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The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded.

Published on Apr 1, 2016in American Journal of Pathology3.762
· DOI :10.1016/j.ajpath.2015.11.011
Robert J. Kurman114
Estimated H-index: 114
(Johns Hopkins University),
IeM Shih84
Estimated H-index: 84
(Johns Hopkins University)
Sources
Abstract
Since our proposal of a dualistic model of epithelial ovarian carcinogenesis more than a decade ago, a large number of molecular and histopathologic studies were published that have provided important insights into the origin and molecular pathogenesis of this disease. This has required that the original model be revised and expanded to incorporate these findings. The new model divides type I tumors into three groups: i) endometriosis-related tumors that include endometrioid, clear cell, and seromucinous carcinomas; ii) low-grade serous carcinomas; and iii) mucinous carcinomas and malignant Brenner tumors. As in the previous model, type II tumors are composed, for the most part, of high-grade serous carcinomas that can be further subdivided into morphologic and molecular subtypes. Type I tumors develop from benign extraovarian lesions that implant on the ovary and which can subsequently undergo malignant transformation, whereas many type II carcinomas develop from intraepithelial carcinomas in the fallopian tube and, as a result, disseminate as carcinomas that involve the ovary and extraovarian sites, which probably accounts for their clinically aggressive behavior. The new molecular genetic data, especially those derived from next-generation sequencing, further underline the heterogeneity of ovarian cancer and identify actionable mutations. The dualistic model highlights these differences between type I and type II tumors which, it can be argued, describe entirely different groups of diseases.
  • References (104)
  • Citations (226)
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References104
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#1Ian J. Jacobs (University of Manchester)H-Index: 66
#2Usha Menon (UCL: University College London)H-Index: 51
Last. Steven J. Skates (Harvard University)H-Index: 59
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325 CitationsSource
#1Russell S VangH-Index: 41
#2Douglas A. Levine (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 65
Last. Robert J. KurmanH-Index: 114
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The Cancer Genome Atlas has reported that 96% of ovarian high-grade serous carcinomas (HGSCs) have TP53 somatic mutations suggesting that mutation of this gene is a defining feature of this neoplasm. In the current study, 5 gynecologic pathologists independently evaluated hematoxylin and eosin slides of 14 available cases from The Cancer Genome Atlas classified as HGSC that lacked a TP53 mutation. The histologic diagnoses rendered by these pathologists and the accompanying molecular genetic data...
48 CitationsSource
The recent 2014 World Health Organization (WHO) Classification of Tumours of the Female Reproductive Organs introduced a new category of ovarian neoplasm designated "seromucinous tumours". The recognition of this distinctive group of tumors is an important addition to the classification but the term "seromucinous" has serious flaws that obscures the nature of these neoplasms. Morphologically, seromucinous tumors in addition to serous and endocervical-type mucinous epithelium, contain endometrioi...
21 CitationsSource
Epithelial ovarian cancer consists of 5 major histotypes: high-grade serous carcinoma (HGSC), endometrioid carcinoma (EC), clear cell carcinoma (CCC), mucinous carcinoma (MC) and low-grade serous (LGSC). Each can have a broad spectrum of morphological appearances, and one histotype can closely mimic histopathological features more typical of another. Historically, there has been a relatively high frequency of mixed, defined by 2 or more distinct histotypes present based on routine histopathologi...
27 CitationsSource
#1Yusuke Kobayashi (Johns Hopkins University)H-Index: 18
#2Hiroyasu Kashima (Johns Hopkins University)H-Index: 16
Last. Tian-Li Wang (Johns Hopkins University)H-Index: 61
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Purpose: Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. Experimental Design: Two ovarian cancer mouse models...
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#1Yihong Wang (ZJU: Zhejiang University)H-Index: 5
#2Ren-Chin Wu (Johns Hopkins University)H-Index: 16
Last. Robert J. Kurman (Johns Hopkins University)H-Index: 114
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The derivation of ovarian intestinal-type mucinous tumours is not well established. Some are derived from teratomas but the origin of the majority is not clear. It has been recently proposed that the non-germ cell group may be derived from Brenner tumours, as the association of a mucinous tumour with a Brenner tumour is frequently observed. In order to explore the histogenesis of these neoplasms, we undertook a clonality analysis of the two components of ten combined Brenner and mucinous tumours...
