Epithelial ovarian cancer has the highest case fatality rate of any gynecological cancer, and it is the leading cause of death among female genital tract malignancies [11, 12]. Because most patients with ovarian cancer are diagnosed at an advanced stage, the clinical outcome for ovarian cancer is poor even after treatment with extirpative surgery and chemotherapy [13]. Despite a high response rate to initial chemotherapy, most patients will suffer relapse and the development of drug-resistant disease [14, 15].

Currently, based on histopathology, ovarian cancers are divided into five main histological types: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma [16]. These tumors account for 98% of all ovarian cancers and can be reproducibly diagnosed by light microscopy [17]. These histological types are essentially distinct diseases, as indicated by differences in precursor lesions, patterns of spread, response to chemotherapy, and prognosis [16, 18].

Recent research into molecular biology of ovarian cancers demonstrated that ovarian cancers comprise both clinically diverse and molecularly heterogeneous malignancies, encompassing subtypes with distinct gene expression patterns that are correlated with different clinical outcomes [11, 19]. In the early twenty-first century, morphologic, immunohistochemical, and molecular studies led to a new paradigm for the pathogenesis of ovarian cancer, which divided ovarian cancer into two groups designated as type I and type II (Table 2.2) [18, 20]. Type I tumors include low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma, which develop in a stepwise fashion from well-recognized precursor lesions, such as borderline tumors or endometriosis [20]. They present as large masses that are confined to the ovary; they are generally indolent and have a favorable prognosis. These tumors are genetically stable and are typically characterized by a variety of somatic sequence mutations, including KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, and ARID1A [16, 18, 19]. On the other hand, type II tumors comprise of high-grade serous carcinoma and undifferentiated carcinoma, which develop de novo, and are highly aggressive, and have a poor prognosis [19, 20]. These tumors are chromosomally highly unstable and harbor TP53 mutations, and BRCA inactivation occurs in up to 40%–50% of high-grade serous carcinoma [21].

Recognition of the dualistic model of ovarian carcinogenesis provided a new opportunity for better management of ovarian cancer patients, and knowledge of molecular mechanisms and the pathogenesis of various types of ovarian cancer could lead to more targeted therapeutic interventions [14, 22].

In 2011, TCGA project reported the results of a wide-range analysis of the genomic and epigenetic changes that occur in 489 high-grade serous ovarian carcinomas and demonstrated several potential therapeutic molecular targets [23]. TCGA scientists determined the presence of TP53 mutation in almost all tumor specimens of high-grade serous carcinoma and a low prevalence but statistically significant frequency of somatic mutations in nine further genes, including BRCA1, BRCA2, NF1, RB1, and CDK12. Identification of these molecular pathways is likely to provide novel therapeutic approaches [23, 24]. Furthermore, the four molecular subtypes were validated in high-grade serous carcinoma cases using approximately 1500 intrinsically variable genes and were termed (a) immunoreactive, (b) differentiated, (c) proliferative, and (d) mesenchymal on the basis of gene expression in the clusters [23].

Understanding the molecular classification of ovarian cancer using comprehensive genomic analysis could lead to the development of prediction of response to therapies and improved prognostic indicators [22, 25]. In fact, these four molecular subtypes have been independently validated and have been shown to be of independent prognostic relevance [25, 26]. Moreover, TCGA data have helped to clarify the effect of BRCA1/2 mutations on survival outcomes in patients with ovarian cancer [27]. These evolving subgroups in ovarian cancer have distinct biologic characteristics that can translate into different therapeutic implications, which will allow gynecologists to identify women likely to benefit from a given cancer therapy [6].

Taken together, ovarian cancer is a spectrum of diseases and not a single disease entity. Nevertheless, current clinical management fails to incorporate these facts into treatment strategies for ovarian cancer patients because of the lack of insight into distinct molecular mechanisms for these cancers. Improvements in ovarian cancer survival should be achieved by translating recent biological insights at the molecular level into personalized individual treatment strategies [2, 7].

Endometrial cancer is one of the most prevalent malignant tumors of the female genital tract, and its incidence rate is increasing rapidly in developed countries [28]. The majority of patients with endometrial cancer are diagnosed at an early stage, resulting in overall favorable prognosis with high cancer-specific survival rates [29]. However, for patients with advanced-stage disease or for those with recurrent endometrial cancer, the prognosis remains poor and the optimal adjuvant therapy is yet to be established [30].

Endometrial cancer is divided into several histologic categories based on cell type. Endometrioid carcinoma is the most common cell type, accounting for 75–80% of cases, and subdivided into grade 1 to grade 3, according to degree of differentiation [31]. In addition, other aggressive pathologic variants include serous, clear cell, mixed, and undifferentiated types [32].

In 1983, Bokhman proposed that there are two different pathogenetic types of endometrial cancer that are primarily based on light microscopic appearance, clinical behavior, and epidemiology [33, 34]. Type I tumors are mostly composed of endometrioid carcinomas and are generally correlated with endometrial hyperplasia, express estrogen, and progesterone receptors [35]. These tumors arise in a background of unopposed estrogen stimulation, occur in premenopausal and perimenopausal women, and histologically show low-grade endometrioid differentiation. In contrast, type II tumors are more aggressive and mostly include high-grade endometrioid, serous, or clear cell histological types, and generally develop from atrophic endometrial tissues unrelated to estrogen stimulation in older women [35–37].

Previous molecular studies of endometrial cancer demonstrated that type I tumors are correlated with mutations in PTEN, KRAS, PIK3CA, and CTNNB1 and frequently show microsatellite instability (MSI) [38, 39] but do not usually have mutations in the TP53 tumor suppressor gene [35]. In contrast, a majority of type II tumors have TP53 mutations, and loss of heterozygosity (LOH) on several chromosomes, as well as molecular alterations affecting p16, STK15, E-cadherin, and c-erb-B2 [35, 36].

In the past decade, it has become more obvious that endometrial cancer comprises a clinically, histologically, and genetically heterogeneous group of tumors. However, Bokhman’s dualistic classification model does not entirely take into account this heterogeneity. As a consequence, traditional classifications are insufficient overall for successful treatment and are limited in predicting response to specific therapies [36].

In 2013, TCGA Research Network reported a comprehensive genomic and transcriptomic analysis of endometrial cancers, using next-generation sequencing technologies in combination with analysis of DNA methylation, reverse phase protein array, and MSI [40]. This study focused on common histological types, including endometrioid (n = 307), serous (n = 53), and mixed endometrioid and serous (n = 13) carcinomas. On the basis of integrated analysis, endometrial cancers were classified into four distinct molecular subgroups: (a) POLE ultramutated, (b) MSI hypermutated, (c) copy-number low, and (d) copy-number high (Table 2.3). The POLE ultramutated group was characterized by extraordinarily high mutation rates and hotspot mutations in the exonuclease domain of POLE, which is a catalytic subunit of DNA polymerase epsilon and is involved in nuclear DNA replication and repair. The MSI hypermutated group had tumors showing increased MSI because of MLH1 promoter methylation. The copy-number low group was microsatellite stable and had a lower mutation frequency. In this group, most of the tumors were grade 1 and 2 endometrioid carcinomas characterized by frequent CTNNB1 mutations. The copy-number high group had a low mutation frequency but a high rate of somatic copy number alterations, and this group contained most of the serous and mixed histology tumors with frequent TP53 mutations [40].