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• W2042633087 abstract "The biology of ovarian carcinoma differs from that of hematogenously metastasizing tumors because ovarian cancer cells primarily disseminate within the peritoneal cavity and are only superficially invasive. However, since the rapidly proliferating tumors compress visceral organs and are only temporarily chemosensitive, ovarian carcinoma is a deadly disease, with a cure rate of only 30%. There are a number of genetic and epigenetic changes that lead to ovarian carcinoma cell transformation. Ovarian carcinoma could originate from any of three potential sites: the surfaces of the ovary, the fallopian tube, or the mesothelium-lined peritoneal cavity. Ovarian cacinoma tumorigenesis then either progresses along a stepwise mutation process from a slow growing borderline tumor to a well-differentiated carcinoma (type I) or involves a genetically unstable high-grade serous carcinoma that metastasizes rapidly (type II). During initial tumorigenesis, ovarian carcinoma cells undergo an epithelial-to-mesenchymal transition, which involves a change in cadherin and integrin expression and up-regulation of proteolytic pathways. Carried by the peritoneal fluid, cancer cell spheroids overcome anoikis and attach preferentially on the abdominal peritoneum or omentum, where the cancer cells revert to their epithelial phenotype. The initial steps of metastasis are regulated by a controlled interaction of adhesion receptors and proteases, and late metastasis is characterized by the oncogene-driven fast growth of tumor nodules on mesothelium covered surfaces, causing ascites, bowel obstruction, and tumor cachexia. The biology of ovarian carcinoma differs from that of hematogenously metastasizing tumors because ovarian cancer cells primarily disseminate within the peritoneal cavity and are only superficially invasive. However, since the rapidly proliferating tumors compress visceral organs and are only temporarily chemosensitive, ovarian carcinoma is a deadly disease, with a cure rate of only 30%. There are a number of genetic and epigenetic changes that lead to ovarian carcinoma cell transformation. Ovarian carcinoma could originate from any of three potential sites: the surfaces of the ovary, the fallopian tube, or the mesothelium-lined peritoneal cavity. Ovarian cacinoma tumorigenesis then either progresses along a stepwise mutation process from a slow growing borderline tumor to a well-differentiated carcinoma (type I) or involves a genetically unstable high-grade serous carcinoma that metastasizes rapidly (type II). During initial tumorigenesis, ovarian carcinoma cells undergo an epithelial-to-mesenchymal transition, which involves a change in cadherin and integrin expression and up-regulation of proteolytic pathways. Carried by the peritoneal fluid, cancer cell spheroids overcome anoikis and attach preferentially on the abdominal peritoneum or omentum, where the cancer cells revert to their epithelial phenotype. The initial steps of metastasis are regulated by a controlled interaction of adhesion receptors and proteases, and late metastasis is characterized by the oncogene-driven fast growth of tumor nodules on mesothelium covered surfaces, causing ascites, bowel obstruction, and tumor cachexia. In 2009, the American Cancer Society reported 21,550 cases of epithelial ovarian carcinoma and 14,600 disease-related deaths, identifying ovarian carcinoma as the gynecologic malignancy with the highest case-to-fatality ratio.1Jemal A Siegel R Ward E Murray T Xu J Smigal C Thun M Cancer statistics, 2009.CA Cancer J Clin. 2009; 59: 225-249Crossref PubMed Scopus (9886) Google Scholar Sixty-nine percent of all patients with ovarian carcinoma will succumb to their disease, as compared with 19% of those with breast cancer. The high mortality of this tumor is largely explained by the fact that the majority (75%) of patients present at an advanced stage, with widely metastatic disease within the peritoneal cavity. Ovarian carcinoma metastasizes either by direct extension from the ovarian/fallopian tumor to neighboring organs (bladder/colon) or when cancer cells detach from the primary tumor. Exfoliated tumor cells are transported