayward, Maria P, Intermaggio, Christopher K, Edlund, Susan J, Ramus, Simon A, Gayther, Louis, Dubeau, Evangelia Ourania, Fourkala, Alexey, Zaikin, Usha, Menon, and Ian J, Jacobs
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BRCA2 Protein ,Ovarian Neoplasms ,Heterozygote ,Estradiol ,BRCA1 Protein ,Breast Neoplasms ,Penetrance ,United Kingdom ,Endometrium ,Logistic Models ,Phenotype ,Area Under Curve ,Case-Control Studies ,Mutation ,Biomarkers, Tumor ,Contraceptive Agents, Female ,Odds Ratio ,Humans ,Female ,Genetic Predisposition to Disease ,Menstrual Cycle ,Progesterone ,Ultrasonography - Abstract
Penetrance for breast cancer, ovarian cancer, or both in carriers of BRCA1/BRCA2 mutations is disproportionately high. Sex hormone dysregulation and altered end-organ hormone sensitivity might explain this organ-specific penetrance. We sought to identify differences in hormone regulation between carriers of BRCA1/2 and women who are negative for BRCA1/2 mutations.We assessed endometrial thickness for each menstrual cycle day (as an index of hormone regulation) in 393 scans from 228 women in the UK Familial Ovarian Cancer Screening Study (UK FOCSS) known to carry either mutation and 1573 scans from 754 women known to be negative for the mutations. To quantify differences in endometrial thickness we focused on days 10-14 and days 21-26, and calculated the area under the curve. We then compared serum oestradiol and progesterone titres during these days of the menstrual cycle in the same groups. Follicular and luteal oestradiol and progesterone serum titres were grouped into quartiles and odds ratios were calculated with logistic regression.Follicular phase endometrial thickness of carriers of the mutations adjusted for age and day of the menstrual cycle was higher (odds ratio [OR] 1·11, 95% CI 1·03-1·20; p=0·0063) and luteal phase endometrial thickness lower (0·90, 0·83-0·98; p=0·027) than for women negative for the mutations. Median luteal phase titres of progesterone were 121% higher (p=0·00037) in carriers than in women negative for the mutations, and for oestradiol were 33% higher (p=0·007)-ie, 59% of carriers had concentrations of serum progesterone that would have been in the top quartile of concentrations in the control group (OR 8·0, 95% CI 2·1-52·57; p=0·008).Carriers of BRCA1/BRCA2 mutations are exposed to higher titres of oestradiol and progesterone-known risk-factors for breast cancer. Higher titres of oestradiol in carriers are compatible with this hormone having a role in ovarian carcinogenesis in such women. Our findings could not be explained by differential contraceptive pill use.
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- 2013
18. PPM1DMosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations
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Usha Menon, Jenny Lester, Alice S. Whittemore, Kunle Odunsi, Martin Widschwendter, Shashi Lele, Brooke L. Fridley, Thilo Dörk, Maria P. Intermaggio, Natalia Bogdanova, Weiva Sieh, Peter Hillemanns, David D.L. Bowtell, Ed Dicks, Caroline Baynes, Kathryn Alsop, Honglin Song, Samantha Poblete, Julie M. Cunningham, Lara E. Sucheston-Campbell, Patricia Harrington, Susan J. Ramus, Ellen L. Goode, Kirsten B. Moysich, Beth Y. Karlan, Valerie McGuire, Aleksandra Gentry-Maharaj, Mine S. Cicek, Simon A. Gayther, and Paul D.P. Pharoah
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Adult ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Antineoplastic Agents ,Brief Communication ,medicine.disease_cause ,Polymerase Chain Reaction ,Germline ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Gene Frequency ,Internal medicine ,Phosphoprotein Phosphatases ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele frequency ,Aged ,Ovarian Neoplasms ,Sanger sequencing ,Mutation ,Massive parallel sequencing ,Mosaicism ,business.industry ,Case-control study ,High-Throughput Nucleotide Sequencing ,Cancer ,Middle Aged ,medicine.disease ,Protein Phosphatase 2C ,030104 developmental biology ,Case-Control Studies ,030220 oncology & carcinogenesis ,Cancer research ,symbols ,Female ,business ,Ovarian cancer - Abstract
Mosaic truncating mutations in the protein phosphatase, Mg(2+)/Mn(2+)-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively parallel sequencing (MPS) we identified truncating PPM1D mutations in 12 of 3236 epithelial ovarian cancer (EOC) case patients (0.37%) but in only one of 3431 unaffected control patients (0.03%) (P = .001). All statistical tests were two-sided. A combination of Sanger sequencing, pyrosequencing, and MPS data suggested that 12 of the 13 mutations were mosaic. All mutations were identified in post-chemotherapy treatment blood samples from case patients (n = 1827) (average 1234 days post-treatment in carriers) rather than from cases collected pretreatment (less than 14 days after diagnosis, n = 1384) (P = .002). These data suggest that PPM1D variants in EOC cases are primarily somatic mosaic mutations caused by treatment and are not associated with germline predisposition to EOC.