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#1Jianfeng Shen (University of Texas MD Anderson Cancer Center)H-Index: 5
#2Yang Peng (University of Texas MD Anderson Cancer Center)H-Index: 7
Last. Guang Peng (HUST: Huazhong University of Science and Technology)H-Index: 2
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ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA da...
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#1Emily Adler (SC: University of Southern California)H-Index: 3
#2Paulette Mhawech-Fauceglia (SC: University of Southern California)H-Index: 12
Last. Kate Lawrenson (SC: University of Southern California)H-Index: 20
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Summary High-grade serous ovarian carcinoma (HGSOC) is usually diagnosed at a late stage and is associated with poor prognosis. Understanding early stage disease biology is essential in developing clinical biomarkers to detect HGSOC earlier. While recent studies indicate that HGSOCs arise from fallopian tube secretory epithelial cells, a considerable body of evidence suggests that HGSOC can also arise from ovarian surface epithelial cells (OSECs). PAX8 is overexpressed in HGSOCs and expressed in...
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Background Somatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.
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#1Ann-Marie Patch (UQ: University of Queensland)H-Index: 32
#2Elizabeth L. Christie (Peter MacCallum Cancer Centre)H-Index: 8
Last. David D.L. Bowtell (Imperial College London)H-Index: 74
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Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactiva...
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Treatment of ovarian cancer (OC) remains the biggest challenge among gynecological malignancies. Immune checkpoint blockade therapy is promising in many cancers but shows low response rates in OC b...
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#1Kazuya Maeda (Osaka Medical College)H-Index: 2
#2Hiroshi Sasaki (Osaka Medical College)H-Index: 8
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BACKGROUND: Ovarian cancer (OC) is a leading cause of cancer-related death in women, and thus an accurate diagnosis of the predisposition and its early detection is necessary. The aims of this study were to determine whether serum exosomal microRNA-34a (miR-34a) in ovarian cancer could be used as a potential biomarker. METHODS: Exosomes from OC patients' serum were collected, and exosomal miRNAs were extracted. The relative expression of miR-34a was calculated from 58 OC samples by quantitative ...
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#1Lucy Wang (NYU: New York University)
#2Douglas Allison (NYU: New York University)
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OBJECTIVES: To review the significance of MDM2 and cyclin D1 expression and loss of p16 expression in malignant and borderline Brenner tumors (BTs) of the ovary. METHODS: We describe 2 new cases of ovarian BT, 1 malignant and 1 borderline. We studied MDM2, p16, and cyclin D1 expression by immunohistochemistry in the benign, borderline, and malignant components of these 2 cases and in 5 additional cases of benign BT. We also reviewed and summarized the literature on the clinical, immunohistochemi...
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A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation following sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and...
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#2Magnus Zethoven (Peter MacCallum Cancer Centre)H-Index: 4
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High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathog...
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#1Michiel Simons (Radboud University Nijmegen)H-Index: 6
#2Femke Simmer (Radboud University Nijmegen)H-Index: 14
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The origin of primary mucinous ovarian tumors is unknown. We explore the hypothesis that they originate from either Brenner tumors or teratomas and examine differences between the tumors that arise in these settings. A total of 104 Brenner tumor-associated mucinous tumors and 58 teratoma-associated mucinous tumors were analyzed. Immunohistochemistry for 21 antigens and fluorescence in situ hybridization for ERBB2 and MYC were performed. Genome-wide copy number analysis and mutation analysis for ...
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Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum-based chemotherapy remaining the mainstay for adjuvant treatment after surgery. The lack of indication for immunotherapy may at least in part result from the lack of suitable biomarkers allowing stratification of potentially responding patients. In this monocentric study of 141 cases with OC, we used real-time quantitative PCR to assess the expression of retinoic acid-inducible gene-I (RIG-I) in primary tumor and heal...
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#1Lorena Alves Teixeira (USP: University of São Paulo)H-Index: 1
#2Francisco José Candido dos Reis (USP: University of São Paulo)H-Index: 15
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