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1.  Mutational analysis of the tyrosine kinome in serous and clear cell endometrial cancer uncovers rare somatic mutations in TNK2 and DDR1 
BMC Cancer  2014;14(1):884.
Background
Endometrial cancer (EC) is the 8th leading cause of cancer death amongst American women. Most ECs are endometrioid, serous, or clear cell carcinomas, or an admixture of histologies. Serous and clear ECs are clinically aggressive tumors for which alternative therapeutic approaches are needed. The purpose of this study was to search for somatic mutations in the tyrosine kinome of serous and clear cell ECs, because mutated kinases can point to potential therapeutic targets.
Methods
In a mutation discovery screen, we PCR amplified and Sanger sequenced the exons encoding the catalytic domains of 86 tyrosine kinases from 24 serous, 11 clear cell, and 5 mixed histology ECs. For somatically mutated genes, we next sequenced the remaining coding exons from the 40 discovery screen tumors and sequenced all coding exons from another 72 ECs (10 clear cell, 21 serous, 41 endometrioid). We assessed the copy number of mutated kinases in this cohort of 112 tumors using quantitative real time PCR, and we used immunoblotting to measure expression of these kinases in endometrial cancer cell lines.
Results
Overall, we identified somatic mutations in TNK2 (tyrosine kinase non-receptor, 2) and DDR1 (discoidin domain receptor tyrosine kinase 1) in 5.3% (6 of 112) and 2.7% (3 of 112) of ECs. Copy number gains of TNK2 and DDR1 were identified in another 4.5% and 0.9% of 112 cases respectively. Immunoblotting confirmed TNK2 and DDR1 expression in endometrial cancer cell lines. Three of five missense mutations in TNK2 and one of two missense mutations in DDR1 are predicted to impact protein function by two or more in silico algorithms. The TNK2P761Rfs*72 frameshift mutation was recurrent in EC, and the DDR1R570Q missense mutation was recurrent across tumor types.
Conclusions
This is the first study to systematically search for mutations in the tyrosine kinome in clear cell endometrial tumors. Our findings indicate that high-frequency somatic mutations in the catalytic domains of the tyrosine kinome are rare in clear cell ECs. We uncovered ten new mutations in TNK2 and DDR1 within serous and endometrioid ECs, thus providing novel insights into the mutation spectrum of each gene in EC.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-884) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-884
PMCID: PMC4258955  PMID: 25427824
Endometrial; Cancer; Mutation; TNK2; ACK1; DDR1; Copy number; Tyrosine kinase; Tyrosine kinome
2.  The prognostic value of BRCA1 promoter methylation in early stage triple negative breast cancer 
Introduction
Methylation of the BRCA1 promoter is frequent in triple negative breast cancers (TNBC) and results in a tumor phenotype similar to BRCA1-mutated tumors. BRCA1 mutation-associated cancers are more sensitive to DNA damaging agents as compared to conventional chemotherapy agents. It is not known if there is an interaction between the presence of BRCA1 promoter methylation (PM) and response to chemotherapy agents in sporadic TNBC. We sought to investigate the prognostic significance of BRCA1 PM in TNBC patients receiving standard chemotherapy.
Methods
Subjects with stage I-III TNBC treated with chemotherapy were identified and their formalin-fixed paraffin-embedded (FFPE) tumor specimens retrieved. Genomic DNA was isolated and subjected to methylation-specific PCR (MSPCR).
Results
DNA was isolated from primary tumor of 39 subjects. BRCA1 PM was detected in 30% of patients. Presence of BRCA1 PM was associated with lower BRCA1 transcript levels, suggesting epigenetic BRCA1 silencing. All patients received chemotherapy (anthracycline:90%, taxane:69%). At a median follow-up of 64 months, 46% of patients have recurred and 36% have died. On univariate analysis, African-American race, node positivity, stage, and BRCA1 PM were associated with worse RFS and OS. Five year OS was 36% for patients with BRCA1 PM vs. 77% for patients without BRCA1 PM (p=0.004). On multivariable analysis, BRCA1 PM was associated with significantly worse RFS and OS.
Conclusions
We show that BRCA1 PM is common in TNBC and has the potential to identify a significant fraction of TNBC patients who have suboptimal outcomes with standard chemotherapy.
doi:10.7243/2049-7962-3-2
PMCID: PMC4147783  PMID: 25177489
Triple negative breast cancer; BRCA1 promoter methylation; prognosis; chemosensitivity; biomarker
3.  Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology† †Author contributions: M. H., Y. Z. and A. K. G. conceived research; M. H. and Y. Z. designed and fabricated the devices; M. H., Y. Z., J. C., and M. R. performed the research; M. H., Y. Z., and A. K. G. analyzed the data; M. H., Y. Z., and A. K. G. wrote the manuscript. ‡ ‡Electronic supplementary information (ESI) available. See DOI: 10.1039/c4lc00662c Click here for additional data file.  
Lab on a Chip  2014;14(19):3773-3780.
A microfluidic technology for integrated exosome analysis allows for specific immunoisolation, subpopulation profiling, and targeted proteomic analysis of circulating exosomes, with minimally invasive sample consumption and markedly improved assay speed and sensitivity.
Developing blood-based tests is appealing for non-invasive disease diagnosis, especially when biopsy is difficult, costly, and sometimes not even an option. Tumor-derived exosomes have attracted increasing interest in non-invasive cancer diagnosis and monitoring of treatment response. However, the biology and clinical value of exosomes remains largely unknown due in part to current technical challenges in rapid isolation, molecular classification and comprehensive analysis of exosomes. Here we developed a new microfluidic approach to streamline and expedite the exosome analysis pipeline by integrating specific immunoisolation and targeted protein analysis of circulating exosomes. Compared to the conventional methods, our approach enables selective subpopulation isolation and quantitative detection of surface and intravesicular biomarkers directly from a minimally invasive amount of plasma samples (30 μL) within ~100 min with markedly improved detection sensitivity. Using this device, we demonstrated phenotyping of exosome subpopulations by targeting a panel of common exosomal and tumor-specific markers and multiparameter analyses of intravesicular biomarkers in the selected subpopulation. We were able to assess the total expression and phosphorylation levels of IGF-1R in non-small-cell lung cancer patients by probing plasma exosomes as a non-invasive alternative to conventional tissue biopsy. We foresee that the microfluidic exosome analysis platform will form the basis for critically needed infrastructures for advancing the biology and clinical utilization of exosomes.
doi:10.1039/c4lc00662c
PMCID: PMC4161194  PMID: 25099143
4.  Drug Repurposing for Gastrointestinal Stromal Tumor 
Molecular cancer therapeutics  2013;12(7):1299-1309.
Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25–30 million people in the U.S. alone. Given the costs associated with the discovery, development and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, “drug repurposing” or “repositioning”, has emerged as an alternative to the traditional drug development process. In this study we screened 796 FDA-approved drugs and found that two of these compounds, auranofin and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs including imatinib-resistant cells. One of the most notable drug hits, auranofin (Ridaura®), an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis (RA), was found to inhibit thioredoxin reductase (TrxR) activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anti-cancer activity associated with auranofin was independent of IM resistant status, but was closely related to the endogenous and inducible levels of ROS, therefore is prior to IM response. Coupled with the fact auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for GIST patients, particularly in those suffering from imatinib-resistant and recurrent forms of this disease.
doi:10.1158/1535-7163.MCT-12-0968
PMCID: PMC3707936  PMID: 23657945
drug repurposing; drug repositioning; auranofin; gastrointestinal stromal tumors treatment; thioredoxin reductase activity
5.  A Phase II Evaluation of Gefitinib in the Treatment of Persistent or Recurrent Endometrial Cancer: A Gynecologic Oncology Group Study 
Gynecologic oncology  2013;129(3):486-494.