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- 2016
19. Abstract POSTER-CTRL-1213: Whole exome and targeted resequencing, of population based ovarian cancer cases and controls, identifies susceptibility genes for ovarian cancer
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Paul D.P. Pharoah, Usha Menon, Kunle Odunsi, Simon A. Gayther, Susan J. Ramus, Maria P. Intermaggio, Susanne K. Kjaer, Jacek Gronwald, Ellen L. Goode, Jane Hayward, Alice Wittemore, Beth Y. Karlan, David D.L. Bowtell, Ed Dicks, Honglin Song, and Jonathan Tyrer
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Genetics ,Cancer Research ,Candidate gene ,endocrine system diseases ,Cancer ,Biology ,medicine.disease ,Penetrance ,female genital diseases and pregnancy complications ,Germline ,Oncology ,medicine ,RAD51C ,Ovarian cancer ,Exome ,Exome sequencing - Abstract
The known genetic variance for epithelial ovarian cancer (EOC) accounts for less than half the familial risks of the disease. BRCA1 and BRCA2 are the major high-penetrance EOC susceptibility genes. More recently genes that interact with BRCA1 and BRCA2 in the same biological pathways, but conferring more moderate penetrance (e.g. RAD51C, RAD51D) have also been identified. Mutations in these genes result in defects in homologous recombination and double strand break repair (HR/DSB). We hypothesized that other genes operating in these and other DNA repair pathways may also confer EOC susceptibility. Whole exome sequencing data, available from more than 400 high-grade serous ovarian cancers, were used to identify 24 candidate genes harboring germline truncating mutations in at least 2 cases, followed by replication analysis using targeted resequencing in ~3,000 cases and 3,000 controls. Subjects were also sequenced for the known susceptibility genes listed above. The data confirmed the previously reported contributions of BRCA1, BRCA2, RAD51C and RAD51D to EOC. In addition, we identified BRIP1, and FANCM as candidate EOC susceptibility genes. Surprisingly, for several genes we found truncating mutations were equally prevalent in cases as they were in controls. These mutations may still represent rare low-penetrance susceptibility alleles for EOC, which we are too limited in sample size and power to confirm; or more likely, it indicates that cells can tolerate heterozygous loss-of-function mutations in apparently critical DNA repair genes without any impact on neoplastic development. These findings may have implications for risk prediction and prevention strategies for EOC and possibly for the identification of novel therapeutic targets. Citation Format: Susan J. Ramus, Honglin Song, Ed Dicks, Maria Intermaggio, Jane Hayward, Jonathan P. Tyrer, Jacek Gronwald, Susanne Krüger Kjær, Alice Wittemore, Beth Karlan, Kunle Odunsi, Usha Menon, David D. Bowtell, Ellen L. Goode, Paul D.P. Pharoah, Simon A. Gayther. Whole exome and targeted resequencing, of population based ovarian cancer cases and controls, identifies susceptibility genes for ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1213.
