**Abstract**

Ovarian cancers mostly arise sporadically, however about 20–25% of the cases arise as a part of hereditary syndromes. There are numerous mutations involved in the ovarian cancer development and more to be discovered. Knowing the pathogenic variants of the mutations present in the ovarian cancers are important in developing and practising of risk reduction strategies in asymptomatic carriers, genetic counselling, prognostication and decision on treatment. This chapter will focus on the various types of mutations found in ovarian cancers and their implications- when considering testing, treatment options and insight for the next level of Improvement in cancer care.

**Keywords:** ovarian cancer, somatic BRCA mutation, germline BRCA mutations, PARP inhibitors, homologous recombination

## **1. Introduction**

*BRCA1/2* somatic and germline, *PTEN* deletion, *CCNE* amplification and *RB1/NF1* loss, *RAD51C, RAD51D, BRIP 1* are some of the known mutations causing the ovarian cancers [1]; the *BRCA1/2* gene mutations are the most common and deleterious to find in this spectrum. From women who inherit a pathogenic *BRCA1* variant and *BRCA2* variant at risk of developing ovarian cancer 39–44% and 11–17% respectively by the age of 70–80 years [2, 3].

The current recommended guidelines for all high grade serous ovarian cancer patients at the diagnosis, apart from mucinous adenocarcinoma of Ovaries, are screen upfront for pathogenic *BRCA1/2* genes, regardless whether they have family history or not. The uptake of this screen is 1:10 patient, and if we extend the screening to tumour somatic testing, the uptake becomes 17% of all ovarian cancer diagnosis with germline and somatic BRCA mutations. Difference between the somatic and the germline BRCA mutations are discussed later in this chapter.

The following is a schematic representation of the various known mutation prevalence in the ovarian Cancers particularly in High grade serous ovarian carcinoma. As obvious *BRCA1* and *BRCA2* are the most common type of mutations found in the OC and signifies the importance, hence this chapter mainly focus on the BRCA mutations (**Figure 1**).

### *Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

**Figure 1.** *Common Pathogenic mutations in high grade serous ovarian cancer.* 

## **2. Genetics of sporadic ovarian cancers**

There's a multitude of genetics involved in the sporadic ovarian cancers, involving multiple cellular pathways. There are 2 types of sporadic ovarian cancers according to their behaviour, histology, genetic according to Kurman and shih's original article "The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory", type 1 and type 2 [4]. Type1 tumours are slow growing, indolent tumours and Type 2 being high grade, aggressive.

Some of the mutations associated with sporadic type1 ovarian cancers are *KRAS*, *BRAF*, *ERBB2*, *PIK3CA*, *ARID1A*, *CTNNB1* and *PTEN*. In normal cells these genes and their products will regulate the cell growth, chromatin remodelling, DNA repair, cellular proliferation and controlling of apoptosis preventing tumour development. Mutations in these genes inevitably causes increases susceptibility to development of malignancies [4].

Type 2 sporadic ovarian cancers which are high grade share the similar genetics as hereditary ovarian cancers *TP53, BRCA1 and BRCA2* [4].

### **3. Genetics of hereditary OC**

Hereditary Breast ovarian cancer syndrome, Lynch Syndrome, Li-Fraumani, Cowden and Peutz-jeghers syndrome are some of the few of Hereditary ovarian cancer syndromes, all of which inherit in autosomal dominant pattern [5, 6]. Patients who presents at young age, multiple primaries and/or a high incidence of family history of malignancy should be considered as having hereditary OC and should be investigated for the genetic mutations. Eighty percent [80%] of this type of ovarian cancers are associated with BRCA1/2 gene mutation and minority are with *RAD51C*, *RAD51D*, *BRIP1, PALB2*, *BARD1*, *NBN* and *MRE11A*.

### **4.** *BRCA1/2* **gene structure and functions**

*BRCA1* and *BRCA2* genes were discovered in early nineties following extensive research on breast cancer patients and families, hence the name Breast cancer susceptibility gene [BRCA] and identified as responsible in the ovarian cancer

**27**

**Figure 2.**

*the biological response to DNA damage [13].*

*Ovarian Cancer Genetics and the Implications DOI: http://dx.doi.org/10.5772/intechopen.96488*

involving the BRCA1/2 proteins (**Figure 2**).

**repair**

causation as well. *BRCA1* and *BRCA2* pathogenic mutations are found in 10–15% of

These genes are tumour suppressor genes encode for tumour suppressor proteins, which will help in maintaining genomic stability. *BRCA1* and *BRCA2* are large genes contain about 100–70 Kilo bases respectively*. BRCA1* situated in long arm of chromosome 17 at 17q21 position and *BRCA2* gene is in chromosome 13 at 13q12.These 2 genes encode for different protein structures although still have got functional similarities [8]. *BRCA1* protein consists of nuclear localization sequence (NLS) and three functional domains; RING, coiled coil, and BRCT domains, whereas *BRCA2* protein has NLS, eight BRC repeats, and a DNA binding domain. *BRCA1* and *BRCA2* genes helps in repairing the double strand breakage in DNA by promoting the homologous recombination, which is a highly accurate process in the maintenance of genomic stability and regulating the cell cycle and apoptosis.

