Breast cancer and ovarian cancer develop through multiple molecular pathways guided by genetic and epigenetic clonal selections. Both cancers have been recognized as a heterogeneous disease with regard to clinical and biological properties. The majority of cancer cases are considered sporadic-appearing tumors in nature because there is no obvious family history, but a number of families with a known genetic cause or inherited predisposition to cancer have been identified (1). Individuals who carry an inherited genetic mutation and epigenetic aberrations in the tumor suppressor genes have an increased lifetime risk of developing cancer. Germline mutations in cancer susceptibility genes cause cancer if the wild-type allele is lost or inactivated. Breast and ovarian cancers (5–10%) may be hereditary and occur in cancer prone syndromes (2–7). Patients predisposed to breast and ovarian cancers are known as the hereditary breast and ovarian cancer (HBOC) syndrome.

HBOC syndrome is an autosomal dominantly inherited disease characterized by a young age of onset, more than one synchronous or metachronous tumor, and a family history of first and second degree relatives with similar cancers (8). Mainly HBOC syndrome results from germline mutations in breast cancer genes BRCA1 or BRCA2. Other genes or low penetrance alleles might be associated with the HBOC phenotype (9). There is an increasing understanding that the interrelationship between BRCA gene cluster and Fanconi anemia (FA), mismatch repair (MMR) and DNA repair gene status plays a key role in the pathogenesis of cancer predisposition syndromes. We reviewed the HBOC syndrome and current knowledge of inherited susceptibility genes.

A computerized literature search was performed to identify relevant studies reported in the English language. We searched MEDLINE electronic databases (http://www.ncbi.nlm.nih.gov/sites/entrez) published between January 1994 and October 2012, combining the keywords ‘hereditary breast and ovarian cancer’, ‘pathogenesis’, ‘BRCA’ and ‘DNA repair’. Various combinations of the terms were used, depending on the database searched. Each gene was also linked to NCBI Entrez Gene pages (http://www.ncbi.nlm.nih.gov/sites/entrez). Additionally, references in each article were searched to identify potentially missed studies.

Between 50–80% of HBOC syndrome can be explained by defective germline mutations in BRCA1 and BRCA2 as well as, to a lesser degree, other genes described above, but for the remaining families the factors driving susceptibility remain unknown (24). Approximately one third of the HBOC families do not have evidence of the germline mutations in BRCA1 and BRCA2. The loss of BRCA function might be due to either germline/somatic mutation or epigenetic silencing. Since little is known about the contribution of epimutations to the remaining BRCA1/2 mutation-negative cases, epigenetic silencing has been explored in HBOC syndrome. The activities of tumor suppressor genes and cancer susceptibility genes could be influenced by genetic and epigenetic alterations. Decreased expression of cancer susceptibility genes has been observed in sporadic breast and ovarian cancer where it is often associated with the aberrant epimutations or hypermethylation of the BRCA1 and BRCA2 genes. The loss of BRCA1 function due to somatic hypermethylation explained ~10% of sporadic breast cancer cases. A subset of the sporadic tumor patients demonstrated hypermethylation of BRCA2 and their interacting protein including HP1γ (heterochromatin protein 1gamma), RAD51C, ATM and PALB2 (25). Based on BRCA1 deletion, TP53 mutations, ER- and PgR-negative status, young age at diagnosis and high grade tumor, phenotypic features of sporadic breast cancers resemble BRCA1 mutated cancers termed ‘BRCAness’. Phenotypic similarities were most closely observed in BRCAness, epigenetic silencing and deletion of the BRCA1 and BRCA2 genes.

Many genes have been implicated in the DNA damage response pathways where the BRCA1 and BRCA2 genes are involved. Genetic susceptibility to cancer is attributed to deleterious germline mutations in the DNA mismatch repair (MMR) genes. Another important non-BRCA1/BRCA2 hereditary condition is hereditary non-polyposis colorectal cancer (HNPCC) syndrome, also known as ‘Lynch syndrome’. Two manifestations of hereditary ovarian cancer are currently recognized: the HBOC syndrome and the HNPCC syndrome. Lynch syndrome has been defined clinically and genetically and is an autosomal-dominant cancer predisposition syndrome that increases the risk for several forms of malignancy, including colorectal (lifetime cancer risk, 70–80%), endometrial (50–60%), stomach cancer (13–19%), ovarian cancer (9–14%), small intestine, liver and biliary tract, brain, as well as transitional cell carcinoma of the ureters and renal pelvis. Mutations in four MMR genes [MLH1 (mutL homolog 1), MSH2 (mutS homolog 2), MSH6 (mutS homolog 6) and PMS2 (postmeiotic segregation increased 2)] are associated with Lynch syndrome and account for another 10% of hereditary ovarian cancer (26). The MMR genes encode proteins involved in the same pathway of DNA mismatch repair. These genetic defects in the DNA MMR system result in DNA replication errors, including base substitutions and insertion-deletion loops, known as microsatellite instability (MSI). MutS α complex (composed of MSH2 and MSH6) or MutS β complex (MSH2–MSH3) recognizes single-base mismatches and small insertion-deletion loops, binds to mismatched DNA, and recruits the MutL α complex (MLH1–PMS2), which leads to strand discrimination and removal of the errors and coordinates the remaining steps in MMR (27–29).

