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Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations

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Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations International Journal of Molecular Sciences Review Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations Isao Otsuka Kameda Medical Center, Department of Obstetrics and Gynecology, Kamogawa 296-8602, Japan; [email protected] Abstract: Ovarian high-grade serous carcinomas (HGSCs) are a heterogeneous group of diseases. They include fallopian-tube-epithelium (FTE)-derived and ovarian-surface-epithelium (OSE)-derived tumors. The risk/protective factors suggest that the etiology of HGSCs is multifactorial. Inflammation caused by ovulation and retrograde bleeding may play a major role. HGSCs are among the most genetically altered cancers, and TP53 mutations are ubiquitous. Key driving events other than TP53 mutations include homologous recombination (HR) deficiency, such as BRCA 1/2 dysfunction, and activation of the CCNE1 pathway. HR deficiency and the CCNE1 amplification appear to be mutually exclusive. Intratumor heterogeneity resulting from genomic instability can be observed at the early stage of tumorigenesis. In this review, I discuss current carcinogenic hypotheses, sites of origin, etiologic factors, and molecular alterations of HGSCs. Keywords: ovarian cancer; high-grade serous carcinoma; carcinogenesis; molecular alterations Citation: Otsuka, I. Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic 1. Introduction Factors, and Molecular Alterations. Ovarian cancer is the most lethal gynecological malignancy. Epithelial ovarian cancers Int. J. Mol. Sci. 2021, 22, 4409. (EOCs) are a heterogeneous group of diseases and can be divided into five main types, https://doi.org/10.3390/ijms based on histopathology and molecular genetics [1]: high-grade serous, low-grade serous, 22094409 endometrioid, clear cell, and mucinous tumors. These tumors may be classified into type I and II tumors. Type I tumors include endometriosis-related tumors (endometrioid and Academic Editor: Takaaki Masuda clear cell carcinomas), low-grade serous carcinoma, and mucinous carcinoma. Type II tumors are composed of high-grade serous carcinomas, for the most part [2]. Although this Received: 8 April 2021 classification conflicts with recent molecular insights into the etiology of EOCs [3], type II Accepted: 20 April 2021 tumors that also include carcinosarcomas could be classed together. Published: 23 April 2021 High-grade serous carcinoma (HGSC) is the most common and lethal subtype of EOC, as most women with HGSC are diagnosed at a late stage, when achieving a cure is rare [4]. Publisher’s Note: MDPI stays neutral The vast majority of serous carcinomas are high-grade tumors [5]. To develop an effective with regard to jurisdictional claims in method for prevention and early detection, elucidation of carcinogenesis is essential. published maps and institutional affil- Recently, our understanding of the origins and pathogenesis of HGSC has substantially iations. progressed through whole genome and bioinformatic analyses. This review discusses the current carcinogenic hypotheses, sites of origin, etiologic factors, and molecular alterations of HGSCs. Copyright: © 2021 by the author. 2. Carcinogenic Hypotheses and Risk/Protective Factors Licensee MDPI, Basel, Switzerland. 2.1. Incessant Ovulation This article is an open access article EOCs were traditionally thought to arise from the ovarian surface epithelium (OSE). distributed under the terms and conditions of the Creative Commons The OSE is the pelvic mesothelium that overlies the ovary and lines ovarian epithelial Attribution (CC BY) license (https:// inclusion cysts, and is derived from the coelomic epithelium [6,7]. The risk/protective creativecommons.org/licenses/by/ factors for EOCs include parity, breast-feeding, and oral contraceptive use; all of these 4.0/). factors reduce ovarian cancer risk [8] (Figure1). These reproductive and hormonal factors Int. J. Mol. Sci. 2021, 22, 4409. https://doi.org/10.3390/ijms22094409 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 16 Int. J. Mol. Sci. 2021, 22, 4409 2 of 15 factors for EOCs include parity, breast-feeding, and oral contraceptive use; all of these factors reduce ovarian cancer risk [8] (Figure 1). These reproductive and hormonal fac- torsare associatedare associated with ovulationwith ovulation suppression. suppression Thus,. theThus, risk the of EOC risk isof thought EOC is to thought be associated to be associatedwith the number with the of number ovulatory of cycles.ovulatory cycles. FigureFigure 1. 