Women with hereditary breast and ovarian cancer (HBOC) syndrome represent a unique group who are diagnosed at a younger age and result in an increased lifetime risk for developing breast, ovarian and other cancers. This review integrates recent progress and insights into the molecular basis that underlie the HBOC syndrome. A review of English language literature was performed by searching MEDLINE published between January 1994 and October 2012. Mutations and common sequence variants in the BRCA1 and BRCA2 (BRCA) genes are responsible for the majority of HBOC syndrome. Lifetime cancer risks in BRCA mutation carriers are 60–80% for breast cancer and 20–40% for ovarian cancer. Mutations in BRCA genes cannot account for all cases of HBOC, indicating that the remaining cases can be attributed to the involvement of constitutive epimutations or other cancer susceptibility genes, which include Fanconi anemia (FA) cluster (FANCD2, FANCA and FANCC), mismatch repair (MMR) cluster (MLH1, MSH2, PMS1, PMS2 and MSH6), DNA repair cluster (ATM, ATR and CHK1/2), and tumor suppressor cluster (TP53, SKT11 and PTEN). Sporadic breast cancers with TP53 mutations or epigenetic silencing (hypermethylation), ER- and PgR-negative status, an earlier age of onset and high tumor grade resemble phenotypically BRCA1 mutated cancers termed ‘BRCAness’, those with no BRCA mutations but with a dysfunction of the DNA repair system. In conclusion, genetic or epigenetic loss-of-function mutations of genes that are known to be involved in the repair of DNA damage may lead to increased risk of developing a broad spectrum of breast and ovarian cancers.
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 (
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 (
A computerized literature search was performed to identify relevant studies reported in the English language. We searched MEDLINE electronic databases (
The breast cancer-associated genes BRCA1 on chromosome 17q and BRCA2 on chromosome 13q are the most well-known breast cancer susceptibility genes (
A recent study showed that breast cancer patients belonging to a population with a high probability of being BRCA1 carriers showed a better prognosis compared with those with sporadic breast cancer (
The mutations include partial or complete gene deletions, duplications, large insertions, splice alteration, frameshifts as well as missense and nonsense mutations. Deletions or insertions usually lead to abnormal structure and function. Germline mutations are usually pathogenic point mutations, and are scattered throughout their coding regions. The potential hot-spot mutations within BRCA 1 and BRCA2 are uncommon. The previously described mutations were identified in the Breast Cancer Information Core website (BIC,
The tumor suppressor BRCA1 and BRCA2 genes are essential components of the double-strand break (DSB) repair by homologous recombination (HR) system. Targeting tumor suppressor loss-of-function is possible based on the concept of synthetic lethality. Thus, the synthetically lethal effect might be observed in tumors defective in BRCA1 or BRCA2 that are required for efficient HR, indicating that ovarian cancer patients carrying germ-line mutations had improved rates of progression-free and overall survival (
BRCA1 functions as a tumor suppressor gene, but paradoxically, BRCA1 knockout mice are embryonically lethal in homozygous state. Lack of BRCA1 is thought to result in cellular lethality, suggesting that BRCA1 regulates stem/progenitor cell proliferation and differentiation. For cell differentiation, BRCA1 regulates apicobasal polarity, together with several genes such as RHAMM (hyaluronan-mediated motility receptor), AURKA (aurora kinase A) and TPX2 (microtubule-associated, homolog). Intracellular RHAMM associates with BRCA1 and BARD1 (BRCA1 associated RING domain 1). The complex attenuates the mitotic-spindle-promoting activity of RHAMM that might contribute to tumor progression. BRCA1 also binds and regulates AURKA, a cell cycle-regulated kinase that appears to be strongly involved in centrosome regulation. Genetic variants in the AURKA gene may contribute to breast cancer development (
From a clinical point of view, the triple-negative breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PgR), and HER2 (also known as ERBB2) accounts for ~15% of breast cancers and is diagnosed more frequently in younger women (
The predominant histologic type of ovarian cancers associated with the HBOC syndrome was high-grade serous carcinomas of the ovary. There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (
Mutations in BRCA1 and BRCA2 do not account for all cases of HBOC, implicating that the remaining cases can be attributed to the involvement of other susceptibility genes. Other genes, including Fanconi anemia (FA) cluster (FANCD2, FANCA and FANCC), MMR cluster (MLH1, MSH2, PMS1, PMS2 and MSH6), DNA checkpoint cluster (ATM, ATR and CHK1/2), and tumor suppressor cluster (TP53, SKT11 and PTEN) have been associated with increased risk of breast and ovarian cancer as part of other cancer syndromes. The contribution of mutations in other genes to the burden of breast or ovarian cancer is indicated in
Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in the recovery of cells from DNA damage and the regulation of the molecular events such as BER, a key pathway in the repair of DNA single-strand breaks (SSB). The inhibition of PARP leads to the induction of synthetic lethality and cell death by targeting HR-mediated DNA repair deficient tumors (
Recently, Kaye
There are two types of DNA repair proteins: the nucleotide excision repair (NER) pathway (ERCC1, excision repair cross-complementing rodent repair deficiency, complementation group 1) and the base excision repair (BER) pathway (XRCC1, X-ray repair complementing defective repair in Chinese hamster cells 1) (
Furthermore, XRCC1 is involved in the repair of DNA SSB and oxidative damage (
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 (
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 (
Both HNPCC and HBOC associated ovarian cancer develop along distinct genetic pathways (
As shown in
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 (
Prophylactic surgeries are appropriate treatment options for BRCA mutation-associated cancer (
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 (
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 (
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.