Background
A phase II trial was performed to evaluate the efficacy and safety of gefitinib in patients with persistent/recurrent endometrial cancer.
Methods
Women with histologically confirmed persistent/recurrent endometrial cancer were treated with 500 mg oral gefitinib daily until progression or severe toxicity, with progression-free survival (PFS) at six months as the primary endpoint. Tumor expression of total epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor A (PRA) and B (PRB), Ki67, pEGFR and activated extracellular signal-regulated kinase (pERK) were examined pre- and post-treatment. EGFR was sequenced, and serum concentrations of soluble EGFR (sEGFR) at baseline also were examined.
Results
Of 29 patients enrolled, 26 were evaluable for efficacy and toxicity. Four patients experienced PFS ≥6 months, and one had a complete response which was not associated with an EGFR mutation. The concentration of sEGFR in pretreatment serum was positively correlated with overall survival (OS), but not with responsiveness to gefitinib in this small patient cohort. Expression of tumor biomarkers was not associated with PFS or OS. Co-expression of ER with PRA in primary and recurrent tumors, and pEGFR with pERK in primary tumors was observed.
Conclusions
This treatment regimen was tolerable but lacked sufficient efficacy to warrant further evaluation in this setting. The possible association between serum sEGFR concentrations and OS, and temporal changes in expression of pEGFR and pERK and the documented CR of one patient are interesting and warrant additional investigation.
doi:10.1016/j.ygyno.2013.02.019
PMCID: PMC3700732  PMID: 23438670
gefitinib; endometrial cancer; epidermal growth factor receptor (EGFR); soluble EGFR; estrogen receptor; progesterone receptor
6.  Shortened Length of Stay Improves Financial Outcomes in Living Donor Kidney Transplantation 
Kidney transplantation is the preferred clinical and most cost-effective option for end-stage renal disease. Significant advances have taken place in the care of the transplant patients with improvements in clinical outcomes. The optimization of the costs of transplantation has been a constant goal as well. We present herein the impact in financial outcomes of a shortened length of stay after kidney transplant.
doi:10.1055/s-0033-1334139
PMCID: PMC3709984  PMID: 24436592
kidney transplantation; postoperative protocols; transplant outcomes; economic outcomes; arithmetic analysis
7.  Bench to bedside and back again: personalizing treatment for patients with GIST 
Molecular cancer therapeutics  2011;10(11):2026-2027.
doi:10.1158/1535-7163.MCT-11-0709
PMCID: PMC4007578  PMID: 22072810
8.  DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers 
Osorio, Ana | Milne, Roger L. | Kuchenbaecker, Karoline | Vaclová, Tereza | Pita, Guillermo | Alonso, Rosario | Peterlongo, Paolo | Blanco, Ignacio | de la Hoya, Miguel | Duran, Mercedes | Díez, Orland | Ramón y Cajal, Teresa | Konstantopoulou, Irene | Martínez-Bouzas, Cristina | Andrés Conejero, Raquel | Soucy, Penny | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | SWE-BRCA,  | Arver, Brita | Rantala, Johanna | Loman, Niklas | Ehrencrona, Hans | Olopade, Olufunmilayo I. | Beattie, Mary S. | Domchek, Susan M. | Nathanson, Katherine | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | John, Esther M. | Whittemore, Alice S. | Daly, Mary B. | Southey, Melissa | Hopper, John | Terry, Mary B. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Steele, Linda | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas v. O. | Jønson, Lars | Ejlertsen, Bent | Gerdes, Anne-Marie | Infante, Mar | Herráez, Belén | Moreno, Leticia Thais | Weitzel, Jeffrey N. | Herzog, Josef | Weeman, Kisa | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Bonanni, Bernardo | Mariette, Frederique | Volorio, Sara | Viel, Alessandra | Varesco, Liliana | Papi, Laura | Ottini, Laura | Tibiletti, Maria Grazia | Radice, Paolo | Yannoukakos, Drakoulis | Garber, Judy | Ellis, Steve | Frost, Debra | Platte, Radka | Fineberg, Elena | Evans, Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Eccles, Diana | Cook, Jackie | Hodgson, Shirley | Brewer, Carole | Tischkowitz, Marc | Douglas, Fiona | Porteous, Mary | Side, Lucy | Walker, Lisa | Morrison, Patrick | Donaldson, Alan | Kennedy, John | Foo, Claire | Godwin, Andrew K. | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hans Jörg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Gehrig, Andrea | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Damiola, Francesca | Poppe, Bruce | Claes, Kathleen | Piedmonte, Marion | Tucker, Kathy | Backes, Floor | Rodríguez, Gustavo | Brewster, Wendy | Wakeley, Katie | Rutherford, Thomas | Caldés, Trinidad | Nevanlinna, Heli | Aittomäki, Kristiina | Rookus, Matti A. | van Os, Theo A. M. | van der Kolk, Lizet | de Lange, J. L. | Meijers-Heijboer, Hanne E. J. | van der Hout, A. H. | van Asperen, Christi J. | Gómez Garcia, Encarna B. | Hoogerbrugge, Nicoline | Collée, J. Margriet | van Deurzen, Carolien H. M. | van der Luijt, Rob B. | Devilee, Peter | HEBON,  | Olah, Edith | Lázaro, Conxi | Teulé, Alex | Menéndez, Mireia | Jakubowska, Anna | Cybulski, Cezary | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Johannsson, Oskar Th. | Maugard, Christine | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Healey, Sue | Investigators, kConFab | Olswold, Curtis | Guidugli, Lucia | Lindor, Noralane | Slager, Susan | Szabo, Csilla I. | Vijai, Joseph | Robson, Mark | Kauff, Noah | Zhang, Liying | Rau-Murthy, Rohini | Fink-Retter, Anneliese | Singer, Christian F. | Rappaport, Christine | Geschwantler Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Berger, Andreas | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Lejbkowicz, Flavio | Andrulis, Irene | Mulligan, Anna Marie | Glendon, Gord | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Sunde, Lone | Thomassen, Mads | Kruse, Torben A. | Jensen, Uffe Birk | Friedman, Eitan | Laitman, Yael | Shimon, Shani Paluch | Simard, Jacques | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Benitez, Javier
PLoS Genetics  2014;10(4):e1004256.