Both HNPCC and HBOC associated ovarian cancer develop along distinct genetic pathways (30). Although some deviating reports exist, breast cancer incidence has been found to be elevated in Lynch syndrome patients (31). Furthermore, germline mutations associated with Lynch syndrome has been described in 2–3% of patients diagnosed with endometrial cancer. Among Lynch syndrome-related cancers, endometrial cancer is riskier than colorectal cancer in terms of estimated lifetime cumulative risk (32). The overall 5-year survival rate for endometrial (88 vs. 82%) or ovarian cancer (64 vs. 58%) was not significantly different between patients with endometrial or ovarian cancer that are associated with Lynch syndrome and the controls with sporadic cases (33,34). Although immunohistochemical analysis of tumor tissue proved to be a good pre-screening test before proceeding to germline mutation analysis, the discordant results are sometimes observed between immunohistochemistry and replication error phenotyping. Notwithstanding this limitation, immunohistochemistry may be helpful in the evaluation of women with a likely diagnosis of Lynch syndrome. Immunohistochemistry for DNA MMR showed loss of proteins in 9% of women with synchronous endometrial and ovarian cancer (35).

As shown in Fig. 1, BRCA1 forms a multi-subunit protein complex, which includes DNA damage repair proteins, including FA and MMR proteins. Recent studies showed a functional interaction between FANCJ and the MMR complex MutL α, which is essential for establishment of DNA interstrand cross-links (36). FANCD2 is required for binding between MSH2 and MLH1, which are involved in the mono-ubiquitination of FANCD2, leading to recruitment of ATR and then activation of CHK1 and TP53. Furthermore, MutS α and MutL α complex have been shown to be required for the recruitment of ATR to DNA damage lesion. Taken together, these results support that there might be a functional overlap between the MMR and FA-BRCA pathways.

Attention has been paid to the role of modifiable risk factors like reproductive histories and exogenous hormones. Potential modifying factors include age of menarche, parity, breastfeeding and oophorectomy. Oral contraceptives (OCs) have a significant protective effect on the risk of ovarian cancer by ~50% in the general population (28). OCs reduce the risk of ovarian cancer also in BRCA1/BRCA2 mutation carriers. The effect of parity may be different in BRCA1 and BRCA2 carriers. Parity protects against breast cancer in BRCA1 mutation carriers. Multiparity may be associated with an increase in risk in BRCA2 carriers. However, the effect of multiparity on ovarian cancer risk for BRCA2 mutation carriers has only been investigated in a small number of studies. Therefore, the association is controversial. Women who took OCs before the age of 30 years and long-term user of 5 or more years have been associated with a slight increase in risk of breast cancer among BRCA1 mutation carriers (29). Furthermore, prolonged hormone replacement therapy (HRT) use is an established risk factor of breast cancer. HRT also affects ovarian cancer risk. Among a subgroup of patients who had a familial history of breast cancer, tamoxifen and raloxifene, selective estrogen receptor modulators, reduced breast cancer risk. Tamoxifen and raloxifene reduced the risk of invasive breast cancer: compared with placebo, raloxifene reduced breast cancer risk by 38%, tamoxifen showed a 50% reduction (37). Additionally, use of PARP inhibitors is a potential synthetic lethal therapeutic strategy and may be considered as targeted chemoprevention in patients with specific DNA-repair defects. Other agents under preclinical and clinical investigation include cyclooxygenase-2 inhibitors, aromatase inhibitors, tyrosine kinase inhibitors, and difluoromethylornithine (a polyamine inhibitor) (38,39). Future efficacy studies are expected.

Prophylactic surgeries are appropriate treatment options for BRCA mutation-associated cancer (4). Prophylactic bilateral mastectomy reduces the risk of breast cancer in BRCA mutation carriers by 90% at any age. Prophylactic bilateral salpingo-oophorectomy (BSO) lowers the ovarian cancer risk by 80%. BSO performed before age 50 years also exhibits a 50% reduction in subsequent breast cancer risk. In conclusion, prophylactic surgeries lead to a reduction in breast and ovarian cancer-specific mortality. Knowledge of these risk factors and prevention strategies will have a great impact on the management of hereditary breast and ovarian cancers.