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- 2015
20. Abstract B14: Rapid RNA-based histotyping of ovarian carcinomas
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Steve E. Kalloger, David G. Huntsman, Robertson Mackenzie, Aline Talhouk, Stefan Kommoss, Michael S. Anglesio, Susan J. Ramus, Maria P. Intermaggio, Christine Chow, Gholamreza Haffari, Blake Gilks, Martin Cheung, Janine Senz, Andreas du Bois, Jacobus Pfisterer, Sherman Lau, Friedrich Kommoss, and Jessica N. McAlpine
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Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,business.industry ,RNA ,Recursive partitioning ,medicine.disease ,Serous fluid ,Internal medicine ,Ovarian carcinoma ,medicine ,Carcinoma ,Ovarian carcinomas ,Ovarian cancer ,business ,Clear cell - Abstract
Background: Ovarian cancer is a series of distinct diseases typically identified by their histopathological appearance as high-grade serous (HGSC; 70% of cases), low-grade serous (LGSC; 5%), endometrioid (ENOCa, 8%), clear cell (CCC, 12%), and mucinous (MC; 5%) carcinomas. Each type has defining molecular events, gene/protein expression patterns, genetic risk factors, sites of origin, and responses to treatment. Gold standard treatment is surgery followed by platinum-taxane chemotherapy despite mounting evidence suggesting CCCs, MCs, and LGSCs are largely platinum-taxane resistant. If outcomes are to be improved, it is critical to adopt a type specific strategy. Retrospective review studies have suggested histotype may be misdiagnosed or omitted in up to 30% of cases. However, pathological diagnosis of histotypes has been greatly refined in recent years and the use of biomarkers as aides is becoming more widespread. Nonetheless a rapid and fully objective classifier of histotypes will undoubtedly improve diagnostic accuracy, especially in the case of pre-surgical biopsies where small amounts of material present a challenge. Methods: Over 1000 ovarian carcinoma samples underwent expert gynecopathological review to establish a gold standard diagnosis for the 5 major carcinoma types. RNA was extracted from FFPE tissues and levels of a pre-selected set of >100 genes were quantified using the NanoString GX system. Cohort was split with ~1/3 set aside for independent validation. Several statistical models were tested to generate a prediction algorithm for histological type including PAM, Random Forest, Lasso, Recursive Partitioning, and Discriminant Analysis. Feature selection methods and prediction error were examined using cross-validation in the train /test series prior to validation in the independent set. Results: Preliminary analysis suggests classification of the 5 major histotypes is possible using NanoString derived RNA expression levels. Accuracy appears to be equivalent to interobserver variation amongst expert gynecopathologist. Conclusions: The NanoString GX platform provides a stable and reproducible platform on which a robust single sample histological type classifier can be established. Our algorithm combined with the NanoString platform provides a rapid, and cost-effective option that does not require modification to current pathology lab tissue processing protocols. Diagnostic prediction require little material and is applicable to pre- and post- surgical specimens where an objective measure is desired to confirm diagnosis or aide in especially challenging cases. Citation Format: Michael S. Anglesio, Aline Talhouk, Steve E. Kalloger, Gholamreza Haffari, Robertson Mackenzie, Martin Cheung, Janine Senz, Christine Chow, Sherman Lau, Maria Intermaggio, Susan J. Ramus, Andreas du Bois, Jacobus Pfisterer, Jessica N. McAlpine, Friedrich Kommoss, Blake Gilks, Stefan Kommoss, David G. Huntsman. Rapid RNA-based histotyping of ovarian carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B14.