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10−3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10−3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Author Summary
Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
doi:10.1371/journal.pgen.1004256
PMCID: PMC3974638  PMID: 24698998
9.  Genome-wide association studies identify four ER negative–specific breast cancer risk loci 
Garcia-Closas, Montserrat | Couch, Fergus J | Lindstrom, Sara | Michailidou, Kyriaki | Schmidt, Marjanka K | Brook, Mark N | orr, Nick | Rhie, Suhn Kyong | Riboli, Elio | Feigelson, Heather s | Le Marchand, Loic | Buring, Julie E | Eccles, Diana | Miron, Penelope | Fasching, Peter A | Brauch, Hiltrud | Chang-Claude, Jenny | Carpenter, Jane | Godwin, Andrew K | Nevanlinna, Heli | Giles, Graham G | Cox, Angela | Hopper, John L | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Dicks, Ed | Howat, Will J | Schoof, Nils | Bojesen, Stig E | Lambrechts, Diether | Broeks, Annegien | Andrulis, Irene L | Guénel, Pascal | Burwinkel, Barbara | Sawyer, Elinor J | Hollestelle, Antoinette | Fletcher, Olivia | Winqvist, Robert | Brenner, Hermann | Mannermaa, Arto | Hamann, Ute | Meindl, Alfons | Lindblom, Annika | Zheng, Wei | Devillee, Peter | Goldberg, Mark S | Lubinski, Jan | Kristensen, Vessela | Swerdlow, Anthony | Anton-Culver, Hoda | Dörk, Thilo | Muir, Kenneth | Matsuo, Keitaro | Wu, Anna H | Radice, Paolo | Teo, Soo Hwang | Shu, Xiao-Ou | Blot, William | Kang, Daehee | Hartman, Mikael | Sangrajrang, Suleeporn | Shen, Chen-Yang | Southey, Melissa C | Park, Daniel J | Hammet, Fleur | Stone, Jennifer | Veer, Laura J Van’t | Rutgers, Emiel J | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Peto, Julian | Schrauder, Michael G | Ekici, Arif B | Beckmann, Matthias W | Silva, Isabel dos Santos | Johnson, Nichola | Warren, Helen | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federick | Schneeweiss, Andreas | Sohn, Christof | Truong, Therese | Laurent-Puig, Pierre | Kerbrat, Pierre | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Milne, Roger L | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Lichtner, Peter | Lochmann, Magdalena | Justenhoven, Christina | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Greco, Dario | Heikkinen, Tuomas | Ito, Hidemi | Iwata, Hiroji | Yatabe, Yasushi | Antonenkova, Natalia N | Margolin, Sara | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Balleine, Rosemary | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Neven, Patrick | Dieudonné, Anne-Sophie | Leunen, Karin | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Peterlongo, Paolo | Peissel, Bernard | Bernard, Loris | Olson, Janet E | Wang, Xianshu | Stevens, Kristen | Severi, Gianluca | Baglietto, Laura | Mclean, Catriona | Coetzee, Gerhard A | Feng, Ye | Henderson, Brian E | Schumacher, Fredrick | Bogdanova, Natalia V | Labrèche, France | Dumont, Martine | Yip, Cheng Har | Taib, Nur Aishah Mohd | Cheng, Ching-Yu | Shrubsole, Martha | Long, Jirong | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Tollenaar, Robertus A E M | Seynaeve, Caroline M | Kriege, Mieke | Hooning, Maartje J | Van den Ouweland, Ans M W | Van Deurzen, Carolien H M | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Balasubramanian, Sabapathy P | Cross, Simon S | Reed, Malcolm W R | Signorello, Lisa | Cai, Qiuyin | Shah, Mitul | Miao, Hui | Chan, Ching Wan | Chia, Kee Seng | Jakubowska, Anna | Jaworska, Katarzyna | Durda, Katarzyna | Hsiung, Chia-Ni | Wu, Pei-Ei | Yu, Jyh-Cherng | Ashworth, Alan | Jones, Michael | Tessier, Daniel C | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Vincent, Daniel | Bacot, Francois | Ambrosone, Christine B | Bandera, Elisa V | John, Esther M | Chen, Gary K | Hu, Jennifer J | Rodriguez-gil, Jorge L | Bernstein, Leslie | Press, Michael F | Ziegler, Regina G | Millikan, Robert M | Deming-Halverson, Sandra L | Nyante, Sarah | Ingles, Sue A | Waisfisz, Quinten | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel | Bui, Minh | Gibson, Lorna | Müller-Myhsok, Bertram | Schmutzler, Rita K | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Turnbull, Clare | Rahman, Nazneen | Meijers-Heijboer, Hanne | Uitterlinden, Andre G | Rivadeneira, Fernando | Olswold, Curtis | Slager, Susan | Pilarski, Robert | Ademuyiwa, Foluso | Konstantopoulou, Irene | Martin, Nicholas G | Montgomery, Grant W | Slamon, Dennis J | Rauh, Claudia | Lux, Michael P | Jud, Sebastian M | Bruning, Thomas | Weaver, Joellen | Sharma, Priyanka | Pathak, Harsh | Tapper, Will | Gerty, Sue | Durcan, Lorraine | Trichopoulos, Dimitrios | Tumino, Rosario | Peeters, Petra H | Kaaks, Rudolf | Campa, Daniele | Canzian, Federico | Weiderpass, Elisabete | Johansson, Mattias | Khaw, Kay-Tee | Travis, Ruth | Clavel-Chapelon, Françoise | Kolonel, Laurence N | Chen, Constance | Beck, Andy | Hankinson, Susan E | Berg, Christine D | Hoover, Robert N | Lissowska, Jolanta | Figueroa, Jonine D | Chasman, Daniel I | Gaudet, Mia M | Diver, W Ryan | Willett, Walter C | Hunter, David J | Simard, Jacques | Benitez, Javier | Dunning, Alison M | Sherman, Mark E | Chenevix-Trench, Georgia | Chanock, Stephen J | Hall, Per | Pharoah, Paul D P | Vachon, Celine | Easton, Douglas F | Haiman, Christopher A | Kraft, Peter
Nature genetics  2013;45(4):392-398e2.
Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
doi:10.1038/ng.2561
PMCID: PMC3771695  PMID: 23535733
10.  A phase II evaluation of lapatinib in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: A gynecologic oncology group study☆ 
Gynecologic oncology  2011;124(3):569-574.
Objective
Activation and dimerization of the ERBB family play a role in the pathogenesis and progression of ovarian cancer. We conducted a phase II trial to evaluate the activity and tolerability of lapatinib in patients with recurrent or persistent epithelial ovarian cancer (EOC) and to explore the clinical value of expression levels of epidermal growth factor receptors (EGFR), phosphorylated EGFR, HER-2/neu, and Ki-67, and the presence of EGFR mutations.
Methods
Eligible patients had recurrent or persistent EOC or primary peritoneal carcinoma, measurable disease, and up to 2 prior chemotherapy regimens for recurrent disease. Patients were treated with lapatinib 1500 mg/day. The primary endpoint of efficacy was 6-month progression free survival (PFS).
Results
Twenty-five of 28 patients were eligible and evaluable for analysis of efficacy and toxicity. Two (8.0%) were alive and progression-free at 6 months. No objective responses were observed. There were 1 grade 4 toxicity (fatigue) and few grade 3 toxicities. Associations between Ki-67 with prior platinum-free interval, PFS, and a polymorphism in EGFR were suggested.
Conclusions
Lapatinib has minimal activity in recurrent ovarian cancer. Ki-67 expression may be associated with prior PFS and a polymorphism in EGFR exon 20 (2361G>A, Q787Q).
doi:10.1016/j.ygyno.2011.10.022
PMCID: PMC3971755  PMID: 22037316
Epidermal growth factor receptor (EGFR); Ki-67; Lapatinib; Ovarian cancer
11.  Loss of A-type lamin expression compromises nuclear envelope integrity in breast cancer 
Chinese journal of cancer  2011;30(6):415-425.
Through advances in technology, the genetic basis of cancer has been investigated at the genomic level, and many fundamental questions have begun to be addressed. Among several key unresolved questions in cancer biology, the molecular basis for the link between nuclear deformation and malignancy has not been determined. Another hallmark of human cancer is aneuploidy; however, the causes and consequences of aneuploidy are unanswered and are hotly contested topics.