Since identification of the mutation screening is currently labor intensive and expensive, the screening should be directed to asymptomatic individuals only if they belong to high-risk families. Various safe and effective screening protocols have been recommended for early cancer detection and reduction of cancer risk in clinical practice. Women with HBOC syndrome often utilize the latest medical advances in increased surveillance, prevention, early detection, chemoprevention and optimal treatment. Among BRCA1 and BRCA2 mutation carriers, use of screening mammography alone led to increased early detection rates of non-palpable breast cancer, but the rate of interval cancers was high (7,40). Therefore, the effectiveness of mammography alone (sensitivity 40%) is questionable for screening high-risk women. In the high risk group of women, magnetic resonance imaging (unenhanced MR imaging with combined diffusion-weighted and T2-weighted images, sensitivity 50%) surveillance largely out performed mammography. Furthermore, dynamic contrast-enhanced MRI exhibited highest sensitivity (86%) (41). MRI is a better screening method and will detect the majority of breast cancers at an early stage. The addition of MRI to screening mammography increased sensitivity (42), supporting the benefits of breast MRI examination annually (the sensitivity was 80%, the false positive rate was 10%) in BRCA mutation carriers (43). Alternating MRI and mammography screening at 6-month intervals might be a clinically effective approach. The HBOC carriers have two options to reduce their risk of ovarian cancer: periodic screening and risk-reducing surgeries (44). Periodic screening consists of annual or semi-annual pelvic examination with the longitudinal CA125 blood test plus concurrent transvaginal ultrasound. Unfortunately, to date, this screening regimen is ineffective for early detection of ovarian cancer in high-risk women. Risk-reducing salpingo-oophorectomy represents a potentially valuable intervention and is the only way for many women at high-risk by age 40 years, or on completion of childbearing. Preventive surgery can reduce ovarian cancer risk by 80–90% and breast cancer risk by 50–60% in BRCA mutation carriers.

HBOC syndrome is the inherited tendency to develop breast, ovarian and other cancers and believed to be transmitted by mutations in the specific genes. Clinical characteristics, including the type of tumor and age at occurrence as well as family history, predict the prevalence of BRCA germline mutations. A number of clinicians usually take into account the age of the youngest breast cancer patient and the number of ovarian cancer cases in a family as well as pathological diagnosis. Up to 80% of the HBOC cases are due to mutations in BRCA1 or BRCA2 genes. Both BRCA1 and BRCA2 mutations are scattered throughout the whole coding exons.

To maintain and restore the genomic integrity, normal cells possess DNA repair mechanisms. The structural modifications, such as DNA base damage, DNA strand break, inter- and intra-strand crosslinks and DNA-protein crosslinks, are involved in mutation and cancer. A variety of intelligent mechanisms can activate DNA repair pathways and cell cycle checkpoints and recognize and repair SSB or DSB by the master sensors and regulators of DNA damage response such as BRCA1 and BRCA2. BRCA1 and BRCA2 genes were recruited to the sites of DNA damage. BRCA1 associates with several proteins and is an integral member of the repair of DNA damage by functional HR, NER and possibly NHEJ. BRCA1 activated by cdk1 physically interacts with MutL α, through the interaction of the FA-BRCA pathway (45). BRCA2, also known as FANCD1, has a more specific role in DNA repair and is directly involved in the mechanism of HR, regulating the activity of RAD51, a gene implicated in the HR pathway as well as interacting with PALB2, a gene implicated in the HR repair and checkpoint functions. Interestingly, the nuclear function of BRCA proteins is tightly regulated by the FA-BRCA, MMR, BER and NER pathway. However, the exact mechanisms of the BRCA-associated interaction and accumulation of other DNA repair proteins are not comprehensively known. Therefore, germline mutations in other susceptibility genes, such as FA genes, MMR genes and DNA repair genes, might be the predisposing factors in HBOC cases. These predisposing genes encode for upstream and downstream regulators of BRCA gene products and also may be associated with the BRCA core complex, including mutations in FANCD1, FANCD2, FANCJ, FANCP, TP53, PTEN, STK11, CDH1, CHK2, ATM, ATR, MSH1, M SH2, MLH1 and PMS2 genes. Families affected by other syndromes, such as Lynch syndrome (mutations in MMR genes), Fanconi anemia, Cowden syndrome (mutations in PTEN), Li-Fraumeni syndrome (mutations in TP53), xeroderma pigmentosum and ataxia-telangiectasia, exhibit additional types of cancers outside the previously defined HBOC cancer spectrum.

In conclusion, genetic or epigenetic loss-of-function mutations of genes that are known to be involved in the repair of DNA damage might lead to increased risk of developing a broad spectrum of breast and ovarian cancers.