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- 2013
21. Prognostic gene expression signature for high-grade serous ovarian cancer
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A. Green, Robertson Mackenzie, J. Hung, J. Boros, Linda E. Kelemen, S. Hernando Polo, Karen Byth, M. Links, J. Maidens, Amy Lum, R. Blum, C. Tseng, E. Sumithran, Oleg Oszurek, K. Nattress, Jolanta Lissowska, Gustavo C. Rodriguez, Ian Hammond, Mercedes Jimenez-Linan, K. Harrap, Andrew Berchuck, Naveena Singh, K. Ferguson, Raghwa Sharma, Paul R. Harnett, Simon A. Gayther, Brenda Y. Hernandez, S. Chen, R. Sayer, Hoa Tran, Susana Banerjee, Tony Bonaventura, Lewis Perrin, Britton Trabert, M. Malt, Kathryn Alsop, Peter Grant, Scott W. Brown, M. T. Goodman, J. Stewart, S.C.Y. Leung, Pamela J. Thompson, Boris Winterhoff, Peter Sinn, Iain A. McNeish, Anna M. Piskorz, Timothy Budden, Tom Jobling, T. Manolitsas, Clara Bodelon, Danny Rischin, R. Stuart-Harris, T. Sadkowsky, Janusz Menkiszak, L. Galletta, M. Cummings, M. C. Pike, Rene A. Zelaya, D. Nevell, Martin Widschwendter, Andreas Obermair, Melissa C. Larson, Penny Blomfield, D. Marsden, Keith Horwood, L.F. Ng, P. Clingan, Jenny Lester, Aline Talhouk, Bo Gao, D. Wyld, J. McNealage, Blake Gilks, Robert M. Rome, Geoff Macintyre, V. Billson, Izhak Haviv, C. Camaris, María Josefa Mosteiro García, Jacek Gronwald, L R Wilkens, Holly R. Harris, Margaret Davy, M. Robbie, Beatrice Susil, V. Jayde, Jennifer A. Doherty, G. Wain, N. Wentzensen, V. Chow, Hanwei Sudderuddin, T. Vanden Bergh, R. Houghton, Gottfried E. Konecny, D. Challis, M. Loughrey, Michael E. Carney, L. Edwards, Paul D.P. Pharoah, Alan L. Parker, Beth Y. Karlan, Catherine J. Kennedy, J. White, A.H. Wu, Stephen Lade, J. Hill, Peter Rogers, Y.E. Chiew, Chad A. Hall, Alicia Beeghly-Fadiel, T. Corrish, Rex C. Bentley, T. Dodd, J. Nicklin, S. Valmadre, R. Crouch, Stephen B. Fox, D.D. Bowtell, M. Jones, Sabine Behrens, G. Gard, Robert S. Brown, David H. Giles, C. Ball, Celeste Leigh Pearce, F. Kirsten, H. Shirley, Paul Waring, Cezary Cybulski, H. Song, J. Shannon, Darren Ennis, Y. Leung, A. Proietto, R. Jaworski, I.L. Ray-Coquard, Stacey J. Winham, E. Herpel, P. Beale, Jan Lubinski, P. Webb, Joy Hendley, Michael C. J. Quinn, L. Jackman, Valerie Rhenius, Amy E. Glasgow, S. Braye, A. Stenlake, Ellen L. Goode, Javier Benítez, T. Ramón y Cajal, H. Luk, Mark E. Sherman, R. McIntosh, Joellen M. Schildkraut, M. Friedlander, Sian Fereday, S. Moore, Anna deFazio, Joshua Millstein, Janine Senz, Vinod Ganju, A. Martyn, P. Ashover, Geoffrey Otton, L A Brinton, Jane Beith, Jennifer Alsop, Sanela Bilic, D. Gertig, a A. Ferrier, Simon Hyde, Deborah Neesham, Gary L. Keeney, Anthony McCartney, B. Young, L. Bowes, Susan J. Ramus, D.S. Chiu, Stefan Kommoss, D. Papadimos, Martin K. Oehler, A. Mellon, Nadia Traficante, R. Laurie, J. Carter, Sharon E. Johnatty, Tayyebeh M. Nazeran, D. Bell, Mila Volchek, A. Brand, Kara L. Cushing-Haugen, Daniel Johnson, Nick Pavlakis, A. Crandon, N. Pandeya, S. Viduka, R.M. Glasspool, Chloe Karpinskyj, Jenny Chang-Claude, A. Toloczko, David G. Huntsman, Euan A. Stronach, Georgia Chenevix-Trench, Jan Pyman, Nikolajs Zeps, Sandra Orsulic, G. Robertson, K. Martin, Liz-Anne Lewsley, A Gentry-Maharaj, Teodora Goranova, C. Young, Julia Brooks, N. O’Callaghan, S. Begbie, J. Rutovitz, Judy Miller, Jesús García-Donas, T. Healy, Samantha Hinsley, David D.L. Bowtell, James