Th present review was supported by grant-in-aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan to the Department of Obstetrics and Gynecology, Nara Medical University (to H.K.).
New insights into DNA repair machinery in BRCA pathways or multiprotein networks. We reviewed the breast and ovarian cancer susceptibility genes and their functional multiprotein networks in promoting DNA repair and the underlying molecular mechanisms involving interaction with the FA, MMR and other DNA repair genes in HBOC syndrome. BRCA1 and BRCA2 maintain cellular events associated with the genomic integrity. Mutations that affect the mechanisms involved in the detection, stabilization and repair of DNA damage cause genome instability.
Modifying hereditary breast and ovarian cancer risks.
No. | Genes | Functions | Refs. |
---|---|---|---|
Genes with high penetrance | |||
1 | CDH1, cadherin 1 type 1 E-cadherin | Loss of CDH1 function contributes to progression in cancer by increasing proliferation, invasion, metastasis and epithelial-mesenchymal transition (EMT). Germline mutations in the CDH1/E-cadherin gene predispose to the development of the autosomal hereditary diffuse gastric cancer (HDGC) syndrome, which leads to the development of breast, colorectal, thyroid and ovarian cancer ( |
( |
2 | NBS1, also known as NBN (nibrin) | The encoded protein nibrin is an integral member of the MRE11/RAD50/NBN (MRN) complex essential for processing DNA double-strand breaks and DNA damage-induced checkpoint activation. Mutations in this gene causes Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The NBN 657del5 mutation plays a role in breast cancer risk, but not ovarian cancer risk. | |
3 | NF1, neurofibromin 1 | NF1 functions as a negative regulator of the Ras/Raf/Erk signal transduction pathway. Mutations in this gene are associated with neurofibromatosis type 1 (NF1) and other neoplasms, including juvenile myelomonocytic leukemia (JMML) and breast cancer ( |
( |
4 | PTEN, phosphatase and tensin homolog | PTEN, a tumor suppressor gene, is mutated in a large number of cancers at high frequency. PTEN is a phosphatidylinositol 3-phosphatase and functions as a tumor suppressor by negatively regulating AKT signaling pathway. Mutations in PTEN gene are associated with the development of Cowden syndrome and also correlated with hamartomatous polyps, early-onset breast, thyroid and endometrial cancers ( |
( |
5 | TP53, tumor protein p53 | The encoded protein p53 responds to diverse cellular stresses to maintain genetic stability, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations, loss of heterozygosity (LOH), overexpression and loss of TP53 function occur as somatic mutations in human malignancies at high frequency. TP53 loss-of-function is essential for BRCA1-associated tumorigenesis ( |
( |
6 | STK11, serine/threonine kinase 11 | STK11 regulates cell polarity and functions as a tumor suppressor. Germline mutations in STK11 gene is associated with Peutz-Jegher syndrome, an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and cancer susceptibility in various organs including testis, ovary, endocervix, breast, pancreas and colon. | |
Genes with moderate penetrance | |||
7 | ATM, ataxia telangiectasia mutated | The protein encoded by this gene belongs to the PI3/PI4-kinase family. The activation of ATM was mediated via interactions with a wide variety of downstream proteins, including checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBN ( |
( |
8 | ATR, ataxia telangiectasia and Rad3 related | ATR also activates several important key proteins, including checkpoint kinase CHK1, TP53, BRCA1, RAD17 and RAD9. Constitutively phosphorylated CHK1 could have activated oncogene signaling pathways including myc signaling. CHK1 phosphorylates the FANCE subunit of the Fanconi anemia (FA) core complex, which is associated with the FA-BRCA pathway ( |
( |
9 | CHEK2, checkpoint kinase 2 | CHEK2, a cell cycle checkpoint regulator, is essential for activation in response to DNA damage. CHEK2 inhibits CDC25C phosphatase, stabilizes p53, and leads to cell cycle. arrest in G1. Since mutations in CHEK2 gene such as c.470T>C and c.1100delC increase the risk of HBOC, CHEK2 has been identified as an breast cancer susceptibility gene in the high-risk BRCA1/2-founder mutation-negative individuals ( |
( |
10 | Fanconi anemia (FA) genes | Mutations of Fanconi anemia (FA) genes have been demonstrated to cause breast and ovarian cancer susceptibility in cases from non-BRCA1/BRCA2 families ( |
( |