throughout the peritoneum by physiological peritoneal fluid and disseminate within the abdominal cavity. Extensive seeding of the peritoneal cavity by tumor cells is often associated with ascites, particularly in advanced, high-grade serous carcinomas. These cancers grow rapidly, metastasize early, and have a very aggressive disease course. Unlike most other cancers, ovarian carcinoma rarely disseminates through the vasculature. However, pelvic and/or para-aortic lymph nodes can be involved.2Eisenkop S Spirtos NM The clinical significance of occult macroscopically positive retroperitoneal nodes in patients with epithelial ovarian cancer.Gynecol Oncol. 2001; 82: 143-149Abstract Full Text PDF PubMed Scopus (67) Google Scholar Usually, patients with ovarian carcinoma have locally advanced disease in the pelvis, with contiguous extension to, or encasement of, the reproductive organs (uterus, fallopian, tube, ovaries) and the sigmoid colon. The omentum, normally a soft 20 × 15 × 2-cm fat pad covering the bowel and the abdominal cavity, is almost always transformed by tumor. This generally causes the patient significant pain because the omental tumor tends to obstruct the stomach and the small and large bowel. Current treatment strategies for advanced ovarian carcinoma consist of aggressive surgery (“cytoreduction” or “tumor debulking”). To clear the cancer in the pelvis, surgery often involves an en bloc resection of the ovarian tumors, reproductive organs, and the sigmoid colon, with a primary bowel reanastomosis (“posterior exenteration”). This is technically possible because ovarian tumors stay within the peritoneal cavity, only invade the mesothelium- lined surface, and grow above the peritoneal reflection in the pelvis. Even large omental tumors only invade the superficial bowel serosa and never the deeper layers, which is why removal of the transverse colon is rarely necessary.3Bristow RE del Carmen M Kaufman H Montz FJ Radical oophorectomy with primary stapled colorectal anastomosis for resection of locally advanced epithelial ovarian cancer.J Am Coll Surg. 2003; 197: 565-574Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar The surgical treatment goal is to remove as much tumor as possible, because several studies have convincingly shown that cytoreduction results in improved patient survival.4Bristow RE Tomacruz RS Armstrong DK Trimble EL Montz FJ Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis.J Clin Oncol. 2002; 20: 1248-1259Crossref PubMed Scopus (1960) Google Scholar, 5Winter WE Maxwell L Tian C Carlson JW Ozols RF Rose P Markmann M Armstrong DK Muggia F McGuire WP Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group study.J Clin Oncol. 2007; 25: 3621-3627Crossref PubMed Scopus (681) Google Scholar This effect of cytoreduction is indicative of a dramatic difference in the biological behavior of ovarian cancer as compared with other malignancies, because in most other cancers the removal of metastatic tumors has not been found to improve survival. Postoperatively, all women, except those with very well-differentiated early-stage cancer, receive chemotherapy with platinum (carboplatin, rarely cisplatin) and a taxane (Taxol, rarely taxotere). The optimal route of administration is still a matter of significant debate, but there is increasing evidence that in patients who have undergone optimal debulking (no residual tumor >1 cm), intraperitoneal (i.p.) delivery of these drugs increases progression-free survival by 5 months and overall survival by 15 months when compared with i.v. administration.6Armstrong DK Bundy B Wenzel L Huang H Baergen R Lele S Copeland LJ Walker JL Burger RA Intraperitoneal cisplatin and paclitaxel in ovarian cancer.N Engl J Med. 2006; 353: 34-43Crossref Scopus (2229) Google Scholar The rationale for this treatment modality is based on the observation that ovarian carcinomas are generally restricted to the abdominal cavity and on pharmacodynamic studies that show that i.p. chemotherapy can achieve very high peritoneal drug concentrations. The World Health Organization has categorized7Tavassoli FA Devilee P Tumors of the ovary and peritoneum.in: Kleihues P Sobin L Tumors of the Breast and Female Genital Organs. IARC