When a BRCA gene is mutated, it may no longer be effective at homologous recombination (HR) DNA repair machinery. Thus people with a BRCA gene mutation are more likely to develop cancer at a younger age. In these tumors, the base excision repair pathway is important for cell survival. The poly(adenosine diphosphate-ribose) polymerase (PARP) enzymes play a key role in BER, and PARP inhibitors are effective in causing cell death in BRCA-mutant cells while sparing normal cells-a concept called synthetic lethality.
Genetic testing is used to find germline/inherited mutations in genes such as BRCA and others that are passed on to us from either parent and are present in all the cells since our birth. Germline testing is usually performed on blood or saliva. Germline mutations in the BRCA genes predispose carriers to breast and ovarian cancer (HBOC) syndrome and other forms of cancers.
Approximately, 55-65% of women with a BRCA1 mutation and 45% of women with a BRCA2 mutation will develop breast cancer by age of 70 respectively. Carriers of BRCA mutations have a higher than average chance of developing second cancer (Recurrence). In the general population lifetime risk of ovarian cancer is up to 1.3%, while women who inherit a harmful BRCA1 mutation and BRCA2 mutation are at 44% and 17% risk to develop ovarian cancer by the age of 80 respectively. 3%-6% of the pancreatic cancer cases carry germline inactivating mutations in BRCA1/2. BRCA2 mutations have been established as the most common genetic cause of familial pancreatic cancer. Although, patients with a germline BRCA mutation makeup a small subgroup of those with metastatic pancreatic cancer, they can benefit from olaparib which has recently been approved by the FDA for its antitumor activity. Pathogenic germline BRCA variants are inherited in an autosomal dominant pattern.
The transformation of a normal cell into a cancer cell takes place through a sequence of a small number of discrete genetic events. Genetic alterations acquired by the cells of our body except the germ cells are known as somatic. A clinical geneticist can look at these alterations in cancer cells by testing a piece of the tumor and provide more precise therapy options such as targeted therapy. Besides being involved in hereditary cancers, recent studies have shown that BRCA genes can also be involved in the development of non-hereditary, sporadic tumors since a proportion of ovarian, breast and pancreatic tumors contain somatic (tumor only) pathogenic BRCA variants. Patients with tumors that harbor a somatic BRCA mutation may benefit from treatment with PARP inhibitors. 16% of the somatic pancreatic acinar cell carcinoma have somatic BRCA alterations. A Canadian study encompassing a larger population reported that 7.9% of ovarian cancer cases among women are without any family history. BRCA1 is a powerful mediator of aggressive sporadic breast cancer. BRCA1/2 mutation prevalence was 3.5% in somatic breast cancer.
Although these statistics are alarming. A vast majority of these cancers can be successfully treated with early detection and upcoming treatment options. Subsequent studies with olaparib (Study 19) and with Rucaparib (Ariel 2 and Study 10) confirmed that BRCA mutated patients derive the greatest clinical benefit from PARP inhibitors and showed no differences in responsiveness to PARP inhibitors between germline and somatic BRCA mutated ovarian cancer. PARP inhibitor like olaparib is approved for deleterious BRCA mutation as detected by an FDA-approved test in
- As a first-line maintenance therapy for metastatic pancreatic cancer patients.
- Advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
- HER2 negative metastatic breast cancers, who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting.
Attempts to quantify cancer risk in the germline or somatic BRCA1/2 mutation carriers vary, depending on study design and source population.
Luzzatto, Lucio. “Erratum to Somatic mutations in cancer development.” Environmental Health 10.1 (2011): S16.
By: Islahi Fatma