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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

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 KP, Wang Y, Visvanathan K, Shih IeM, Kurman RJ
Source: Am J Surg Pathol, 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 CG, Vang R, Cope L, Junge J, Kjaer SK, Kurman RJ, Shih IeM
Source: J Pathol, 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 CG, Vang R, Junge J, Kjaerbye-Thygesen A, Kurman RJ, Kjaer SK
Source: Gynecol Oncol, 2012 Jun;125(3), p. 655-60.
EPub date: 2012 Feb 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 JJ, Guan B, Tsai FJ, Hsiao EY, Chen CM, Seruca R, Wang TL, Shih IeM
Source: Am J Pathol, 2012 Mar;180(3), p. 1179-88.
EPub date: 2012 Jan 5.
PMID: 22227015
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Low-grade serous carcinomas of the ovary contain very few point mutations.
Authors: Jones S, Wang TL, Kurman RJ, Nakayama K, Velculescu VE, Vogelstein B, Kinzler KW, Papadopoulos N, Shih IeM
Source: J Pathol, 2012 Feb;226(3), p. 413-20.
EPub date: 2011 Dec 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 RJ, Vang R, Junge J, Hannibal CG, Kjaer SK, Shih IeM
Source: Am J Surg Pathol, 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 RJ, Shih IeM
Source: Hum Pathol, 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 TL, Panuganti PK, Kuhn E, Kurman RJ, Maeda D, Chen E, Jeng YM, Wang TL, Shih IeM
Source: Am J Surg Pathol, 2011 May;35(5), p. 625-32.
PMID: 21412130
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DNA copy numbers profiles in affinity-purified ovarian clear cell carcinoma.
Authors: Kuo KT, Mao TL, Chen X, Feng Y, Nakayama K, Wang Y, Glas R, Ma MJ, Kurman RJ, Shih IeM, Wang TL
Source: Clin Cancer Res, 2010 Apr 1;16(7), p. 1997-2008.
EPub date: 2010 Mar 16.
PMID: 20233889
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The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory.
Authors: Kurman RJ, Shih IeM
Source: Am J Surg Pathol, 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 IeM, Kurman RJ
Source: Adv Anat Pathol, 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 RJ, Yemelyanova A, Vang R, Logani S, Seidman JD, Shih IeM
Source: Am J Surg Pathol, 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 KT, Guan B, Feng Y, Mao TL, Chen X, Jinawath N, Wang Y, Kurman RJ, Shih IeM, Wang TL
Source: Cancer Res, 2009 May 1;69(9), p. 4036-42.
EPub date: 2009 Apr 21.
PMID: 19383911
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Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma.
Authors: Kuo KT, Mao TL, Jones S, Veras E, Ayhan A, Wang TL, Glas R, Slamon D, Velculescu VE, Kuman RJ, Shih IeM
Source: Am J Pathol, 2009 May;174(5), p. 1597-601.
EPub date: 2009 Apr 6.
PMID: 19349352
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Low-grade serous carcinoma of the ovary displaying a macropapillary pattern of invasion.
Authors: Yemelyanova A, Mao TL, Nakayama N, Shih IeM, Kurman RJ
Source: Am J Surg Pathol, 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 RJ, Visvanathan K, Roden R, Wu TC, Shih IeM
Source: Am J Obstet Gynecol, 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 RJ, Shih IeM
Source: Int J Gynecol Pathol, 2008 Apr;27(2), p. 151-60.
PMID: 18317228
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