D. Brenton, Usha Menon, Wafaa Elatre, Scott H. Kaufmann, P. Mamers, Bruce M. Brown, David C. Whiteman, Mary Anne Rossing, C. Dalrymple, Kelly-Anne Phillips, Douglas A. Levine, Helen Steed, P. Russell, Peter A. Fasching, Michael D. Buck, Michelle J. Henderson, David W. Allen, DJ Slamon, R. Bell, Neville F. Hacker, J. Grygiel, B. Ranieri, Joshy George, Casey S. Greene, Tiffany M. Schmidt, Lawrence W. Green, Jennifer M Koziak, P.R. Harnett, B. Ward, H. Sullivan, Renée T. Fortner, David L. Healy, S. Baron-Hay, David M. Purdie, B. Alexander, I. Simpson, P. Mackenzie, Michael S. Anglesio, K. Pittman, J. Pierdes, Martin Köbel, H.S. Leong, Chen Wang, Lydia Glavinas, Paul Haluska, C. Underhill, D. Henderson, Maria P. Intermaggio, William K. Murray, R. Robertson, D. Silva De Silva, Sven Mahner, Imperial College Healthcare NHS Trust- BRC Funding, Cancer Research UK, Ovarian Cancer Action, Rhenius, Valerie [0000-0003-4215-3235], Brenton, James [0000-0002-5738-6683], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Oncology ,False discovery rate ,medicine.medical_specialty ,overall survival ,Article ,Transcriptome ,03 medical and health sciences ,Ovarian tumor ,0302 clinical medicine ,Internal medicine ,high-grade serous ovarian cancer ,Medicine ,Humans ,1112 Oncology and Carcinogenesis ,Oncology & Carcinogenesis ,Cystadenocarcinoma ,Survival analysis ,Proportional Hazards Models ,Ovarian Neoplasms ,business.industry ,Proportional hazards model ,AOCS Group ,Hematology ,formalin-fixed paraffin-embedded ,medicine.disease ,Prognosis ,Survival Analysis ,3. Good health ,Cystadenocarcinoma, Serous ,Clinical trial ,Serous fluid ,030104 developmental biology ,030220 oncology & carcinogenesis ,gene expression ,Female ,prognosis ,business - Abstract
Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is similar to 4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
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22. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.
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Song H, Dicks E, Ramus SJ, Tyrer JP, Intermaggio MP, Hayward J, Edlund CK, Conti D, Harrington P, Fraser L, Philpott S, Anderson C, Rosenthal A, Gentry-Maharaj A, Bowtell DD, Alsop K, Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, Høgdall E, Høgdall CK, Jensen A, Kjaer SK, Lubiński J, Huzarski T, Jakubowska A, Gronwald J, Poblete S, Lele S, Sucheston-Campbell L, Moysich KB, Odunsi K, Goode EL, Menon U, Jacobs IJ, Gayther SA, and Pharoah PD
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- Adult, Aged, Carcinoma, Ovarian Epithelial, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Humans, Middle Aged, Neoplasms, Glandular and Epithelial etiology, Neoplasms, Glandular and Epithelial pathology, Ovarian Neoplasms etiology, Ovarian Neoplasms pathology, DNA-Binding Proteins genetics, Germ-Line Mutation, Neoplasms, Glandular and Epithelial genetics, Ovarian Neoplasms genetics
- Abstract
Purpose: The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer., Patients and Methods: The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis., Results: In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001)., Conclusion: These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing., (© 2015 by American Society of Clinical Oncology.)
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- 2015
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