**3. Ovarian cancer pathogenesis**

EOCs were, for years, believed to arise primarily from the ovarian surface epithelium. However, two novel hypotheses for the pathogenesis of HGS ovarian cancer have been proposed. In the first mechanism, genetic alterations occurring within the normal ovarian surface epithelium or inclusion cysts which either proceed via a high-grade pathway with no perceivable intermediate histology or a low-grade pathway encompassing several, benign and noninvasive steps (**Figure 8**). This first hypothesis was established in the 1970s and proposed that ovarian surface epithelial cells underwent repeated stress through multiple rounds of ovulation, leading to inflammation, DNA damage, and the initiation of tumorigenesis [141]. This hypothesis was in part supported by evidence on the decreased risk of ovarian cancer with the use of oral contraceptives, which inhibit complete ovulation [142, 143]. Other evidence supported the correlation between the number of lifetime ovulation cycles and the increase in ovarian cancer incidence [144]. Likewise, ovarian cancers are rare in other primates which have fewer ovulations cycles than humans [145]. However, ovarian tumors are more common in hens which have been induced to frequently ovulate [146, 147]. To further study the incessant ovulation theory, additional animal models will clearly be needed. In fact, Godwin and colleagues were some of the first investigators to establish ovarian surface epithelial cultures from rat and human ovaries and use model incessant ovulation *in vitro* as a mechanism for transformation and tumorigenesis [148–161]. Inactivation of p53 and Rb1 in mouse ovarian surface cells also led to tumorigenic transformation [162].

The second theory, which has gain much traction over the past decade, describes a progression model in which ovarian cancer precursors develop in the fimbria from occult serous tubal intraepithelial carcinoma (STIC), prior to metastasis to the ovary [163, 164]. Due to the aggressive nature of HGS tumors and the presence of early genomic instability, it is hypothesized that HGS ovarian tumors are instead metastatic lesions from the fallopian tube epithelial cells (**Figure 8**). To reduce the risk of HGS ovarian cancer in women *BRCA* mutation carriers it is beneficial to undergo a bilateral salpingo-oophorectomy (removal of both the ovaries along with the fallopian tubes) instead of just an oophorectomy (removal of only the ovaries) [165, 166]. The primary risk reduction for ovarian cancer following salpingo-oophorectomy was found to be serous disease [167]. Not only did these studies suggest a fallopian origin for serous disease, the use of salpingo-oophorectomy for preventative treatment for high-risk patients gave researchers and pathologist tissue to study and search for early ovarian cancer or precursor lesions. Microdissection of the fallopian tube epithelium following salpingo-oophorectomy from patients with a disposition to ovarian cancer showed lesions with *BRCA* and *TP53* alterations that resemble HGS tumors [168–171]. To follow-up, extensive evaluation of both the fallopian tube and ovarian surface from *BRCA* mutant patients also showed common precursor lesions in the fimbria and not the ovarian surface [164, 172– 174]. In genetic mouse models, conditional inactivation of commonly mutated ovarian cancer genes (*BRCA1*, *TP53* and *RB1*) in ovarian surface epithelium cells leads to the formation of leiomyosarcomas and not HGSC following implantation into the mouse bursal sack [175]. Along with genetic alterations, fallopian lesions from *BRCA* patients showed gene expression profiles that mimicked HGS cancers [176]. Immortalization of human fallopian tube secretory epithelial cells (using hTERT and SV40 large T antigen) were transformed *in vivo* and *in vitro* by oncogenic *RAS* or *MYC* [177]. In contrast to ovarian surface epithelial cells, the inactivation of *Brca*, *Tp53* or *Pten* in *Pax8* over expressing mouse fallopian tubal secretory cells led to the development of HGSC [178]. Other genomic alterations common in HGS disease such as *CCNE1* amplification and other copy number alterations are also found in STIC lesions and might be an early step in the progression of HGS ovarian cancer [179, 180]. For example, *CCNE1* amplifications are common in both tubal lesions and HGS tumors, while centrosome amplification is more pronounced in HGS disease, indicating *CCNE1* copy number gain is an early step in tumorigenesis that later promotes centrosome amplification [181]. However, some evidence exists to show an independent clonal evolution between tubular lesions and

the patient's synchronous carcinoma, indicating small number of fallopian tube lesions may