Press, Lyon, France2003: 113-203Google Scholar epithelial ovarian carcinoma (which represents 80% of ovarian cancers) according to the predominant epithelial cell type (Figure 1). Thus, serous carcinoma has, when well or moderately differentiated, often a glandular or papillary architecture that resembles the papillary surface epithelium of the fallopian tube, (Figure 1, A–J) which is why it is also referred to as serous-papillary ovarian carcinoma. Endometrioid carcinoma, which is composed of endometrioid-like glands, is often associated with endometriosis and resembles endometrioid carcinomas of the uterus (Figure 1, K–M). Mucinous carcinomas resemble, in more well-differentiated areas, either endocervical glands or gastrointestinal epithelium (Figure 1, N–R). It is sometimes difficult to differentiate ovarian carcinomas from tumors of the gastrointestinal tract (eg, colon) that have metastasized to the ovary, but immunohistochemical staining for cytokeratin 7 and 20 (CK7 and CK20) may assist in their identification. Serous ovarian carcinomas are often CK7 positive and CK20 negative, whereas gastrointestinal carcinomas tend to be CK7 negative and CK 20 positive (Figure 1, I and J). This expression pattern, however, is not always organ specific, because colon and gastric adenocarcinomas can express CK7, whereas 33% of mucinous ovarian adenocarcinomas are CK20 positive. The fourth major histological category is the clear-cell carcinoma of the ovary (Figure 1, S and T), a rare subtype also associated with endometriosis, which shares morphological features with both serous and endometrioid ovarian carcionoma. A very elegant gene expression study showed that genes expressed in different ovarian carcinomas are concordantly expressed in the normal tissues they resemble histologically.8Marquez RT Baggerly KA Patterson AP Liu J Broaddus R Frumovitz M Atkinson EN Smith DI Hartmann L Fishman D Berchuk A Whitaker R Gershenson D Mills GB Bast RC Lu K Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon.Clin Cancer Res. 2005; 11: 6116-6126Crossref PubMed Scopus (249) Google Scholar Three anatomical sites are the potential origin of high-grade serous carcinomas: the ovarian surface epithelium, the fallopian tube epithelium, and the mesothelium covering the surface of the peritoneal cavity. Over the past 40 years, the idea that the single layer of ovarian surface epithelium gives rise to serous carcinoma gained wide acceptance.9Fathalla M Factors in the causation and incidence of ovarian cancer.Obstetr Gynecol Survey. 1972; 27: 751-768Crossref PubMed Scopus (111) Google Scholar, 10Auersperg N Edelson MI Mok SC Johnson SW Hamilton TC The biology of ovarian cancer.Semin Oncol. 1998; 25: 281-304PubMed Google Scholar The “incessant ovulation” theory holds that the frequent cycle of ovulation and surface repair, and the tendency of the ovarian epithelium to become trapped in inclusion cysts contribute to malignant transformation. The ovarian surface epithelium, a single layer of cells covering the ovary, is derived from the coelomic epithelium next to the gonadal ridge, whereas the uterus, cervix, and fallopian tube develop from the müllerian (paramesonephric) ducts. The ovarian surface epithelial cells express both epithelial (keratin) and mesenchymal (vimentin) markers, as do the mesothelial cells covering the peritoneum, pleura, and pericardium. Until recently, it was not clear how these epithelial cells could develop into müllerian-like tissues, when the epithelium is not of müllerian origin. An elegant study out of Dr. Naora's laboratory examined HOX genes, which are involved in body segmentation and the morphogenesis of the different tissues in the female reproductive tract.11Cheng W Liu J Yoshida H Rosen D Naora H Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract.Nat Med. 2008; 11: 531-537Crossref Scopus (233) Google Scholar, 12Naora H Developmental patterning in the wrong context: the paradox of epithelial ovarian cancer.Cell Cycle. 