**6. Somatic vs. germline** *BRCA* **mutations**

*BRCA1/2* mutations can occur in the germline causing the hereditary susceptibility to ovarian and other types of cancers. There are *BRCA* mutations can occur in the somatic cells as well -within the tumour itself which consists of 3% of whole *BRCA* mutation found in the high grade serous ovarian cancers, without mutation in the germline. Presence of germline *BRCA* mutation gives rise to specific behaviour of the ovarian cancer, response to treatment and the prognosis. Patients with germline *BRCA* mutations will develop cancers at young age, commonly have visceral disease at presentation and shows high sensitivity to platinum-based chemotherapy and PARP inhibitors.

Clear relationship between the somatic *BRCA* mutations and the features of the response to the treatment and the clinical features are yet to be identified [14].

### **7. Implications of** *BRCA* **testing in ovarian cancer**

Currently there's no proven benefit of population screening for sporadic ovarian cancer as the trial results are still pending to show reduction in the mortality and survival benefit from the early screening of asymptomatic patients in this category. However screening strategies in hereditary ovarian cancers are important for the prophylactic procedures such as bilateral Salpingo-oophorectomy which can reduce the risk of development of cancer by 79% in endometrium, fallopian tube, ovaries which has been proven by meta-analysis.

### **8. Testing for germline** *BRCA* **mutations in ovarian cancer patients**

Genetic testing for germline-*BRCA1/BRCA2* mutations in epithelial ovarian cancer (EOC) was commissioned by National Health Service England in 2015 [15]. In the United Kingdom, all genetic counselling take place in Cancer Centres, and all first degree family member will be given a letter to inform them of the risk in them carrying this gene and a mean to have germline BRCA status tested on the NHS. The NHS will also provide risk reduction surgery to prophylactic Breast and Ovarian surgery once the family planning is completed and the decision made by affected family members. For those who do not wish to embark on these prophylactic surgeries, there are guidelines for surveillance with Mammograms and blood test Ca 125 for the affected gene mutation carriers. For male gene carriers, there are now early PSA surveillance available for General physician to follow.

Germline BRCA testing is done via a blood test following gaining the consent of the patient, according to the NCCP [National cancer control programme] guidelines, which is then being sent to the Cancer Molecular Diagnostics Laboratory.

### **9. Testing for somatic** *BRCA* **mutations in ovarian cancer patients**

Testing for somatic *BRCA* mutation was introduced in October 2020 in UK. The samples from the previous biopsy or surgery including the ovarian cancer

**29**

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

5 working days of patient registration.

standardised interpretation.

geneity of the tumour cells.

one or the other due to funding issues.

improving 5 year disease free survival.

**11. What are PARP inhibitors?**

**10. The significance of** *BRCA* **mutation in HGSOC**

tor was discovered in 1980 as a chemotherapy sensitizer [17].

understanding of how the PARP inhibitors work (**Figure 3**).

recurrent ovarian cancer – Olaparib, Rucaparib and Niraparib.

below.

mutations.

tissue block/slides are needed for somatic *BRCA* mutation testing. The block must be of reasonable quality, neoplastic cell content >50% included. This should be sent at room temperature with a copy of the block(s) histopathology report within

Although the germline *BRCA* testing could be a straightforward blood test, the somatic BRCA mutation comes with some challenges, which are summarised

1.Issues with extracting high quality DNA samples from the preserved tumour samples-which needs tumour microdissection, so that a small tumour samples will not be enough for the purpose. Also poor fixation samples can cause fragmented and damaged DNA and also formalin used in fixation can cause deamination of the nucleic acids leading to sequencing errors and false

2.Analysis and interpretation of sequencing data as there is currently no

3.The stability of the somatic *BRCA* mutations can change over time due to cancer selection, resistance, treatment and within the tumour itself due to hetero-

