**Ovarian Cancer Genetics: Subtypes and Risk Factors**

**Ovarian Cancer Genetics: Subtypes and Risk Factors**

DOI: 10.5772/intechopen.72705

Jeff Hirst, Jennifer Crow and Andrew Godwin Jeff Hirst, Jennifer Crow and Andrew Godwin Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72705

#### **Abstract**

The genetics of ovarian cancer are a complex, ever evolving concept that presents hurdles in classification, diagnosis, and treatment in the clinic. Instead of common driver mutations, genomic instability is one of the hallmarks of ovarian cancer. While ovarian cancer is stratified into different clinical subtypes, there still exists extensive genetic and progressive diversity within each subtype. In high-grade serous ovarian cancer, the most common subtype, *TP53* is mutated in over 90% of all patients while the next most common mutation is less than 20%. However, next-generation sequencing and biological statistics have shown that mutations within DNA repair pathways, including *BRCA1* and *BRCA2*, are common in about 50% of all high-grade serous patients leading to the development of a breakthrough therapy of poly ADP ribose polymerase (PARP) inhibitors. This is just one example of how a better understanding of the complex genetic background of ovarian cancer can improve clinical treatment. A thorough review of ovarian cancer genetics and the effect it has on disease development, diagnosis, progression, and treatment will enhance the understanding of how to better research and treat ovarian cancer.

**Keywords:** genetics, subtypes, pathogenesis, *BRCA1*, *BRCA2*, *TP53*, risk factors

## **1. Introduction**

Ovarian cancer is a generic term used to classify cancers involving the ovaries though they can arise from many different cell types within the Müllerian compartment. Ovarian cancer presents as a distinct subset of cancers with a wide variety of genomic variation (*e.g.,* somatic *TP53* mutations, germline *BRCA1/2* mutations, copy number gains in *BRAF*, *CCNE1*, *TERC*, *TERT*, and copy number loss of *RB1* and/or *PTEN*) as demonstrated through a Pan-Cancer analysis using The Cancer Genome Atlas (TGCA) database (**Figure 1**). The pathogenesis and the debate of cellular origins of ovarian cancer will be discussed in Section 4.

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

ADP ribose polymerase (PARP) inhibitors, a breakthrough in the treatment of specific ovarian

Ovarian Cancer Genetics: Subtypes and Risk Factors http://dx.doi.org/10.5772/intechopen.72705 5

Finally, we will discuss genetic and lifestyle factors that can contribute to the development or progression of ovarian cancer. Since ovarian cancer is difficult to detect at early stages, knowing genetic and lifestyle risk factors for the development of the disease is critical. In fact, studying familial breast and ovarian cancer led to the discovery of inherited mutation in either *BRCA1* or *BRCA2* and improved detection of patients at risk for both cancers. While germline *BRCA1/2* mutations are two of the highest risk factors for developing ovarian, other genetic and lifestyle factors have been shown to influence the risk of disease development. A more thorough understanding of the risks of ovarian cancer is needed to stratify the chances

Ovarian cancers of epithelial cell origin account for more than 85% of all ovarian tumors when compared to tumors that arise from germ, epidermoid, stromal, and border cells [1]. Since EOCs are the most common and deadly form of ovarian cancer, we will refer to EOC as ovarian cancer for the remainder of this chapter and primarily discuss ovarian cancers of epithelial origin [2, 3]. Typically, EOC is classified into five different histological subtypes: high-grade serous (HGS), low-grade serous (LGS), endometrioid, clear cell and mucinous [3, 4] (**Table 1**). Low-grade and high-grade disease can typically be distinguished based on the extent of nuclear atypia and mitosis [5]. Low-grade tumors are slower growing, more genetically stable and do not respond to chemotherapy as well as the faster growing, gnomically instable high-grade tumors [6–8]. High-grade serous carcinomas are the most common ovarian cancer subtype (more than 70%) followed by endometrioid, clear cell and low-grade serous [9]. Mixed ovarian cancers that represent more than one subtype are more rare, accounting for less than 1% of all ovarian cancers [10, 11]. Globally, each subtype follows a similar distribution of incidence outside of Asia, where clear cell and endometrioid tumors are more frequent compared to other locations [12]. Each subtype behaves as a discrete disease with differences in presentation, progression, mutation profile, association with hereditary cancer syndromes, and response to chemotherapy (**Table 1**) [13]. The 10-year survival for each subtype can be influenced by each of these factors and ranges from mucinous (87%),

Each subtype has distinct histological protein expression patterns, mutations and even epigenetic signatures. Further classification based on molecular profiles may provide insights into improving therapy selection [16, 17]. Recent studies have helped to further stratify the genomic differences between each subtype where 12 different loci contribute to the susceptibility of serous (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2, 22q12.1, 2q13, 8q24.1 and 12q24.31), mucinous (3q22.3 and 9q31.1) and endometrioid (5q12.3) subtypes of ovarian cancer [18]. Molecular classification has been shown to stratify low-grade diseases into separate clusters, whereas high-grade diseases have less genetic separation [19–21], indicating early pathogenesis of the disease might be the best time to molecularly phenotype or develop targeted therapies.

cancer patients.

of developing ovarian cancer for each patient.

**2. Classification of ovarian cancer**

endometrioid (59.7%), clear cell (58.7%), to serous (24.4%) [14, 15].

**Figure 1.** Common genetic alterations in ovarian cancer represented across pan-Cancer analysis from the TCGA. Bar graphs depict % of cases with mutations (green), amplification (red), and/or deletion of commonly dysregulated genes across a panel of cancers in the TCGA.

Ovarian cancer is a pathological and genetically diverse disease that presents many hurdles towards clinical detection and treatment. These clinical barriers have prevented significant improvement in patient survival for the past three decades. The heterogeneity of ovarian cancer is one of the driving factors limiting clinical progress. In this chapter, we will discuss the diversity of ovarian cancers and how these genetic factors effect clinical detection, progression, and treatment. A better understanding of the genetic differences in ovarian cancer will open up new areas for research and treatment.

Ovarian cancer can be classified into subclasses based on pathological and genetic observations. Each subclass has distinct genetic alterations, disease pathogenesis, tumor progression, and survival outcomes in response to therapy. Not only does each subclass behave differently, heterogeneity within specific subclasses presents challenges in regards to treatment options, drug resistance, and overall clinical response. Genetic diversity has greatly limited the development of targeted therapies, which have been successful in other cancers, such as *HER2* amplified breast cancers (trastuzumab, Herceptin®), *BCR-ABL* fusion in chronic myelogenous leukemia (CML) or *KIT* mutant gastrointestinal stromal tumor (imatinib mesylate, Gleevec®), and *BRAF* V600E mutant melanoma, vemurafenib (Zelboraf®). However, understanding genetic vulnerabilities such as deficiencies in homologous DNA repair prompted the development of poly ADP ribose polymerase (PARP) inhibitors, a breakthrough in the treatment of specific ovarian cancer patients.

Finally, we will discuss genetic and lifestyle factors that can contribute to the development or progression of ovarian cancer. Since ovarian cancer is difficult to detect at early stages, knowing genetic and lifestyle risk factors for the development of the disease is critical. In fact, studying familial breast and ovarian cancer led to the discovery of inherited mutation in either *BRCA1* or *BRCA2* and improved detection of patients at risk for both cancers. While germline *BRCA1/2* mutations are two of the highest risk factors for developing ovarian, other genetic and lifestyle factors have been shown to influence the risk of disease development. A more thorough understanding of the risks of ovarian cancer is needed to stratify the chances of developing ovarian cancer for each patient.