2005; 4: 1033-1035Crossref PubMed Scopus (23) Google Scholar HOX genes encode transcription factors that serve as master regulators for several genes important for morphogenesis. When HOXA9 was expressed in undifferentiated transformed mouse ovarian surface epithelial cells, these cells underwent differentiation and formed tumors that histologically resembled serous carcinomas. Similarly, the expression of HOXA10 induced an endometrioid-like ovarian carcinomas, and HOXA11 expression induced a mucinous like ovarian carcinoma. Although these data do not prove that ovarian carcinoma develops through this mechanism, it does show how the physiologically simple, undifferentiated ovarian surface epithelial cells may differentiate during transformation into a müllerian-like morphology, mimicking different epithelia of the reproductive tract. However, because pathologists were generally unable to find an in situ ovarian lesion, doubt remained that ovarian carcinoma originates in the ovarian surface epithelium. Indeed, high-grade ovarian serous carcinoma is the only epithelial cancer currently without an established precancerous component. Recently, the fimbriael epithelium of the fallopian tube (Figure 1, U–Z) has been postulated as a possible site of origin for ovarian cancer, based on the observation by Piek et al13Piek JM van Diest PJ Zweemer RP Jansen JW Poort-Keesom RJ Menko FH Gille JJ Jongsma AP Pals G Kenemans P Verheijen RH Diagnostic changes in prophylactically removed fallopian tubes of women predisposed to developing ovarian cancer.J Pathol. 2001; 195: 451-456Crossref PubMed Scopus (566) Google Scholar that in BRCA-positive patients the fimbriae often harbor a tubal intraepithelial carcinoma.14Powell B Kenley E Chen LM Crawford B McLennan J Zaloudek C Komaromy M Beattie M Ziegler J Risk-reducing salpingo-ophorectomy in BRCA mutation carriers: role of serial sectioning in the detection of occult malignancy.J Clin Oncol. 2005; 23: 127-132Crossref PubMed Scopus (324) Google Scholar The idea that far more sporadic serous cancers originate in the fallopian tube than was previously believed was further studied by Dr. Crum and his group.15Kindelberger DW Lee Y Miron A Hirsch MS Feltmate C Medeiros F Callahan MJ Garner EO Gordon RW Birch C Berkowitz RS Muto MG Crum CP Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship.Am J Surg Pathol. 2007; 31: 161-169Crossref PubMed Scopus (854) Google Scholar, 16Folkins AK Jarboe EA Roh MH Crum CP Precursor to pelvic serous carcinoma and their clinical implications.Gynecol Oncol. 2009; 113: 391-396Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Complete sectioning of the fallopian tubes from 55 patients with pelvic serous carcinomas showed involvement of the inner lining of the fallopian tube in 41 (75%). Most importantly, 29 (52%) had tubal intraepithelial carcinomas, suggesting that the serous carcinomas had originated in the fallopian tube. The intraepithelial carcinomas found in the fallopian tube arose from secretory epithelial cells, exhibited strong p53 staining indicative of p53 inactivation/mutation, and overexpressed γ-H2AX protein, a surrogate marker for DNA damage in epithelial cells.15Kindelberger DW Lee Y Miron A Hirsch MS Feltmate C Medeiros F Callahan MJ Garner EO Gordon RW Birch C Berkowitz RS Muto MG Crum CP Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship.Am J Surg Pathol. 2007; 31: 161-169Crossref PubMed Scopus (854) Google Scholar, 16Folkins AK Jarboe EA Roh MH Crum CP Precursor to pelvic serous carcinoma and their clinical implications.Gynecol Oncol. 2009; 113: 391-396Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Fallopian tube origin is also supported by a detailed understanding of pelvic organ embryology. Ovarian carcinomas (Figure 1, E–H) resemble histologically normal fallopian tube (Figure 1, A and B), endocervical glands and endometrium, (Figure 1K) sharing a common embryological origin in the müllerian duct, which is mesodermally derived.17Dubeau L The cell of origin of ovarian epithelial tumors.Lancet Oncol. 2008; 9: 1191-1197Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar In contrast, the ovary and its covering surface epithelium are of coelomic origin, making it more difficult to understand how the epithelium transforms into a tumor that resembles tissues of the müllerian duct. Two hypotheses have been formulated to explain how both the fallopian tube and the ovary might contribute to tumorigenesis. The first speculates that at the transition of the fallopian tube and the ovary is an area of epithelial transition that is vulnerable to malignant transformation, very much like the transition zone of the cervix.18Auersperg N Woo MMM Gilks CB The origin of ovarian carcinomas: a developmental view.Gynecol Oncol. 