We found that nuclear lamina proteins lamin A/C are absent in a significant fraction (38%) of human breast cancer tissues. Even in lamin A/C–positive breast cancer, lamin A/C expression is heterogeneous or aberrant (such as non-nuclear distribution) in the population of tumor cells, as determined by immunohistology and immunofluorescence microscopy. In most breast cancer cell lines, a significant fraction of the lamin A/C–negative population was observed. To determine the consequences of the loss of lamin A/C, we suppressed their expression by shRNA in non-cancerous primary breast epithelial cells. Down-regulation of lamin A/C in breast epithelial cells led to morphological deformation, resembling that of cancer cells, as observed by immunofluorescence microscopy. The lamin A/C–suppressed breast epithelial cells developed aneuploidy as determined by both flow cytometry and fluorescence in situ hybridization. We conclude that the loss of nuclear envelope structural proteins lamin A/C in breast cancer underlies the two hallmarks of cancer—aberrations in nuclear morphology and aneuploidy.
PMCID: PMC3941915  PMID: 21627864
Nuclear envelope; lamin A/C; aneuploidy; polyploidy; nuclear grade; nuclear morphology; breast cancer
12.  Tumor-derived exosomes 
Intercellular communication is a key process in the development and progression of cancer. The dynamic and reciprocal interplays between the tumor and its microenvironment orchestrate events critical to the establishment of primary and metastatic niches and maintenance of a permissive environment at the tumor−stroma interface. Atay and colleagues found that gastrointestinal stromal tumor cells secrete vesicles known as exosomes. These exosomes contain oncogenic KIT and their transfer and uptake by surrounding smooth muscle cells lead to enhanced AKT and MAPK signaling and phenotypic modulation of several cellular processes, including morphological changes, expression of tumor-associated markers, secretion of matrix metalloproteinases, and enhanced tumor cell invasion. This provocative study emphasizes that exosome-mediated signaling within the tumor microenvironment acts as a positive feedback loop that contributes to invasiveness and that interfering with this message delivery system may represent promising therapeutic approaches, not only for GIST, but for other types of cancer.
doi:10.4161/cib.28231
PMCID: PMC3995727  PMID: 24778765
Exosomes; GIST; tumor micro-environment; invasion; feedback loop
13.  Over-expression of IGF1R and Frequent Mutational Inactivation of SDHA in Wild-type SDHB-negative Gastrointestinal Stromal Tumors 
Genes, chromosomes & cancer  2012;52(2):214-224.
Approximately 15% of gastrointestinal stromal tumors (GISTs) in adults and 85% in children lack mutations in KIT and PDGFRA and are known as wild type GISTs. Wild type GISTs from adults and children express high levels of insulin-like growth factor 1 receptor (IGF1R) and exhibit stable genomes compared to mutant GISTs. Pediatric wild type GISTs, GISTs from the multi-tumor Carney-Stratakis syndrome and the Carney triad share other clinico-pathological properties (e.g. early-onset, multifocal GISTs with epitheliod cell morphology) suggesting a common etiology. Carney-Stratakis is an inherited association of GIST and paragangliomas caused by germline mutations in succinate dehydrogenase (SDH) genes. The connection between defective cellular respiration and GIST pathology has been strengthened by the utilization of SDHB immunohistochemistry to identify SDH deficiency in pediatric GISTs, syndromic GISTs, and some adult wild type GISTs. SDHB and IGF1R expression was examined in 12 wild type and 12 mutant GIST cases. Wild type GISTs were screened for coding-region alterations in SDH genes and for chromosomal aberrations using genome-wide SNP and MIP arrays. SDHB-deficiency, identified in 11/12 wild type GIST cases, was tightly associated with over-expression of IGF1R protein and transcript. Biallelic inactivation of the SDHA gene was a surprisingly frequent event, identified in 5/11 SDHB-negative cases, generally due to germline point mutations accompanied by somatic SDHA allelic losses. As a novel finding, inactivation of the SDHC gene from a combination of a heterozygous coding-region mutation and hyper-methylation of the wild type allele was found in one SDHB-negative case.
doi:10.1002/gcc.22023
PMCID: PMC3564228  PMID: 23109135
14.  Aurora Kinase A Mediates Epithelial Ovarian Cancer Cell Migration and Adhesion 
Oncogene  2013;33(5):539-549.
Aurora kinase A (AURKA) localizes to centrosomes and mitotic spindles where it mediates mitotic progression and chromosomal stability. Overexpression of AURKA is common in cancer, resulting in acquisition of alternate non-mitotic functions. In the current study, we identified a novel role for AURKA in regulating ovarian cancer cell dissemination and evaluated the efficacy of an AURKA-selective small molecule inhibitor, alisertib (MLN8237), as a single agent and combined with paclitaxel using an orthotopic xenograft model of epithelial ovarian cancer (EOC). Ovarian carcinoma cell lines were used to evaluate the effects of AURKA inhibition and overexpression on migration and adhesion. Pharmacologic or RNAi-mediated inhibition of AURKA significantly reduced ovarian carcinoma cell migration and adhesion and the activation-associated phosphorylation of the cytoskeletal regulatory protein SRC at tyrosine 416 (pSRCY416). Conversely, enforced expression of AURKA resulted in increased migration, adhesion and activation of SRC in cultured cells. In vivo tumor growth and dissemination were inhibited by alisertib treatment as a single agent. Moreover, combination of alisertib with paclitaxel, an agent commonly used in treatment of EOC, resulted in more potent inhibition of tumor growth and dissemination compared to either drug alone. Taken together, these findings support a role for AURKA in EOC dissemination by regulating migration and adhesion. They also point to the potential utility of combining AURKA inhibitors with taxanes as a therapeutic strategy for the treatment of EOC patients.
doi:10.1038/onc.2012.632
PMCID: PMC3640671  PMID: 23334327
Aurora kinase A; SRC; ovarian cancer; migration; alisertib; adhesion
15.  A Multicenter Pilot Study Examining the Role of Circulating Tumor Cells as a Blood-Based Tumor Marker in Patients with Extensive Small-Cell Lung Cancer 
Frontiers in Oncology  2014;4:271.
Background: Small-cell lung cancer (SCLC), a variant of lung cancer marked by early metastases, accounts for 13% of all lung cancers diagnosed in US. Despite high response rates to treatment, it is an aggressive disease with a median survival of 9–11 months for patients with extensive stage (EX-SCLC). Detection of circulating tumor cells (CTCs) is a novel laboratory technique currently in use to determine response to therapy and to predict prognosis in breast, colorectal, and prostate cancer. We initiated a pilot study to analyze the role of CTCs as a biomarker of response and relapse in patients with EX-SCLC.
Methods: We collected blood samples from chemotherapy naïve patients with EX-SCLC prior to initiation of therapy, after completion of systemic therapy, and follow-up every 6–8 weeks and at relapse. The number of CTCs was determined using the cell search system in a central laboratory. The study was conducted in four different sites, and it was reviewed and approved by respective research review committees and IRBs.
Results: We enrolled 26 patients with EX-SCLC, 1 was excluded due to ineligibility, all were treated with platinum and etoposide. We observed partial response in 16 patients, stable disease in 3 patients, 1 patient with disease progression, and 6 patients were not assessed (5 deceased, 1 not available). The overall median number of CTCs in 24 patients measured at baseline and post-tx was 75 (range 0–3430) and 2 (range 0–526), respectively. A significant reduction in CTCs from baseline to post-treatment was identified for 15 subjects; the median reduction was 97.4% (range −100 to +100%, p < 0.001). Higher baseline CTCs and percentage change in post-treatment CTCs were associated with decreased survival.