1. CarcinogenicCarcinogenic hypotheses hypotheses and and risk/protectiv risk/protectivee factors. factors. * including * including menstruation menstruation and and postmenopausalpostmenopausal bleeding. TheThe incessant incessant ovulation ovulation hypothesis hypothesis was was prop proposedosed by Fathalla in 1971 based on these observationsobservations [9]. [9]. This This hypothesis hypothesis proposes proposes that that recurrent recurrent damage damage and and repair repair of of the the OSE fromfrom repeatedrepeated ovulationovulation increase increase the the risk risk of cellof cell damage damage and subsequentand subsequent neoplastic neoplastic trans- transformation.formation. A study A study showed showed that athat higher a higher number number of ovulatory of ovulatory cycles cycles may bemay associated be asso- ciatedwith increased with increased amounts amou of DNAnts of damageDNA damage [10]. [10]. 2.2. Gonadotropin Stimulation 2.2. Gonadotropin Stimulation The majority of women with ovarian cancer present in the postmenopausal period, The majority of women with ovarian cancer present in the postmenopausal period, when pituitary gonadotropin levels are elevated. The gonadotropin stimulation hypothesis when pituitary gonadotropin levels are elevated. The gonadotropin stimulation hypoth- proposes that high gonadotropin levels can have an effect on OSE cells and promote carcino- esis proposes that high gonadotropin levels can have an effect on OSE cells and promote genesis [11,12]. Gonadotropins that persist in high levels for many years after menopause carcinogenesis [11,12]. Gonadotropins that persist in high levels for many years after may stimulate the OSE, in which gonadotropin receptors are expressed, and OSE cells may menopausesubsequently may undergo stimulate malignant the OSE, transformation in which gonadotropin [12]. Surges receptors of gonadotropins are expressed, that initiate and OSEeach cells ovulation may subsequently may also play undergo a role in malignan carcinogenesis;t transformation thus, the incessant[12]. Surges ovulation of gonado- and tropinsgonadotropin that initiate hypotheses each ovulation are interrelated. may also play a role in carcinogenesis; thus, the in- cessant ovulation and gonadotropin hypotheses are interrelated. 2.3. Tubal Inflammation 2.3. TubalThese Inflammation two hypotheses, however, have limitations. If the number of lifetime ovulatory cyclesThese and exposuretwo hypotheses, to high levelshowever, of gonadotropins have limitations. are associated If the number with EOCof lifetime development, ovula- toryfertility cycles treatment and exposure might increase to high thelevels risk of of gonadotropins EOC via the multiple are associated ovulations with stimulated EOC de- velopment,by gonadotropins, fertility specifically treatment might luteinizing increase hormone the risk (LH) of EOC and folliclevia the stimulating multiple ovulations hormone stimulated(FSH). In fact, by gonadotropins, studies suggest specifically that there isluteinizing no significant hormone relationship (LH) and between follicle instimu- vitro latingfertilization hormone treatment (FSH). using In fact, gonadotropin studies suggest stimulation that there and subsequentis no significant risk of relationship EOC [13,14]. betweenIn addition, in vitro as the fertilization ovulatory treatment rupture sitesusing appear gonadotropin to be random, stimulation the repeated and subsequent rupture riskand of repair EOC that[13,14]. occurs In addition, with each as ovulationthe ovulatory should rupture not sites affect appear the same to be population random, the of repeatedsurface epithelial rupture cellsand repair [15]. Furthermore, that occurs neitherwith each the ovulation incessant ovulationshould not nor affect gonadotropin the same populationstimulation of hypotheses surface epithelial explains thecells protective [15]. Furthermore, effect of tubal neither ligation the andincessant hysterectomy ovulation on northe developmentgonadotropin ofstimulation EOC [16]. hypotheses explains the protective effect of tubal ligation and hysterectomyThe fallopian on tube, the in development particular the of fimbriae, EOC [16]. emerged as another site of origin based on findingsThe fallopian related tube, to prophylactic in particular surgerythe fimbriae for ovarian, emerged cancer as another risk reduction site of origin in women based onwith findings genetic related predisposition to prophylactic to the diseasesurgery [for17]. ovarian Based oncancer these risk observations, reduction in the women tubal withinflammation genetic predisposition hypothesis was to proposedthe disease by [17] Salvador. Based [on7]. these Chronic observations, inflammation the istubal known in- flammationto be a risk forhypothesis cancer. The was fallopian proposed tube by isSalvador regularly [7]. exposed Chronic to inflammation a variety of inflammatory is known to beagents, a
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