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Grant Details

Grant Number: 5R01CA116184-04 Interpret this number
Primary Investigator: Kurman, Robert
Organization: Johns Hopkins University
Project Title: Pathogenesis of Ovarian Serous Borderline Tumors
Fiscal Year: 2010
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Abstract

DESCRIPTION (provided by applicant): The objectives of this study are to assess the molecular genetic signatures of peritoneal implants associated with ovarian serous borderline tumors (SBTs) to determine if the molecular genetic changes can predict the clinical outcome in advanced stage SBTs. Since SBTs have a highly variable and unpredictable outcome, this study would have important implications in the clinical management of this disease. SBTs are a puzzling group of neoplasms that mainly occur in younger women. Their behavior is enigmatic, their pathogenesis unclear, and their clinical management controversial. Although SBTs are nearly always benign when tumor is confined to the ovary they are malignant in about 30% of cases when outside the ovary. These extraovarian tumors are termed "implants" because it is currently not known if the tumor implants represent i) a low-grade carcinoma that has metastasized from the primary ovarian tumor ii) an independent primary peritoneal carcinoma, or iii) a non-neoplastic benign peritoneal lesion. Based on our previous clinicopathologic studies, we hypothesize that: Peritoneal implants are not a single disease but a heterogeneous group of lesions. Molecular genetic analyses can characterize the different types of implants and when correlated with clinical outcome will distinguish these lesions better than the current morphologic classification. Our overall objective is to test these hypotheses by performing a comprehensive clinicopathologic and molecular genetic analysis of peritoneal implants that are associated with advanced stage SBTs collected from a nation-wide tumor registry in Denmark. The specific aims are as follows. Aim 1: Analyze the clinicopathologic features and behavior of SBTs with peritoneal implants from a nation-wide tumor registry. Aim 2: Analyze allelic imbalance in peritoneal implants and corresponding SBTs. Aim 3: Mutational analysis of protein kinases in peritoneal implants and corresponding SBTs. Aim 4: Determine the molecular genetic features of peritoneal implants and correlate them with clinical outcome. The results from this study will be translational as molecular profiling of implants and their associated SBTs with careful morphologic correlation will elucidate the molecular pathogenesis and behavior of SBTs at advanced stages. This will refine diagnostic and prognostic markers of advanced stage tumors. These results will be expected to have a significant impact on the clinical management of patients with this disease.