2008; 110: 452-454Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar The second theory posits that during ovulation, tubal epithelial cells from the fimbriae implant on the denuded surface of the ovary, resulting in the formation of inclusion cysts that become transformed in the ovarian microenvironment.19Kurman R Shih I-M The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory.Am J Surg Pathol. 2010; 34: 433-443Crossref PubMed Scopus (1327) Google Scholar In the last decade, significant progress has been made in our understanding of ovarian carcinoma tumorigenesis. The current working model, pioneered by Drs. Shih and Kurman,20Singer G Oldt R Cohen Y Wang B Sidransky D Kurman R Shih I-M Mutations in B-raf and K-ras characterize the development of low-grade ovarion serous carcinoma.J Natl Cancer Inst. 2003; 95: 484-486Crossref PubMed Scopus (702) Google Scholar, 21Shih I-M Kurman R Ovarian tumorigenesis: a proposed model based on morpholgical and molecular genetic analysis.Am J Pathol. 2004; 164: 1511-1518Abstract Full Text Full Text PDF PubMed Scopus (1022) Google Scholar tries to match the different histological subtypes to genetic changes and conceptualizes two main molecular pathways that lead to ovarian carcinoma. The first category (type I cancers; Figure 1, C–F and M) is composed of low-grade serous-papillary, endometrioid, and borderline tumors of low malignant potential, and in the second category are the high-grade serous carcinomas (type II cancers; Figure 1, G–J). In general, the type I cancers are characterized by a young age at diagnosis, by an indolent disease course with a prolonged overall survival time (median 82 months),22Gershenson D Sun CC Lu K Coleman RL Sood AK Malpica A Deavers M Silva EG Bodurka-Bevers D Clinical behavior of stage II-IV low-grade serous carcinoma of the ovary.Obstet Gynecol. 2006; 108: 361-368Crossref PubMed Scopus (224) Google Scholar and by relative resistance to standard carboplatinum and Taxol chemotherapy. In contrast, the type II cancers, which are most prevalent in postmenopausal women, are initially very chemosensitive to platinum containing chemotherapy, but patients have a median survival of only 30 months. The genetic changes in well-differentiated (Figure 1, E and F) serous neoplasms (type I tumors) seem to accumulate over time, transforming benign epithelium into a low-grade malignant tumor (Figure 1, A–F). They almost always arise within an existing serous neoplasm, usually a serous borderline tumor that has micropapillary architecture (Figure 1D). On histopathological examination, these carcinomas show the whole spectrum of epithelial differentiation, containing areas representative of benign serous cystadenomas, typical borderline tumors (Figure 1C), micropapillary borderline tumors (Figure 1D), and invasive well-differentiated carcinomas (Figure 1, E and F). Type I tumors typically have mutations in BRAF, KRAS, ERBB2, microsatellite instability, and follow the adenoma-to-carcinoma sequence first described for colon cancer.23Kinzler KW Vogelstein B Lessons from hereditary colorectal cancer.Cell. 1996; 87: 159-170Abstract Full Text Full Text PDF PubMed Scopus (4269) Google Scholar Active mitogen-activated protein kinase is expressed in >80% of these low-grade tumors,24Hsu C-Y Bristow RE Cha MS Wang B Ho CL Kurman R Wang TL Shih I-M Characterization of active mitogen-activated protein kinase in ovarian serous carcinomas.Clin Cancer Res. 2004; 10: 6432-6436Crossref PubMed Scopus (112) Google Scholar whereas it is expressed in 41% of high-grade serous tumors. As a consequence of these genetic insights, which suggest a prominent role for the Ras/Raf/mitogen-activated protein kinase pathway in ovarian carcinoma, the Gynecologic Oncology Group recently completed a clinical trial (GOG number 239) that studied the efficacy of an orally available non-ATP small molecule inhibitor of mitogen-activated protein kinase