Conclusion: We demonstrated that it is feasible to detect CTCs in EX-SCLC. If validated in other prospective studies, CTCs could be a useful biomarker in the management of EX-SCLC by predicting patients’ clinical responses to therapy.
doi:10.3389/fonc.2014.00271
PMCID: PMC4196518  PMID: 25353007
small-cell lung carcinoma; circulating tumor cells; biomarkers; prognosis; extensive stage
16.  A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11 
Siddiq, Afshan | Couch, Fergus J. | Chen, Gary K. | Lindström, Sara | Eccles, Diana | Millikan, Robert C. | Michailidou, Kyriaki | Stram, Daniel O. | Beckmann, Lars | Rhie, Suhn Kyong | Ambrosone, Christine B. | Aittomäki, Kristiina | Amiano, Pilar | Apicella, Carmel | Baglietto, Laura | Bandera, Elisa V. | Beckmann, Matthias W. | Berg, Christine D. | Bernstein, Leslie | Blomqvist, Carl | Brauch, Hiltrud | Brinton, Louise | Bui, Quang M. | Buring, Julie E. | Buys, Saundra S. | Campa, Daniele | Carpenter, Jane E. | Chasman, Daniel I. | Chang-Claude, Jenny | Chen, Constance | Clavel-Chapelon, Françoise | Cox, Angela | Cross, Simon S. | Czene, Kamila | Deming, Sandra L. | Diasio, Robert B. | Diver, W. Ryan | Dunning, Alison M. | Durcan, Lorraine | Ekici, Arif B. | Fasching, Peter A. | Feigelson, Heather Spencer | Fejerman, Laura | Figueroa, Jonine D. | Fletcher, Olivia | Flesch-Janys, Dieter | Gaudet, Mia M. | Gerty, Susan M. | Rodriguez-Gil, Jorge L. | Giles, Graham G. | van Gils, Carla H. | Godwin, Andrew K. | Graham, Nikki | Greco, Dario | Hall, Per | Hankinson, Susan E. | Hartmann, Arndt | Hein, Rebecca | Heinz, Judith | Hoover, Robert N. | Hopper, John L. | Hu, Jennifer J. | Huntsman, Scott | Ingles, Sue A. | Irwanto, Astrid | Isaacs, Claudine | Jacobs, Kevin B. | John, Esther M. | Justenhoven, Christina | Kaaks, Rudolf | Kolonel, Laurence N. | Coetzee, Gerhard A. | Lathrop, Mark | Le Marchand, Loic | Lee, Adam M. | Lee, I-Min | Lesnick, Timothy | Lichtner, Peter | Liu, Jianjun | Lund, Eiliv | Makalic, Enes | Martin, Nicholas G. | McLean, Catriona A. | Meijers-Heijboer, Hanne | Meindl, Alfons | Miron, Penelope | Monroe, Kristine R. | Montgomery, Grant W. | Müller-Myhsok, Bertram | Nickels, Stefan | Nyante, Sarah J. | Olswold, Curtis | Overvad, Kim | Palli, Domenico | Park, Daniel J. | Palmer, Julie R. | Pathak, Harsh | Peto, Julian | Pharoah, Paul | Rahman, Nazneen | Rivadeneira, Fernando | Schmidt, Daniel F. | Schmutzler, Rita K. | Slager, Susan | Southey, Melissa C. | Stevens, Kristen N. | Sinn, Hans-Peter | Press, Michael F. | Ross, Eric | Riboli, Elio | Ridker, Paul M. | Schumacher, Fredrick R. | Severi, Gianluca | dos Santos Silva, Isabel | Stone, Jennifer | Sund, Malin | Tapper, William J. | Thun, Michael J. | Travis, Ruth C. | Turnbull, Clare | Uitterlinden, Andre G. | Waisfisz, Quinten | Wang, Xianshu | Wang, Zhaoming | Weaver, JoEllen | Schulz-Wendtland, Rüdiger | Wilkens, Lynne R. | Van Den Berg, David | Zheng, Wei | Ziegler, Regina G. | Ziv, Elad | Nevanlinna, Heli | Easton, Douglas F. | Hunter, David J. | Henderson, Brian E. | Chanock, Stephen J. | Garcia-Closas, Montserrat | Kraft, Peter | Haiman, Christopher A. | Vachon, Celine M.
Human Molecular Genetics  2012;21(24):5373-5384.
Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10-5 in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10−8) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10–6) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10−9), and with both ER-positive (OR = 1.09; P = 1.5 × 10−5) and ER-negative (OR = 1.16, P = 2.5 × 10−7) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
doi:10.1093/hmg/dds381
PMCID: PMC3510753  PMID: 22976474
17.  A Phase II Evaluation of Aflibercept in the Treatment of Recurrent or Persistent Endometrial Cancer: a Gynecologic Oncology Group study 
Gynecologic oncology  2012;127(3):538-543.
Purpose
Aflibercept targets vascular endothelial growth factor and placental growth factor. We evaluated activity and toxicity of aflibercept in recurrent/persistent endometrial cancer patients. Biomarkers and association with clinical characteristics and outcome were explored.
Methods
Eligible patients had measurable disease; 1–2 prior cytotoxic regimens; performance status 0–2. Aflibercept 4 mg/kg IV q14 days (28-day cycles) was administered until disease progression or prohibitive toxicity. Primary endpoints were the proportion of patients with progression-free survival at six months (PFS6) and tumor response rate. A flexible two-stage group sequential design to detect 20% increases in the proportion of patients responding or enduring PFS6 with 90% power (α=10%) was employed.
Results
Forty-nine patients were enrolled; five were excluded: wrong primary (2), second primary (1), wrong cell type (1); never treated (1). Median age was 64 (range 48–83). Eighteen patients (41%) had two prior regimens; 61%(27) had prior radiation. The PFS6 rate was 41%; three patients 7%, 90% CI:2–17) had partial response. Of note, 10 patients (23%) met the PFS6 endpoint without starting a subsequent therapy; the remaining eight patients discontinued therapy for toxicity and started another therapy before six months elapsed. Median PFS and overall survival were 2.9 months and 14.6 months, respectively. Significant grade 3/4 toxicities were: cardiovascular (23%/5%), constitutional (7%/0), hemorrhage (2%/5%), metabolic (7%/2%), pain (18%/0). Two treatment-related deaths were recorded: GI perforation (1), arterial rupture (1). FGF1 expression was associated with response.
Conclusions
Aflibercept met pretrial activity parameters, but was associated with significant toxicity at this dose and schedule in this population.
doi:10.1016/j.ygyno.2012.08.020
PMCID: PMC3568489  PMID: 22922531
Aflibercept; endometrial cancer; VEGF Trap; Toxicity; Fibroblast growth factor
18.  Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers 
Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [Hazard ratio (HR)=1.55, 95% CI 1.25–1.92, p=6.0×10−5]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers [HR=1.09, 95% CI 0.96–1.24, p=0.18]. No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.
doi:10.1007/s10549-012-2255-6
PMCID: PMC3482828  PMID: 23011509
BRCA1; BRCA2; genetic modifier; association study
19.  Lapatinib and Potential Prognostic Value of EGFR Mutations in a Gynecologic Oncology Group Phase II Trial of Persistent or Recurrent Endometrial Cancer 
Gynecologic oncology  2012;127(2):345-350.