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Publications

Long-term Behavior of Serous Borderline Tumors Subdivided Into Atypical Proliferative Tumors and Noninvasive Low-grade Carcinomas: A Population-based Clinicopathologic Study of 942 Cases.
Authors: Vang R. , Hannibal C.G. , Junge J. , Frederiksen K. , Kjaer S.K. , Kurman R.J. .
Source: The American journal of surgical pathology, 2017 Jun; 41(6), p. 725-737.
PMID: 28248817
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A nationwide study of ovarian serous borderline tumors in Denmark 1978-2002. Risk of recurrence, and development of ovarian serous carcinoma.
Authors: Hannibal C.G. , Vang R. , Junge J. , Frederiksen K. , Kurman R.J. , Kjaer S.K. .
Source: Gynecologic oncology, 2017 Jan; 144(1), p. 174-180.
EPub date: 2016-11-09.
PMID: 27836204
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BRAF mutation is associated with a specific cell type with features suggestive of senescence in ovarian serous borderline (atypical proliferative) tumors.
Authors: Zeppernick F. , Ardighieri L. , Hannibal C.G. , Vang R. , Junge J. , Kjaer S.K. , Zhang R. , Kurman R.J. , Shih I.M. .
Source: The American journal of surgical pathology, 2014 Dec; 38(12), p. 1603-11.
PMID: 25188864
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Characterization of the immune cell repertoire in the normal fallopian tube.
Authors: Ardighieri L. , Lonardi S. , Moratto D. , Facchetti F. , Shih I.M. , Vermi W. , Kurman R.J. .
Source: International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists, 2014 Nov; 33(6), p. 581-91.
PMID: 25272297
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A nationwide study of serous "borderline" ovarian tumors in Denmark 1978-2002: centralized pathology review and overall survival compared with the general population.
Authors: Hannibal C.G. , Vang R. , Junge J. , Frederiksen K. , Kjaerbye-Thygesen A. , Andersen K.K. , Tabor A. , Kurman R.J. , Kjaer S.K. .
Source: Gynecologic oncology, 2014 Aug; 134(2), p. 267-73.
EPub date: 2014-06-10.
PMID: 24924123
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Evaluation of microinvasion and lymph node involvement in ovarian serous borderline/atypical proliferative serous tumors: a morphologic and immunohistochemical analysis of 37 cases.
Authors: Maniar K.P. , Wang Y. , Visvanathan K. , Shih I.M. , Kurman R.J. .
Source: The American journal of surgical pathology, 2014 Jun; 38(6), p. 743-55.
PMID: 24441661
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Mutational analysis of BRAF and KRAS in ovarian serous borderline (atypical proliferative) tumours and associated peritoneal implants.
Authors: Ardighieri L. , Zeppernick F. , Hannibal C.G. , Vang R. , Cope L. , Junge J. , Kjaer S.K. , Kurman R.J. , Shih I.M. .
Source: The Journal of pathology, 2014 Jan; 232(1), p. 16-22.
PMID: 24307542
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A binary histologic grading system for ovarian serous carcinoma is an independent prognostic factor: a population-based study of 4317 women diagnosed in Denmark 1978-2006.
Authors: Hannibal C.G. , Vang R. , Junge J. , Kjaerbye-Thygesen A. , Kurman R.J. , Kjaer S.K. .
Source: Gynecologic oncology, 2012 Jun; 125(3), p. 655-60.
EPub date: 2012-02-24.
PMID: 22370600
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Mutant BRAF induces DNA strand breaks, activates DNA damage response pathway, and up-regulates glucose transporter-1 in nontransformed epithelial cells.
Authors: Sheu J.J. , Guan B. , Tsai F.J. , Hsiao E.Y. , Chen C.M. , Seruca R. , Wang T.L. , Shih I.M. .
Source: The American journal of pathology, 2012 Mar; 180(3), p. 1179-88.
EPub date: 2012-01-05.
PMID: 22227015
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Low-grade serous carcinomas of the ovary contain very few point mutations.
Authors: Jones S. , Wang T.L. , Kurman R.J. , Nakayama K. , Velculescu V.E. , Vogelstein B. , Kinzler K.W. , Papadopoulos N. , Shih I.M. .
Source: The Journal of pathology, 2012 Feb; 226(3), p. 413-20.
EPub date: 2011-12-20.
PMID: 22102435
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Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis.
Authors: Kurman R.J. , Vang R. , Junge J. , Hannibal C.G. , Kjaer S.K. , Shih I.M. .
Source: The American journal of surgical pathology, 2011 Nov; 35(11), p. 1605-14.
PMID: 21997682
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Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer--shifting the paradigm.
Authors: Kurman R.J. , Shih I.M. .
Source: Human pathology, 2011 Jul; 42(7), p. 918-31.
PMID: 21683865
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Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma.
Authors: Guan B. , Mao T.L. , Panuganti P.K. , Kuhn E. , Kurman R.J. , Maeda D. , Chen E. , Jeng Y.M. , Wang T.L. , Shih I.M. .
Source: The American journal of surgical pathology, 2011 May; 35(5), p. 625-32.
PMID: 21412130
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Somatic mutations of PPP2R1A in ovarian and uterine carcinomas.
Authors: Shih I.M. , Panuganti P.K. , Kuo K.T. , Mao T.L. , Kuhn E. , Jones S. , Velculescu V.E. , Kurman R.J. , Wang T.L. .
Source: The American journal of pathology, 2011 Apr; 178(4), p. 1442-7.
EPub date: 2011-02-26.
PMID: 21435433
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DNA copy numbers profiles in affinity-purified ovarian clear cell carcinoma.
Authors: Kuo K.T. , Mao T.L. , Chen X. , Feng Y. , Nakayama K. , Wang Y. , Glas R. , Ma M.J. , Kurman R.J. , Shih I.M. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2010-04-01; 16(7), p. 1997-2008.
EPub date: 2010-03-16.
PMID: 20233889
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The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory.
Authors: Kurman R.J. , Shih I.M. .
Source: The American journal of surgical pathology, 2010 Mar; 34(3), p. 433-43.
PMID: 20154587
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Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems.
Authors: Vang R. , Shih I.M. , Kurman R.J. .
Source: Advances in anatomic pathology, 2009 Sep; 16(5), p. 267-82.
PMID: 19700937
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Defining the cut point between low-grade and high-grade ovarian serous carcinomas: a clinicopathologic and molecular genetic analysis.
Authors: Ayhan A. , Kurman R.J. , Yemelyanova A. , Vang R. , Logani S. , Seidman J.D. , Shih I.M. .
Source: The American journal of surgical pathology, 2009 Aug; 33(8), p. 1220-4.
PMID: 19461510
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Analysis of DNA copy number alterations in ovarian serous tumors identifies new molecular genetic changes in low-grade and high-grade carcinomas.
Authors: Kuo K.T. , Guan B. , Feng Y. , Mao T.L. , Chen X. , Jinawath N. , Wang Y. , Kurman R.J. , Shih I.M. , Wang T.L. .
Source: Cancer research, 2009-05-01; 69(9), p. 4036-42.
EPub date: 2009-04-21.
PMID: 19383911
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Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma.
Authors: Kuo K.T. , Mao T.L. , Jones S. , Veras E. , Ayhan A. , Wang T.L. , Glas R. , Slamon D. , Velculescu V.E. , Kuman R.J. , et al. .
Source: The American journal of pathology, 2009 May; 174(5), p. 1597-601.
EPub date: 2009-04-06.
PMID: 19349352
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Low-grade serous carcinoma of the ovary displaying a macropapillary pattern of invasion.
Authors: Yemelyanova A. , Mao T.L. , Nakayama N. , Shih I.M. , Kurman R.J. .
Source: The American journal of surgical pathology, 2008 Dec; 32(12), p. 1800-6.
PMID: 18779727
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Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis.
Authors: Kurman R.J. , Visvanathan K. , Roden R. , Wu T.C. , Shih I.M. .
Source: American journal of obstetrics and gynecology, 2008 Apr; 198(4), p. 351-6.
PMID: 18395030
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Pathogenesis of ovarian cancer: lessons from morphology and molecular biology and their clinical implications.
Authors: Kurman R.J. , Shih I.M. .
Source: International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists, 2008 Apr; 27(2), p. 151-60.
PMID: 18317228
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