kinase in patients with recurrent low-grade invasive epithelial ovarian carcinoma. The endometrioid (Figure 1M), mucinous (Figure 1, Q and R) and clear cell (Figure 1, S and T) histological subtypes of ovarian carcinomas share many genetic and clinical features with the type I carcinomas but have some distinct mutations and amplifications (eg, β-catenin, phosphatase and tensin homolog (PTEN)20Singer G Oldt R Cohen Y Wang B Sidransky D Kurman R Shih I-M Mutations in B-raf and K-ras characterize the development of low-grade ovarion serous carcinoma.J Natl Cancer Inst. 2003; 95: 484-486Crossref PubMed Scopus (702) Google Scholar, 21Shih I-M Kurman R Ovarian tumorigenesis: a proposed model based on morpholgical and molecular genetic analysis.Am J Pathol. 2004; 164: 1511-1518Abstract Full Text Full Text PDF PubMed Scopus (1022) Google Scholar) when compared with the well-differentiated serous carcinomas. KRAS mutations are very frequent in mucinous carcinomas. Clinically, both clear cell and endometrioid ovarian carcinomas share a common presentation: most patients present with early-stage disease that has rarely metastasized but has grown into one large ovarian tumor mass. In 20% of patients with endometrioid and clear-cell ovarian carcinomas, the disease is associated with endometriosis, which has been clearly identified as a precursor for both endometroid and clear-cell ovarian carcinoma. Loss of heterozygosity was detected in the same allele both in the tumor and in the adjacent endometriotic lesion of patients with these ovarian carcinoma subtypes.25Prowse A Manek S Varma R Liu J Godwin AK Maher E Tomlinson I Kennedy S Molecular genetic evidence that endometriosis is a precursor of ovarian cancer.Int J Cancer. 2006; 1189: 556-562Crossref Scopus (131) Google Scholar Also, endometriotic lesions and endometroid ovarian carcinoma share overexpression of a distinct set of genes (eg, SICA2, CCL14, and Cripto-1) that are not deregulated in serous carcinomas.26Banz C Ungethuem U Kuban RJ Diedrich K Lengyel E Hornung D The molecular signature of endometriosis-associated endometroid ovarian cancer differs significantly from endometriosis-independent endometroid ovarian cancer.Fertil Steril. 2009; https://doi.org/10.1016/j.fertnstert.2009.06.039Abstract Full Text Full Text PDF Scopus (36) Google Scholar The mutational data gathered in human cancer tissue from patients with endometrioid ovarian carcinomas were confirmed in a genetic mouse model of ovarian carcinoma. Expression of oncogenic KRAS or deletion of phosphatase and tensin homolog (PTEN) gave rise to endometriosis in the mouse ovary. When the two mutations were combined, the mice developed metastatic ovarian carcinoma, which often appeared endometrioid.27Dinulescu D Ince T Quade B Shafer S Crowley D Jacks T Role of K-ras and PTEN in the development of mouse models of endometriosis and endometrioid ovarin cancer.Nat Med. 2005; 11: 63-70Crossref PubMed Scopus (489) Google Scholar, 28Romero I Gordon I Jagadeeswaran S Mui KL Lee WS Dinulescu D Krausz T Kim H Gilliam M Lengyel E Effects of oral contraceptives or a gonadotropin-releasing hormone agonist on ovarian carcinogenesis in genetically engineered mice.Cancer Prev Res. 2009; 2: 792-799Crossref PubMed Scopus (14) Google Scholar The sequence of genetic events in high-grade serous-papillary carcinomas is not as well understood. Clinical experience and a recent study29Brown PO Palmer C The preclinical natural history of serous ovarian cancer: defining the target for early detection.PLoS Med. 2009; 6: 1-11Crossref Scopus (194) Google Scholar suggest that these tumors grow quickly and disseminate widely within the mesothelial cell-covered peritoneal cavity (or as an effusion in the mesothelial cell covered pleural space). High-grade serous carcinomas show widespread DNA copy number gains and losses involving all chromosomes, which is a characteristic of their significant genetic instability.30Kuo KT Guan B Feng Y Mao TL Chen X Jinawath N Wang Y Kurman R Shih I-M Wang TL Analysis of DNA copy number alterations in ovarian serous tumors identified new molecular genetic changes in low-grade and high-grade carcnomas.Cancer Res. 2009; 69: 4036-4042Crossref PubMed Scopus (144) Google Scholar, 31Haverty PM Hon LS Kaminker JS Chant J Zhang Z High resolution analysis of copy number alterations and associated expression changes in ovarian tumors.BMC Med Genomics. 