ABSTRACT
BRCA1 and 2 are tumor suppressor genes that are located on chromosome 17 and 13, respectively. Wild-type BRCA genes code for proteins that are integral for HR. The BRCA1 protein migrates to the DSB site to recruit proteins that aid in DNA repair and is involved in cell cycle replication arrest. BRCA2 is directly involved in repairing the DNA, at least in part by chaperoning RAD51, the recombination enzyme [7, 11]. Genetic mutations of BRCA1 or 2 genes predispose to an increased risk of developing cancers, mainly breast, ovarian, prostate, and pancreatic cancer, and at relatively younger ages [21]. Having the BRCA mutation increases the risk of contracting ovarian cancer up to 63% and breast cancer up to 87%. BRCA1 is associated more with ovarian, cervical, uterine, pancreatic, and colon cancer in women, and possibly testicular cancer whereas, BRCA2 has a higher association with male breast cancer, prostate cancer, pancreatic, stomach, bile duct cancers, and melanoma. BRCA mutations are most prevalent in
people of Ashkenazi Jewish (Jews from Eastern European) descent. In that population, the predominant mutations are 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Although these mutations occur only in 2.5% of the Ashkenazi population, they account for 70-85% of germline mutations in patients with hereditary breast cancer and ovarian cancer. Although the incidence appears high, when the overall population is considered, only 5-10% of breast cancers and 13% of high-grade serous ovarian cancers are associated with germline mutations in the BRCA gene [20-24]. Interestingly, 50% of high-grade serous ovarian carcinoma is associated with HR mutations, including BRCA mutations and others. In addition, high-grade serous ovarian carcinoma was found to have 22% incidence of BRCA mutations, when sporadic mutations were included [13]. It has been reported also that 20% of triple negative breast cancer (TNBC) has BRCA mutations [25]. Usually the germline is heterozygous, not homozygous, for the BRCA mutation; however, double and even triple heterozygous combinations have been identified in rare instances. These genotypes are not associated with worse prognostic features, like age of onset, lifetime risks, and numbers of tumors, compared with the single heterozygous state. However, for the purposes of assessing risks and providing genetic counseling, it is important to evaluate for a multiple heterozygous state [26]. Patients who have inherited the heterozygous pattern are thought to undergo a second hit within the tumor cells to account for tumorgenesis. The testing for BRCA mutation is a genetic test that analyze for known deleterious polymorphisms. The test is available commercially [27]. There are 500 known mutations in BRCA 1. Some BRCA variants, such as S1613G, impart increased risk of cancer, whereas others, such as K1183R, have been found to be associated with decreased risk [28]. The reason for testing, of course, is to intervene by increased screening, chemoprevention or prophylactic surgeries to remove the organs at highest risk in patients who carry the abnormal gene. The 2007 American Cancer Society guidelines suggest using MRI in addition to mammography for screening high-risk women. High risk includes patients with BRCA mutations, first-degree relatives of BRCA carriers who have not been tested for the mutation, and patients with lifetime risk 20% or greater based on clinical history models [29]. Scales have been developed to provide guidance on when to test for mutations in BRCA1 or 2, including
FHAT, Manchester Score, Frank, Couch and Bayesian Probabilistic Model (BRCAPRO) The most accurate is the BRCAPRO [30,31]. These scales are based on family history of breast and ovarian cancers, early age of onset of breast and ovarian cancer in the patient and/or family members, multiple tumors in a single patient, breast cancer in men, cancer-free survival in first-or second-degree relatives, and ethnicity. In 2002 a study using a computer model showed that chemoprevention and/or surgical prophylaxis can increase the survival of a 30-year-old woman with BRCA mutation by up to 5 years over surveillance alone [32]. Another strategy for determining risk developed by the International Consensus Panel on Breast Cancer Risk includes patients with medullary type breast cancer and triple negative and basal-like breast cancers, especially in patients younger than 50 years old [33]. The incidence of the BRCA germline mutations is low in the general population; however, some tumors have somatic mutations or epigenetic changes to the BRCA gene or other mutations that impair HR that lead to similar behavior to that of tumors with germline BRCA mutations (Fig. 15.1). The similar characteristics of these tumors consist of defective HR and improved response to platinum agents. These tumors are said to express “BRCAness” [2]. Some breast and ovarian cancers without the documented mutations in the BRCA gene have decrease in the expression of BRCA1. This decreased expression may be due to allelic loss [34,35] or hypermethylation of BRCA1, which inhibits transcription of the gene. Hypermethylation has been discovered in sporadic breast and ovarian tumors [3,36-38]. Sporadic breast cancers have been found to have two times less messenger RNA expression and nine times higher level of the BRCA1 negative regulator, ID4 [39] suggesting that BRCA function is important in preventing the development of cancer. Sixty-three percent of metaplastic breast cancer, a rare form of basal-like breast cancer, had BRCA1 promoter methylation compared with 12% of noncancerous controls [40]. Microarrays also show similar gene expression patterns between familial BRCA1 breast cancers and basal-like sporadic breast cancers [40,42]. TNBC, basal-like breast cancers, and BRCA1 germline breast cancers might all harbor the same tumorgenesis mechanism through BRCA1 dysfunction. For that reason, these subtypes of breast cancer are being explored as possible histologies that might benefit from PARP inhibitors. Some sporadic ovarian tumors also showed gene expression profiles that
were either BRCA1-like or BRCA2 like [43]. Twenty-five percent of BRCA mutations in the ovarian tumors and 9-20% of the mutations in high-grade serous ovarian tumors are somatic [44,13, 45], another population that may benefit from the use of PARP inhibitors. Defects in BRCA could be due to genomic, somatic or epigenetic alterations. Currently only certain genetic BRCA mutations can be commercially tested to identify patients for appropriate treatment.