**Figure 8.** Pathogenesis pathways of ovarian cancer. Schematic representation of the prevailing theories behind ovarian

Ovarian Cancer Genetics: Subtypes and Risk Factors http://dx.doi.org/10.5772/intechopen.72705 15

Other studies suggest a different route of the pathogenesis of cancers, where somatic stem cells undergo oncogenic mutation and create cancer stem cells that populate tumors [183–187]. While this mechanism has been contested with evidence that cancer cell plasticity can induce a stem cell phenotype in cancer cells from differentiated tissue [188], understanding any stem cell niche in ovaries and fallopian tubes may provide insight into the pathogenesis of ovarian cancer. Both the ovarian surface epithelium and fallopian tube epithelium have stem cell niches with cells with regenerative properties that could serves as progenitor cells for ovarian cancer [189–191]. Some evidence supports there could be a stem cell niche within the junction between

be micrometastases from uterine endometrioid carcinomas [182].

cancer development.

ovarian surface epithelial cells underwent repeated stress through multiple rounds of ovulation, leading to inflammation, DNA damage, and the initiation of tumorigenesis [141]. This hypothesis was in part supported by evidence on the decreased risk of ovarian cancer with the use of oral contraceptives, which inhibit complete ovulation [142, 143]. Other evidence supported the correlation between the number of lifetime ovulation cycles and the increase in ovarian cancer incidence [144]. Likewise, ovarian cancers are rare in other primates which have fewer ovulations cycles than humans [145]. However, ovarian tumors are more common in hens which have been induced to frequently ovulate [146, 147]. To further study the incessant ovulation theory, additional animal models will clearly be needed. In fact, Godwin and colleagues were some of the first investigators to establish ovarian surface epithelial cultures from rat and human ovaries and use model incessant ovulation *in vitro* as a mechanism for transformation and tumorigenesis [148–161]. Inactivation of p53 and Rb1 in mouse ovarian

The second theory, which has gain much traction over the past decade, describes a progression model in which ovarian cancer precursors develop in the fimbria from occult serous tubal intraepithelial carcinoma (STIC), prior to metastasis to the ovary [163, 164]. Due to the aggressive nature of HGS tumors and the presence of early genomic instability, it is hypothesized that HGS ovarian tumors are instead metastatic lesions from the fallopian tube epithelial cells (**Figure 8**). To reduce the risk of HGS ovarian cancer in women *BRCA* mutation carriers it is beneficial to undergo a bilateral salpingo-oophorectomy (removal of both the ovaries along with the fallopian tubes) instead of just an oophorectomy (removal of only the ovaries) [165, 166]. The primary risk reduction for ovarian cancer following salpingo-oophorectomy was found to be serous disease [167]. Not only did these studies suggest a fallopian origin for serous disease, the use of salpingo-oophorectomy for preventative treatment for high-risk patients gave researchers and pathologist tissue to study and search for early ovarian cancer or precursor lesions. Microdissection of the fallopian tube epithelium following salpingo-oophorectomy from patients with a disposition to ovarian cancer showed lesions with *BRCA* and *TP53* alterations that resemble HGS tumors [168–171]. To follow-up, extensive evaluation of both the fallopian tube and ovarian surface from *BRCA* mutant patients also showed common precursor lesions in the fimbria and not the ovarian surface [164, 172– 174]. In genetic mouse models, conditional inactivation of commonly mutated ovarian cancer genes (*BRCA1*, *TP53* and *RB1*) in ovarian surface epithelium cells leads to the formation of leiomyosarcomas and not HGSC following implantation into the mouse bursal sack [175]. Along with genetic alterations, fallopian lesions from *BRCA* patients showed gene expression profiles that mimicked HGS cancers [176]. Immortalization of human fallopian tube secretory epithelial cells (using hTERT and SV40 large T antigen) were transformed *in vivo* and *in vitro* by oncogenic *RAS* or *MYC* [177]. In contrast to ovarian surface epithelial cells, the inactivation of *Brca*, *Tp53* or *Pten* in *Pax8* over expressing mouse fallopian tubal secretory cells led to the development of HGSC [178]. Other genomic alterations common in HGS disease such as *CCNE1* amplification and other copy number alterations are also found in STIC lesions and might be an early step in the progression of HGS ovarian cancer [179, 180]. For example, *CCNE1* amplifications are common in both tubal lesions and HGS tumors, while centrosome amplification is more pronounced in HGS disease, indicating *CCNE1* copy number gain is an early step in tumorigenesis that later promotes centrosome amplification [181]. However, some evidence exists to show an independent clonal evolution between tubular lesions and

surface cells also led to tumorigenic transformation [162].