BACKGROUND
A phase II trial was performed to evaluate the efficacy and safety of the tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, lapatinib, and to explore EGFR, HER2 (EGFR2), phosphorylated ERK MAP Kinase (pERK), and Ki67 expression, as well as EGFR mutations in persistent/recurrent endometrial cancer (EC).
METHODS
Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 1500 mg oral lapatinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with 6 month PFS as the primary endpoint. The trial had a 10% type I error rate with 90% power. EGFR, HER2, pERK, and Ki67 were evaluated by immunohistochemistry (IHC) from hysterectomy specimens, pre-treatment biopsies, and post-treatment biopsies (when available). Exons 18-21 of EGFR were sequenced.
RESULTS
Three patients of 30 evaluable had PFS ≥6 months, one had a partial response, seven had stable disease, 21 had progressive disease and one was indeterminate. Three mutations in EGFR were identified. Two of these, L688F and K754E, were not associated with response or PFS. However, a newly identified mutation in exon 18, E690K, occurred in the patient with a partial response and progression-free survival extending past six months.
CONCLUSION
While lapatinib has limited activity in unselected cases, the identification of a previously unreported mutation in EGFR (E690K) with a response, suggests that lapatinib may be beneficial in some cases of EC.
doi:10.1016/j.ygyno.2012.07.127
PMCID: PMC3518448  PMID: 22885469
endometrial cancer; epidermal growth factor receptor; mutation; lapatinib; tyrosine kinase inhibitor
20.  Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer 
Bojesen, Stig E | Pooley, Karen A | Johnatty, Sharon E | Beesley, Jonathan | Michailidou, Kyriaki | Tyrer, Jonathan P | Edwards, Stacey L | Pickett, Hilda A | Shen, Howard C | Smart, Chanel E | Hillman, Kristine M | Mai, Phuong L | Lawrenson, Kate | Stutz, Michael D | Lu, Yi | Karevan, Rod | Woods, Nicholas | Johnston, Rebecca L | French, Juliet D | Chen, Xiaoqing | Weischer, Maren | Nielsen, Sune F | Maranian, Melanie J | Ghoussaini, Maya | Ahmed, Shahana | Baynes, Caroline | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | Healey, Sue | Lush, Michael | Tessier, Daniel C | Vincent, Daniel | Bacot, Françis | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Risch, Harvey A | González-Neira, Anna | Rossing, Mary Anne | Pita, Guillermo | Doherty, Jennifer A | Álvarez, Nuria | Larson, Melissa C | Fridley, Brooke L | Schoof, Nils | Chang-Claude, Jenny | Cicek, Mine S | Peto, Julian | Kalli, Kimberly R | Broeks, Annegien | Armasu, Sebastian M | Schmidt, Marjanka K | Braaf, Linde M | Winterhoff, Boris | Nevanlinna, Heli | Konecny, Gottfried E | Lambrechts, Diether | Rogmann, Lisa | Guénel, Pascal | Teoman, Attila | Milne, Roger L | Garcia, Joaquin J | Cox, Angela | Shridhar, Vijayalakshmi | Burwinkel, Barbara | Marme, Frederik | Hein, Rebecca | Sawyer, Elinor J | Haiman, Christopher A | Wang-Gohrke, Shan | Andrulis, Irene L | Moysich, Kirsten B | Hopper, John L | Odunsi, Kunle | Lindblom, Annika | Giles, Graham G | Brenner, Hermann | Simard, Jacques | Lurie, Galina | Fasching, Peter A | Carney, Michael E | Radice, Paolo | Wilkens, Lynne R | Swerdlow, Anthony | Goodman, Marc T | Brauch, Hiltrud | García-Closas, Montserrat | Hillemanns, Peter | Winqvist, Robert | Dürst, Matthias | Devilee, Peter | Runnebaum, Ingo | Jakubowska, Anna | Lubinski, Jan | Mannermaa, Arto | Butzow, Ralf | Bogdanova, Natalia V | Dörk, Thilo | Pelttari, Liisa M | Zheng, Wei | Leminen, Arto | Anton-Culver, Hoda | Bunker, Clareann H | Kristensen, Vessela | Ness, Roberta B | Muir, Kenneth | Edwards, Robert | Meindl, Alfons | Heitz, Florian | Matsuo, Keitaro | du Bois, Andreas | Wu, Anna H | Harter, Philipp | Teo, Soo-Hwang | Schwaab, Ira | Shu, Xiao-Ou | Blot, William | Hosono, Satoyo | Kang, Daehee | Nakanishi, Toru | Hartman, Mikael | Yatabe, Yasushi | Hamann, Ute | Karlan, Beth Y | Sangrajrang, Suleeporn | Kjaer, Susanne Krüger | Gaborieau, Valerie | Jensen, Allan | Eccles, Diana | Høgdall, Estrid | Shen, Chen-Yang | Brown, Judith | Woo, Yin Ling | Shah, Mitul | Azmi, Mat Adenan Noor | Luben, Robert | Omar, Siti Zawiah | Czene, Kamila | Vierkant, Robert A | Nordestgaard, Børge G | Flyger, Henrik | Vachon, Celine | Olson, Janet E | Wang, Xianshu | Levine, Douglas A | Rudolph, Anja | Weber, Rachel Palmieri | Flesch-Janys, Dieter | Iversen, Edwin | Nickels, Stefan | Schildkraut, Joellen M | Silva, Isabel Dos Santos | Cramer, Daniel W | Gibson, Lorna | Terry, Kathryn L | Fletcher, Olivia | Vitonis, Allison F | van der Schoot, C Ellen | Poole, Elizabeth M | Hogervorst, Frans B L | Tworoger, Shelley S | Liu, Jianjun | Bandera, Elisa V | Li, Jingmei | Olson, Sara H | Humphreys, Keith | Orlow, Irene | Blomqvist, Carl | Rodriguez-Rodriguez, Lorna | Aittomäki, Kristiina | Salvesen, Helga B | Muranen, Taru A | Wik, Elisabeth | Brouwers, Barbara | Krakstad, Camilla | Wauters, Els | Halle, Mari K | Wildiers, Hans | Kiemeney, Lambertus A | Mulot, Claire | Aben, Katja K | Laurent-Puig, Pierre | van Altena, Anne M | Truong, Thérèse | Massuger, Leon F A G | Benitez, Javier | Pejovic, Tanja | Perez, Jose Ignacio Arias | Hoatlin, Maureen | Zamora, M Pilar | Cook, Linda S | Balasubramanian, Sabapathy P | Kelemen, Linda E | Schneeweiss, Andreas | Le, Nhu D | Sohn, Christof | Brooks-Wilson, Angela | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Cybulski, Cezary | Henderson, Brian E | Menkiszak, Janusz | Schumacher, Fredrick | Wentzensen, Nicolas | Marchand, Loic Le | Yang, Hannah P | Mulligan, Anna Marie | Glendon, Gord | Engelholm, Svend Aage | Knight, Julia A | Høgdall, Claus K | Apicella, Carmel | Gore, Martin | Tsimiklis, Helen | Song, Honglin | Southey, Melissa C | Jager, Agnes | van den Ouweland, Ans M W | Brown, Robert | Martens, John W M | Flanagan, James M | Kriege, Mieke | Paul, James | Margolin, Sara | Siddiqui, Nadeem | Severi, Gianluca | Whittemore, Alice S | Baglietto, Laura | McGuire, Valerie | Stegmaier, Christa | Sieh, Weiva | Müller, Heiko | Arndt, Volker | Labrèche, France | Gao, Yu-Tang | Goldberg, Mark S | Yang, Gong | Dumont, Martine | McLaughlin, John R | Hartmann, Arndt | Ekici, Arif B | Beckmann, Matthias W | Phelan, Catherine M | Lux, Michael P | Permuth-Wey, Jenny | Peissel, Bernard | Sellers, Thomas A | Ficarazzi, Filomena | Barile, Monica | Ziogas, Argyrios | Ashworth, Alan | Gentry-Maharaj, Aleksandra | Jones, Michael | Ramus, Susan J | Orr, Nick | Menon, Usha | Pearce, Celeste L | Brüning, Thomas | Pike, Malcolm C | Ko, Yon-Dschun | Lissowska, Jolanta | Figueroa, Jonine | Kupryjanczyk, Jolanta | Chanock, Stephen J | Dansonka-Mieszkowska, Agnieszka | Jukkola-Vuorinen, Arja | Rzepecka, Iwona K | Pylkäs, Katri | Bidzinski, Mariusz | Kauppila, Saila | Hollestelle, Antoinette | Seynaeve, Caroline | Tollenaar, Rob A E M | Durda, Katarzyna | Jaworska, Katarzyna | Hartikainen, Jaana M | Kosma, Veli-Matti | Kataja, Vesa | Antonenkova, Natalia N | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Lophatananon, Artitaya | Siriwanarangsan, Pornthep | Stewart-Brown, Sarah | Ditsch, Nina | Lichtner, Peter | Schmutzler, Rita K | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Tseng, Chiu-Chen | Stram, Daniel O | van den Berg, David | Yip, Cheng Har | Ikram, M Kamran | Teh, Yew-Ching | Cai, Hui | Lu, Wei | Signorello, Lisa B | Cai, Qiuyin | Noh, Dong-Young | Yoo, Keun-Young | Miao, Hui | Iau, Philip Tsau-Choong | Teo, Yik Ying | McKay, James | Shapiro, Charles | Ademuyiwa, Foluso | Fountzilas, George | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Healey, Catherine S | Luccarini, Craig | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Rebbeck, Timothy R | Piedmonte, Marion | Singer, Christian F | Friedman, Eitan | Thomassen, Mads | Offit, Kenneth | Hansen, Thomas V O | Neuhausen, Susan L | Szabo, Csilla I | Blanco, Ignacio | Garber, Judy | Narod, Steven A | Weitzel, Jeffrey N | Montagna, Marco | Olah, Edith | Godwin, Andrew K | Yannoukakos, Drakoulis | Goldgar, David E | Caldes, Trinidad | Imyanitov, Evgeny N | Tihomirova, Laima | Arun, Banu K | Campbell, Ian | Mensenkamp, Arjen R | van Asperen, Christi J | van Roozendaal, Kees E P | Meijers-Heijboer, Hanne | Collée, J Margriet | Oosterwijk, Jan C | Hooning, Maartje J | Rookus, Matti A | van der Luijt, Rob B | van Os, Theo A M | Evans, D Gareth | Frost, Debra | Fineberg, Elena | Barwell, Julian | Walker, Lisa | Kennedy, M John | Platte, Radka | Davidson, Rosemarie | Ellis, Steve D | Cole, Trevor | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Damiola, Francesca | Faivre, Laurence | Frenay, Marc | Sinilnikova, Olga M | Caron, Olivier | Giraud, Sophie | Mazoyer, Sylvie | Bonadona, Valérie | Caux-Moncoutier, Virginie | Toloczko-Grabarek, Aleksandra | Gronwald, Jacek | Byrski, Tomasz | Spurdle, Amanda B | Bonanni, Bernardo | Zaffaroni, Daniela | Giannini, Giuseppe | Bernard, Loris | Dolcetti, Riccardo | Manoukian, Siranoush | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Rhiem, Kerstin | Niederacher, Dieter | Plendl, Hansjoerg | Sutter, Christian | Wappenschmidt, Barbara | Borg, Åke | Melin, Beatrice | Rantala, Johanna | Soller, Maria | Nathanson, Katherine L | Domchek, Susan M | Rodriguez, Gustavo C | Salani, Ritu | Kaulich, Daphne Gschwantler | Tea, Muy-Kheng | Paluch, Shani Shimon | Laitman, Yael | Skytte, Anne-Bine | Kruse, Torben A | Jensen, Uffe Birk | Robson, Mark | Gerdes, Anne-Marie | Ejlertsen, Bent | Foretova, Lenka | Savage, Sharon A | Lester, Jenny | Soucy, Penny | Kuchenbaecker, Karoline B | Olswold, Curtis | Cunningham, Julie M | Slager, Susan | Pankratz, Vernon S | Dicks, Ed | Lakhani, Sunil R | Couch, Fergus J | Hall, Per | Monteiro, Alvaro N A | Gayther, Simon A | Pharoah, Paul D P | Reddel, Roger R | Goode, Ellen L | Greene, Mark H | Easton, Douglas F | Berchuck, Andrew | Antoniou, Antonis C | Chenevix-Trench, Georgia | Dunning, Alison M
Nature genetics  2013;45(4):371-384e2.
TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant.
doi:10.1038/ng.2566
PMCID: PMC3670748  PMID: 23535731
21.  Phase II evaluation of Dasatinib in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group study 
Gynecologic oncology  2012;127(1):70-74.
Objective
Preclinical data suggest an important role for the sarcoma proto-oncogene tyrosine kinase (SRC) in the oncogenesis of epithelial ovarian cancer (EOC) or primary peritoneal carcinoma (PPC). The Gynecologic Oncology Group (GOG) conducted a Phase II trial to evaluate the efficacy and safety of dasatinib, an oral SRC-family inhibitor in EOC/PPC and explored biomarkers for possible association with clinical outcome.
Methods
Eligible women had measurable, recurrent or persistent EOC/PPC and had received one or two prior regimens which must have contained a platinum and a taxane. Patients were treated with 100 mg orally daily of dasatinib continuously until progression of disease or adverse effects prevented further treatment. Primary endpoints were progression-free survival (PFS) ≥6 months and response rate. Serial plasma samples were assayed for multiple biomarkers. Circulating free DNA was quantified as were circulating tumor and endothelial cells.
Results
Thirty-five (35) patients were enrolled in a two-stage sequential design. Of the 34 eligible and evaluable patients, 20.6% (90% confidence interval: 10.1%, 35.2%) had a PFS ≥6 months; there were no objective responses. Grade 3–4 toxicities were gastrointestinal (mostly nausea and emesis; n=4), pulmonary (dyspnea and/or pleural effusion; n=4) and pain (n=5), and infrequent instances of anemia, malaise, insomnia, rash, and central nervous system hemorrhage. Lack of clinical activity limited any correlation of biomarkers with outcome.
Conclusion
Dasatinib has minimal activity as a single-agent in patients with recurrent EOC/PPC.
doi:10.1016/j.ygyno.2012.06.009
PMCID: PMC3748717  PMID: 22710075
dasatinib; ovarian; cancer; SRC; inhibition
22.  Correction: Epimorphin-Induced MET Sensitizes Ovarian Cancer Cells to Platinum 
PLoS ONE  2013;8(10):10.1371/annotation/9c557fb1-7997-4c21-bd11-03bf5c3d4418.
doi:10.1371/annotation/9c557fb1-7997-4c21-bd11-03bf5c3d4418
PMCID: PMC3810514
23.  Epimorphin-Induced MET Sensitizes Ovarian Cancer Cells to Platinum 
PLoS ONE  2013;8(9):e72637.