For most countries the method for detecting the *BRCA* mutation still limited to

As mentioned earlier in the chapter being positive for *BRCA* mutations when compared with the wild type, gives the ovarian cancer specific features – importantly higher response rate to platinum and other types of non-platinum chemotherapeutic agents [16] and more importantly high sensitivity to Poly(ADP-ribose) polymerase (PARP) inhibitors, which is highly important as a maintenance therapy of the patients who have responded to first line platinum based chemotherapy in

Poly (ADP-ribose) polymerase (*PARP*) is a protein mediated the DNA double strand break repair, which was first identified in early sixties and first PARP inhibi-

Following figure illustrates the normal action of the PARP proteins to aid the

In 2005 and 2006, inhibiting PARP enzymes was first observed to be highly effective against cancers with homologous recombination deficiencies [19], are being utilised in the clinical setting to manage recurrent ovarian cancers. However, PARPi – Niraparib also show significant clinical benefit in patients without HR deficiencies [20]. There are currently three FDA-approved PARP inhibitors for

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

*Ovarian Cancer - Updates in Tumour Biology and Therapeutics*

**6. Somatic vs. germline** *BRCA* **mutations**

cell apoptosis in abnormal cells.

causing cancer development through uncontrolled cellular proliferation, impaired

*BRCA1/2* mutations can occur in the germline causing the hereditary susceptibility to ovarian and other types of cancers. There are *BRCA* mutations can occur in the somatic cells as well -within the tumour itself which consists of 3% of whole *BRCA* mutation found in the high grade serous ovarian cancers, without mutation in the germline. Presence of germline *BRCA* mutation gives rise to specific behaviour of the ovarian cancer, response to treatment and the prognosis. Patients with germline *BRCA* mutations will develop cancers at young age, commonly have visceral disease at presentation and shows high sensitivity to platinum-based chemotherapy and PARP inhibitors.

Clear relationship between the somatic *BRCA* mutations and the features of the

Currently there's no proven benefit of population screening for sporadic ovarian cancer as the trial results are still pending to show reduction in the mortality and survival benefit from the early screening of asymptomatic patients in this category. However screening strategies in hereditary ovarian cancers are important for the prophylactic procedures such as bilateral Salpingo-oophorectomy which can reduce the risk of development of cancer by 79% in endometrium, fallopian tube, ovaries

response to the treatment and the clinical features are yet to be identified [14].

**8. Testing for germline** *BRCA* **mutations in ovarian cancer patients**

Genetic testing for germline-*BRCA1/BRCA2* mutations in epithelial ovarian cancer (EOC) was commissioned by National Health Service England in 2015 [15]. In the United Kingdom, all genetic counselling take place in Cancer Centres, and all first degree family member will be given a letter to inform them of the risk in them carrying this gene and a mean to have germline BRCA status tested on the NHS. The NHS will also provide risk reduction surgery to prophylactic Breast and Ovarian surgery once the family planning is completed and the decision made by affected family members. For those who do not wish to embark on these prophylactic surgeries, there are guidelines for surveillance with Mammograms and blood test Ca 125 for the affected gene mutation carriers. For male gene carriers, there are now early

Germline BRCA testing is done via a blood test following gaining the consent of the patient, according to the NCCP [National cancer control programme] guidelines, which is then being sent to the Cancer Molecular Diagnostics Laboratory.

**9. Testing for somatic** *BRCA* **mutations in ovarian cancer patients**

Testing for somatic *BRCA* mutation was introduced in October 2020 in UK. The samples from the previous biopsy or surgery including the ovarian cancer

**7. Implications of** *BRCA* **testing in ovarian cancer**

PSA surveillance available for General physician to follow.

which has been proven by meta-analysis.

**28**

tissue block/slides are needed for somatic *BRCA* mutation testing. The block must be of reasonable quality, neoplastic cell content >50% included. This should be sent at room temperature with a copy of the block(s) histopathology report within 5 working days of patient registration.

Although the germline *BRCA* testing could be a straightforward blood test, the somatic BRCA mutation comes with some challenges, which are summarised below.


For most countries the method for detecting the *BRCA* mutation still limited to one or the other due to funding issues.