14 Ovarian Cancer - From Pathogenesis to Treatment

**Figure 8.** Pathogenesis pathways of ovarian cancer. Schematic representation of the prevailing theories behind ovarian cancer development.

the patient's synchronous carcinoma, indicating small number of fallopian tube lesions may be micrometastases from uterine endometrioid carcinomas [182].

Other studies suggest a different route of the pathogenesis of cancers, where somatic stem cells undergo oncogenic mutation and create cancer stem cells that populate tumors [183–187]. While this mechanism has been contested with evidence that cancer cell plasticity can induce a stem cell phenotype in cancer cells from differentiated tissue [188], understanding any stem cell niche in ovaries and fallopian tubes may provide insight into the pathogenesis of ovarian cancer. Both the ovarian surface epithelium and fallopian tube epithelium have stem cell niches with cells with regenerative properties that could serves as progenitor cells for ovarian cancer [189–191]. Some evidence supports there could be a stem cell niche within the junction between the ovarian surface the fallopian tube that helps repair the damage to the ovarian surface following follicle release [192]. Notch and Wnt, canonical stem cell pathways, have been shown to regulate differentiation in fallopian tube organoids and could contribute to fallopian tube repair [193]. Fallopian stem-like cells (CD44<sup>+</sup> and PAX8+ ) can be isolated from distal end of the tube and are capable of clonal growth and self-renewal [194, 195]. Since these stem cell niches are located near the areas of ovarian and fallopian surface repair and precursor lesions they could be hotspots for the development of tumors from mutations in somatic stem cells. One recent study has shown that *SOX2* is overexpressed in the fallopian tubes of patients with HGS disease and in *BRCA1*/*BRCA2* mutation carries [196], indicating a possible stem cell precursor lesion. The role of stem cells in cancer and cancer progression will remain an influential area of research and can provide potential insight into ovarian cancer pathogenesis in the future.

CIMBA consortium have comprehensively evaluated the characteristics of the over 1600 unique *BRCA1* and more than 1700 unique *BRCA2* deleterious (disease-associated) mutations found in the carriers [215]. The most common mutation types in these genes are frameshift mutations, followed by nonsense mutations. Therefore, understanding the type of mutations in *BRCA1* or *BRCA2* is important for risk assessment and determining medical management for patients. Most subtypes of ovarian cancer have been linked to *BRCA1* or *BRCA2* germline mutations but the development of HGS disease is the most common in these women carriers [223]. *BRCA1* and *BRCA2* mutations are more common in Ashkenazi Jewish women [206, 224, 225] due to the three common Jewish founder mutations *BRCA1* c.5266dup (5382insC) and *BRCA1* c.68\_69del (185delAG) and *BRCA2* c.5946del (6174delT) which have long been used as a primary genetic screening test for women of Jewish descent. Other mutations that are relatively common in specific populations, referred to as founder mutations, can be used to in limited screening tests. For example, in Iceland, only two mutations have been reported: the common founder mutation *BRCA2* c.771\_775del and the rarer *BRCA1* c.5074G > A [226]. Despite having a higher risk for developing ovarian cancer, *BRCA1/2* carriers have a better clinical outcome in terms of survival, with *BRCA2* carriers having a more favorable outcome than *BRCA1* carriers [54]. This

Ovarian Cancer Genetics: Subtypes and Risk Factors http://dx.doi.org/10.5772/intechopen.72705 17

**Figure 9.** Hereditary ovarian cancer and BRCA mutations. Pedigree descripting "BRCAness" and risk of ovarian cancer

(top). The relative risk and prognosis for women with germline *BRCA1/2* mutations.

Taken together, these data support that the pathogenesis of ovarian cancer is complex and thus contributes to the clinical difficulties in detecting the disease early. As our understanding of the genomic complexities of ovarian cancer continues to evolve and the cell type of origin is further defined, we should be able to use this information to improve detection at a time when disease can be cured and develop more precise therapies based on tumor profiling and precision medicine.