**5. Action of** *BRCA1* **and** *BRCA2* **proteins in DNA double strand damage** 

Although the action of the *BRCA1* and *BRCA2* gene products in cancer causation is not fully discovered [9], their function in maintaining the genomic stability is well understood. This involves the DNA double strand break repair [DSB] which is the most deleterious type of DNA damage as no healthy DNA strand left for the repair mechanism [10]. The DSB will be repaired by 2 mechanisms in the healthy eukaryotic cells -The Homologous directed repair [HDR] pathway, which is a highly accurate system and Non-Homologous end joining [NHEJ] pathway which is prone to errors. BRCA1 and BRCA2 proteins involve in the HDR mechanism following stimulated by the cellular DNA damage response. This function is facilitated by other cellular proteins including RAD51 [11, 12], Ataxia-Telangiectasia kinase [ATM-kinase].

The following flow chart shows the mechanism of DNA DSB repair and the steps

Mutation of the *BRCA1/2* genes causing loss of the encoded protein functions causes abnormal checkpoint stimulation and genomic errors in DNA repair

*Action of BRCA1/2 protein in DNA double strand break repair. Source - functions of* BRCA1 *and* BRCA2 *in* 

sporadic ovarian cancers and about 40% of Hereditary ovarian cancers [7].

### *Ovarian Cancer Genetics and the Implications DOI: http://dx.doi.org/10.5772/intechopen.96488*

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

**2. Genetics of sporadic ovarian cancers**

*Common Pathogenic mutations in high grade serous ovarian cancer.* 

**Figure 1.**

indolent tumours and Type 2 being high grade, aggressive.

as hereditary ovarian cancers *TP53, BRCA1 and BRCA2* [4].

with *RAD51C*, *RAD51D*, *BRIP1, PALB2*, *BARD1*, *NBN* and *MRE11A*.

**4.** *BRCA1/2* **gene structure and functions**

**3. Genetics of hereditary OC**

There's a multitude of genetics involved in the sporadic ovarian cancers, involv-

Some of the mutations associated with sporadic type1 ovarian cancers are *KRAS*, *BRAF*, *ERBB2*, *PIK3CA*, *ARID1A*, *CTNNB1* and *PTEN*. In normal cells these genes and their products will regulate the cell growth, chromatin remodelling, DNA repair, cellular proliferation and controlling of apoptosis preventing tumour development. Mutations in these genes inevitably causes increases susceptibility to development of malignancies [4]. Type 2 sporadic ovarian cancers which are high grade share the similar genetics

Hereditary Breast ovarian cancer syndrome, Lynch Syndrome, Li-Fraumani, Cowden and Peutz-jeghers syndrome are some of the few of Hereditary ovarian cancer syndromes, all of which inherit in autosomal dominant pattern [5, 6]. Patients who presents at young age, multiple primaries and/or a high incidence of family history of malignancy should be considered as having hereditary OC and should be investigated for the genetic mutations. Eighty percent [80%] of this type of ovarian cancers are associated with BRCA1/2 gene mutation and minority are

*BRCA1* and *BRCA2* genes were discovered in early nineties following extensive

research on breast cancer patients and families, hence the name Breast cancer susceptibility gene [BRCA] and identified as responsible in the ovarian cancer

ing multiple cellular pathways. There are 2 types of sporadic ovarian cancers according to their behaviour, histology, genetic according to Kurman and shih's original article "The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory", type 1 and type 2 [4]. Type1 tumours are slow growing,

**26**

causation as well. *BRCA1* and *BRCA2* pathogenic mutations are found in 10–15% of sporadic ovarian cancers and about 40% of Hereditary ovarian cancers [7].

These genes are tumour suppressor genes encode for tumour suppressor proteins, which will help in maintaining genomic stability. *BRCA1* and *BRCA2* are large genes contain about 100–70 Kilo bases respectively*. BRCA1* situated in long arm of chromosome 17 at 17q21 position and *BRCA2* gene is in chromosome 13 at 13q12.These 2 genes encode for different protein structures although still have got functional similarities [8]. *BRCA1* protein consists of nuclear localization sequence (NLS) and three functional domains; RING, coiled coil, and BRCT domains, whereas *BRCA2* protein has NLS, eight BRC repeats, and a DNA binding domain.

*BRCA1* and *BRCA2* genes helps in repairing the double strand breakage in DNA by promoting the homologous recombination, which is a highly accurate process in the maintenance of genomic stability and regulating the cell cycle and apoptosis.