11 | FANCJ, Fanconi anemia group J protein, also known as BRCA1 interacting protein, C-terminal helicase 1 | FANCJ is the BRCA1 associated C-terminal helicase (BACH1). The BRCA1-FANCJ interaction is required for promoting error-free repair, DNA DSB repair, and interstrand cross-links repair by linking to MMR protein complex MLH1-PMS2 (MutL α) and checkpoint control. Tumors associated with FANCJ mutations will compromise error free NHEJ (non-homologous end-joining) and resemble BRCA1-associated cancer ( |
( |
12 | PALB2, partner and localizer of BRCA2 | PALB2 (the partner and localizer of BRCA2), also known as FANCN, was identified as a BRCA1- and BRCA2-interacting protein. PALB2 is associated with the formation of the BRCA1-PALB2-BRCA2 complex and has rare, but moderate-risk for breast cancer ( |
( |
13 | CDK1, cyclin-dependent kinase | Cyclin-dependent kinase (CDK) is the driver for cell cycle progression. CDK was generally suppressed in response to DNA damage, but certain CDK seems necessary for proper DNA damage response. CDK1 phosphorylates BRCA1, and is essential for efficient formation of BRCA1 foci ( |
( |
14 | RAD50, RAD50 homolog | Other predisposition genes involved in DNA repair may account for a proportion of HBOC families. RAD genes are involved in DNA DSB repair and required for both types of the repair processes, NHEJ and HR ( |
( |
Genes with low penetrance | |||
15 | FGFR2, fibroblast growth factor receptor 2 | Mutations in the FGFR2 gene cause several disorders, including Crouzon syndrome, Pfeiffer syndrome, craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. The rs2981582, rs2420946, and rs1219648FGFR2 polymorphisms act as modifiers of breast cancer susceptibility, particularly in the group of non-carriers of BRCA1/2 mutations ( |
( |
16 | LSP1, lymphocyte-specific protein 1 | LSP1 encodes an intracellular F-actin binding protein and regulates LS neutrophil motility, adhesion to fibrinogen matrix proteins, and transendothelial migration. The LSP1 rs3817198 polymorphism is associated to a modified risk of breast cancer. | |
17 | MAP3K1, mitogen- activated protein kinase kinase kinase 1 E3 ubiquitin protein ligase | MAP3K1 is associated with activation of the ERK and JNK kinase pathways as well as the NF-κB pathway. Functional polymorphism of MAP3K1 rs889312 has been shown to influence the risk of familial and early-onset breast cancer. | |
18 | TGFB1, transforming growth factor, β1 | Mutations in the TGFB1 gene is a genetic risk factor for Camurati-Engelmann disease featuring histopathological changes of osteomalacia. The rs1982073 TGFB1 polymorphism has been implicated in an elevated risk of progesterone receptor negative breast cancer. | |
19 | TOX3, TOX high mobility group box family member 3 | TOX3 is involved in alteration of chromatin structure. The rs3803662 TOX3 polymorphism is associated with an increased risk of and overall survival in breast cancer. | |
20 | VEGF, vascular endothelial growth factor | VEGF plays an important role in tumor angiogenesis. Genetic variation in VEGF may contribute to cancer susceptibility. An association of the CC, CT, or TT genotypes exhibited modification of breast and ovarian cancer risks. The 936_C>T polymorphism in the VEGF gene has a functional influence on disease risks in BRCA1 carriers ( |
( |
21 | PGR, progesterone eceptor | The variant progesterone receptor allele named PROGINS polymorphism (rs1042838) is characterized by a 306-bp Alu insertion into intron 7 and two additional sequence variations in exons 4 and 5 of the PGR gene, Val660Leu and His770His. The presence of one or more PROGINS alleles has an increased risk of developing ovarian and endometrial cancers ( |
( |
22 | KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog | A single amino acid substitution of KRAS, a member of the small GTPase superfamily, is responsible for an activating mutation and results in various malignancies, including lung, pancreas and colorectal cancers. Interestingly, the KRAS-variant at rs61764370 is associated with an increased risk of developing ovarian cancer in HBOC families without other known genetic abnormalities ( |
( |
Germline mutations in BRCA1 and BRCA2 are associated with an increased risk of HBOC syndrome. Non-BRCA mutations only account for a minority of cases. Members of mutation-negative families are also at increased risk of breast and ovarian cancers. Genome-wide association studies identified other genetic factors that increase the risk of breast and ovarian cancers. In addition to BRCA1 and BRCA2 mutations, putative susceptibility genes for hereditary breast and ovarian cancer include BRCA1/2 function modifier genes and DNA repair modifier genes with high penetrance (CDH1, NBS1, NF1, PTEN, TP53 and STK11), moderate penetrance (ATM, ATR, BRIP1,CHEK2, PALB2, CDK1 and RAD50), and low penetrance (FGFR2, LSP1, MAP3K1, TGFB1, TOX3, VEGF, PGR, KRAS and PARP) (