Distinctive genotypic and phenotypic features of ovarian cancer via epithelial-mesenchymal transition (EMT) have been correlated with drug resistance and disease recurrence. We investigated whether therapeutic reversal of EMT could re-sensitize ovarian cancer cells (OCCs) to existing chemotherapy. We report that epimorphin, a morphogenic protein, has pivotal control over mesenchymal versus epithelial cell lineage decision of the putative OCCs. Exposure to epimorphin induced morphological changes reminiscent of mesenchymal-to-epithelial transition (MET), but in a dose dependent manner, i.e., at 10 µg/mL of epimorphin cells obtain a more mesenchymal-like morphology while at 20 µg/mL of epimorphin cells display an epithelial morphology. The latter changes were accompanied by suppression of mesenchymal markers, such as vimentin (∼8-fold↓, p<0.02), Twist1 (∼7-fold↓, p<0.03), dystroglycan (∼4-fold↓, p<0.01) and palladin (∼3-fold↓, p<0.01). Conversely, significant elevations of KLF4 (∼28-fold↑, p<0.002), β-catenin (∼6-fold↑, p<0.004), EpCAM (∼6-fold↑, p<0.0002) and occludin (∼15-fold↑, p<0.004) mRNAs as part of the commitment to the epithelial cell lineage were detected in response to 20 µg/mL of exogenous epimorphin. Changes in occludin mRNA levels were accompanied by a parallel, albeit weaker expression at the protein level (∼5-fold↑, p<0.001). Likewise, acquisition of epithelial-like properties, including mucin1, CK19, and β-catenin gene expression, was also obtained following epimorphin treatment. Further, MMP3 production was found to be reduced whereas laminin secretion was strongly amplified upon epimorphin-induced MET. These results suggest there is a dosage window for actions of epimorphin on cellular differentiation, wherein it can either suppress or enhance epithelial differentiation of OCCs. Importantly, induction of epithelial-like phenotypes by epimorphin led to an enhanced sensitivity to carboplatin. Overall, we demonstrate that epimorphin can revert OCCs away from their mesenchymal phenotype and toward an epithelial phenotype, thereby enhancing their sensitivity to a front-line chemotherapeutic agent.
doi:10.1371/journal.pone.0072637
PMCID: PMC3767807  PMID: 24039787
24.  FOXA1 Represses the Molecular Phenotype of Basal Breast Cancer Cells 
Oncogene  2012;32(5):554-563.
Breast cancer is a heterogeneous disease comprised of multiple subtypes. Luminal subtype tumors confer a more favorable patient prognosis, which is in part, attributed to estrogen receptor-α (ER) positivity and anti-hormone responsiveness. Expression of the forkhead box transcription factor, FOXA1, similarly correlates with the luminal subtype and patient survival, but is also present in a subset of ER-negative tumors. FOXA1 is also consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, breast cancer cell lines representing the basal subtype do not express FOXA1. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favorable prognosis, we performed cDNA microarray analyses on FOXA1-positive, ER-positive (MCF7, T47D) or FOXA1-positive, ER-negative (MDA-MB-453, SKBR3) luminal cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal-signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Gene Set Enrichment Analyses (GSEA) revealed FOXA1 silencing causes a partial transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to a subset of both luminal and basal genes within luminal breast cancer cells, and loss of FOXA1 increases enhancer RNA (eRNA) transcription for a representative basal gene (CD58). These data suggest FOXA1 directly represses basal signature genes. Functionally, FOXA1 silencing increases migration and invasion of luminal cancer cells, both characteristics of basal subtype cells. We conclude FOXA1 controls plasticity between basal and luminal breast cancer cells, not only by inducing luminal genes, but also by repressing the basal phenotype, and thus aggressiveness. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward more aggressive cancers.
doi:10.1038/onc.2012.62
PMCID: PMC3371315  PMID: 22391567
FOXA1; luminal; basal; breast cancer
25.  Association Between BRCA1 and BRCA2 Mutations and Survival in Women with Invasive Epithelial Ovarian Cancer 
Bolton, Kelly L. | Chenevix-Trench, Georgia | Goh, Cindy | Sadetzki, Siegal | Ramus, Susan J. | Karlan, Beth Y. | Lambrechts, Diether | Despierre, Evelyn | Barrowdale, Daniel | McGuffog, Lesley | Healey, Sue | Easton, Douglas F. | Sinilnikova, Olga | Benitez, Javier | García, María J. | Neuhausen, Susan | Gail, Mitchell H. | Hartge, Patricia | Peock, Susan | Frost, Debra | Evans, D. Gareth | Eeles, Ros | Godwin, Andrew K. | Daly, Mary B. | Kwong, Ava | Ma, Edmond SK | Lázaro, Conxi | Blanco, Ignacio | Montagna, Marco | D’Andrea, Emma | Nicoletto, Ornella | Investigators, kConFab | Johnatty, Sharon E. | Kjær, Susanne Krüger | Jensen, Allan | Høgdall, Estrid | Goode, Ellen L. | Fridley, Brooke L. | Loud, Jennifer T. | Greene, Mark H. | Mai, Phuong L. | Chetrit, Angela | Lubin, Flora | Hirsh-Yechezkel, Galit | Glendon, Gord | Andrulis, Irene L. | Toland, Amanda E. | Senter, Leigha | Gore, Martin E. | Gourley, Charlie | Michie, Caroline O | Song, Honglin | Tyrer, Jonathan | Whittemore, Alice S. | McGuire, Valerie | Sieh, Weiva | Kristoffersson, Ulf | Olsson, Håkan | Borg, Åke | Levine, Douglas A. | Steele, Linda | Beattie, Mary S. | Chan, Salina | Nussbaum, Robert | Moysich, Kirsten B. | Gross, Jenny | Cass, Ilana | Walsh, Christine | Li, Andrew J. | Leuchter, Ronald | Gordon, Ora | Garcia-Closas, Montserrat | Gayther, Simon A. | Chanock, Stephen J. | Antoniou, Antonis C. | Pharoah, Paul D.P.
Context
Approximately 10 percent of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent report suggested that BRCA2 related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear.
Objective
To characterize the survival of BRCA carriers with EOC compared to non-carriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.
Design, Setting, and Participants
We pooled data from 26 studies on the survival of women with ovarian cancer. This included data on 1,213 EOC cases with pathogenic germline mutations in BRCA1 (909) or BRCA2 (304) and 2,666 non-carriers recruited and followed for variable times between 1987 and 2010; the median year of diagnosis was 1998.
Main Outcome Measures
Five year overall mortality.
Results
The five-year overall survival was 36 percent (95% CI: 34–38) for non-carriers, 44 percent (95% CI: 40–48) for BRCA1 carriers and 52 percent (95% CI: 46–58) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 carriers showed a more favorable survival than non-carriers (BRCA1, HR=0.78; 95% CI=0.68–0.89, P=2×10−4; BRCA2, HR = 0.61; 95% CI=0.50–0.76, P=6×10−6). These survival differences remained after additional adjustment for stage, grade, histology and age at diagnosis (BRCA1, HR=0.73, 95% CI=0.64–0.84, P=2×10−5; BRCA2, HR = 0.49, 95% CI=0.39–0.61, P=3×10−10).
Conclusions
Among patients with invasive epithelial ovarian cancer, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival.
doi:10.1001/jama.2012.20
PMCID: PMC3727895  PMID: 22274685

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