2009; 2: 21Crossref PubMed Scopus (77) Google Scholar Kuo et al30Kuo KT Guan B Feng Y Mao TL Chen X Jinawath N Wang Y Kurman R Shih I-M Wang TL Analysis of DNA copy number alterations in ovarian serous tumors identified new molecular genetic changes in low-grade and high-grade carcnomas.Cancer Res. 2009; 69: 4036-4042Crossref PubMed Scopus (144) Google Scholar found reduced expression of RB1 and p16 protein in >50% of all tumors and identified frequent homozygous deletions of RB1 and CDKN2A/B in 17% of serous carcinomas. Interestingly, a few years before their paper was published, deletion of RB1 and TP53 resulted in a mouse ovarian cancer model with serous histology.32Flesken-Nikitin A Choi K Eng JP Shmidt EN Nikitin A Induction of carcinogenesis by concurrent inactivation of p53 and Rb1 in the mouse ovarian surface epithelium.Cancer Res. 2003; 63: 3459-3463PubMed Google Scholar The most frequent genetic change in high-grade serous carcinomas involves p53 mutations, which occur in 50–80% of this form of cancer.33Kohler MF Marks JR Wiseman R Jacobs IJ Davidoff AM Clarke-Pearson DL Soper JT Bast RC Berchuk A Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer.J Natl Cancer Inst. 1993; 85: 1513-1519Crossref PubMed Scopus (188) Google Scholar, 34Singer G Stöhr R Cope L Dehari R Hartman A Cao DF Wang TL Kurman R Shih I-M Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation.Am J Surg Pathol. 2005; 29: 218-224Crossref PubMed Scopus (356) Google Scholar Mutations are found in tumors of all stages, suggesting that they originate in an early event in the progression of the disease.35Milner BJ Allan LA Eccles DM Kitchener HC Leonard RCF Kelly KF Parkin DE Haites NE p53 mutation is a common genetic event in ovarian carcinoma.Cancer Res. 1993; 53: 2128-2132PubMed Google Scholar The timing of the mutation might explain why a large phase III trial of adenoviral wild-type p53 delivery combined with Taxol and carboplatinum did not show any positive results.36Zeimet AG Marth C Why did p53 gene therapy fail in ovarian cancer?.Lancet Oncol. 2003; 4: 415-419Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar Since p53 function loss leading to overexpression is seen in the earliest events of ovarian/fallopian carcinoma tumorigenesis, including in situ cancers15Kindelberger DW Lee Y Miron A Hirsch MS Feltmate C Medeiros F Callahan MJ Garner EO Gordon RW Birch C Berkowitz RS Muto MG Crum CP Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship.Am J Surg Pathol. 2007; 31: 161-169Crossref PubMed Scopus (854) Google Scholar, 16Folkins AK Jarboe EA Roh MH Crum CP Precursor to pelvic serous carcinoma and their clinical implications.Gynecol Oncol. 2009; 113: 391-396Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar (Figure 1W), it could be that once the tumor has metastasized and is chemoresistant (as were the patients enrolled on this trial) tumor growth no longer depends on p53. Other important genetic alterations in high-grade serous tumors include BRCA 1 and 2 mutations and amplification of the AKT2 serine/threonine kinase and the phosphatidylinositol 3-kinase genes (40%).37Cheng JQ Godwin AK Bellacosa A Taguchi T Franke TF Hamilton TC Tsichlis PN Testa J AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarain carcinomas.Proc Natl Acad Sci USA. 1992; 89: 9267-9271Crossref PubMed Scopus (647) Google Scholar, 38Shayesteh L Lu Y Kuo W Baldocchi R Godfrey T Collins C Pinkel D Powell B Mills GB Gray J PIK3CA is implicated as an oncogene in ovarian cancer.Nat Genet. 1999; 21: 99-102Crossref PubMed Scopus (1008) Google Scholar Phosphatidylinositol 3-k" @default.
• W2042633087 created "2016-06-24" @default.
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• W2042633087 date "2010-09-01" @default.
• W2042633087 modified "2023-10-14" @default.
• W2042633087 title "Ovarian Cancer Development and Metastasis" @default.
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• W2042633087 doi "https://doi.org/10.2353/ajpath.2010.100105" @default.
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