BRCA2-associated hereditary breast and ovarian cancer syndrome (BOCS) is one of the most common family cancer syndromes. Germline mutations in the BRCA2 gene are associated with a very high lifetime risk for breast cancer and malignancies of the ovaries. Accordingly, members of families known to be affected by BRCA2-associated BOCS should be tested for mutations in the respective gene and be referred for prophylactic surgery or clinical and radiological surveillance.
The clinical presentation of BRCA2-associated malignancies doesn't differ from that of non-hereditary cancers. Symptoms are usually non-specific and may comprise palpable mass lesions, pain, and constitutional symptoms like fever, night sweats, chills, loss of appetite and weight. With regard to breast cancer, changes of the nipple or overlying skin may be presenting symptoms. Additionally, discharge may be described. Ovarian cancer may also be associated with discharge, or with rather common gastrointestinal and genitourinary complaints like early satiety, bloating and urinary urgency. Prostate cancer may not cause any symptoms but may also be related to frequent urination and dysuria. The presence of metastases usually broadens the spectrum of symptoms and may intensify the aforementioned constitutional symptoms.
Although clinical findings don't allow for the differentiation of BRCA2-associated malignancies and other types of cancer, anamnestic data may certainly provide valuable information to this end. Patients developing cancer due to hereditary cancer syndromes are rather young, often younger than 50 years. They may have a family and personal history of cancer, and tend to develop multiple tumors. Breast cancer in males is in itself suggestive of a predisposition to cancer .
Entire Body System
In that respect, Lord and Ashworth have recently suggested BRCA2-deficient tumor cells to be susceptible to PARP inhibitors like olaparib because these compounds mediate what is known as "synthetic lethality". [symptoma.com]
Genetic testing is recommended primarily for people who have a personal and/or family history that suggests HBOC. [cancer.net]
It has been suggested that the type of family history of cancer and the mutation position on the gene are associated with variation in ovarian cancer risks in BRCA1/2 mutation carriers. [docplayer.net]
Data suggests that the use of both imaging techniques is more sensitive. An MRI can also be used to help to determine the extent and exact location of cancer associated with HBOC syndrome. [rarediseases.org]
Ovarian cancer may also be associated with discharge, or with rather common gastrointestinal and genitourinary complaints like early satiety, bloating and urinary urgency. [symptoma.com]
Prostate cancer may not cause any symptoms but may also be related to frequent urination and dysuria. The presence of metastases usually broadens the spectrum of symptoms and may intensify the aforementioned constitutional symptoms. [symptoma.com]
The diagnosis of breast and ovarian cancer is based on clinical, laboratory, imaging and histological data, regardless of a possible predisposition to cancer. The same applies to other malignancies that may arise in carriers of BRCA2 mutations. A positive family history of breast and/or ovarian cancer should, however, raise suspicion as to a genetic defect that may increase the individual risk of developing such malignancies and prompt molecular biological testing.
The detection of a heterozygous germline pathogenic variant in BRCA2 is diagnostic of BRCA2-associated BOCS . In an ideal scenario, patients are tested for BRCA2 mutations before they develop any tumors. But genetic studies should also be carried out if an elder patient's personal or family history suggests a hereditary cancer syndrome: The results of these studies are relevant for their own prognosis and the identification of family members at risk. Targeted analyses may be carried out if a determined mutation has been found in a family member or if the patient at hand belongs to an ethnic group with a known founder mutation . If BRCA2 mutations can't be identified, other genes have to be sequenced, e.g. BRCA1 (BRCA1-associated-BOCS), TP53 (Li-Fraumeni syndrome), PTEN (PTEN hamartoma tumor syndrome), CDH1 (hereditary diffuse gastric cancer), and STK11 (Peutz-Jeghers syndrome)   .
Briefly, the following measures may be taken to diagnose BOCS-associated malignancies. They may either be carried out in symptomatic patients or in the scope of surveillance programs:
- Palpation of breast and axilla, abdomen, and prostate gland to detect mass lesions.
- Measurements of concentrations of tumor markers like cancer antigen 125 and prostate-specific antigen in serum samples.
- Sonography, radiography, computed tomography, and magnetic resonance imaging as well as other forms of diagnostic imaging to visualize anatomical and structural anomalies.
- Microscopic examination of tissue samples obtained by fine-needle aspiration, biopsy or surgery. Histological and immunohistochemical features should be considered. Carriers of pathogenic BRCA2 variants are most likely to develop ductal carcinoma. Lobular carcinoma and mixed ductal/lobular tumors are also common, so the frequency of histological types of mammary tumors largely resembles that observed in the general population . Concerning BRCA2-related ovarian malignancies, serous adenocarcinoma is particularly common .
There is no universal grading system for malignancies due to BRCA2 mutations. Grading and staging systems specific to the tumor site are used, e.g., the TNM-based staging system for breast cancer and the FIGO staging system for ovarian cancer  . These systems are not perfect but are certainly helpful to orient therapeutic decisions.
Surgery is the mainstay of treatment. Because poor long-term survival is often attributed to second primary tumors in the breast or ovaries, women diagnosed with BRCA2-related breast or ovarian cancer are usually recommended ipsilateral mastectomy, contralateral risk-reducing mastectomy, and salpingo-oophorectomy   . Beyond that, there are no general guidelines on the management of BRCA2-related tumors. Treatment decisions generally rest on site-specific recommendations for cancer management and are thus made on a case-by-case basis. In this context, adjuvant chemotherapy is often administered, with platin-based treatment regimens being more effective in carriers of pathogenic BRCA2 variants than in non-carriers . BRCA2-associated malignancies may also respond to radiotherapy, hormone therapy, and molecular targeted therapy. The latter is the focus of intense research. Scientists are currently analyzing potential relationships between BRCA2 genotypes and associated tumors' susceptibility to certain therapies. In that respect, Lord and Ashworth have recently suggested BRCA2-deficient tumor cells to be susceptible to PARP inhibitors like olaparib because these compounds mediate what is known as "synthetic lethality" . It is hoped that further specific recommendations can be given in the near future.
BRCA2-associated BOCS patients have an estimated lifetime risk of 38-84% for breast cancer, and about 11% of those who have once been diagnosed with breast cancer will develop a second mammary tumor within ten years. Women carrying pathogenic BRCA2 variants have a lifetime risk of 17-27% for malignancies of the ovaries. In males, the lifetime risk for breast cancer amounts to 9%, and approximately 15% of male carriers are diagnosed with prostate cancer by the age of 65 years. Additionally, all patients have an increased risk for pancreatic cancer and melanoma .
BRCA2-related tumors are usually high-grade malignancies associated with an unfavorable prognosis for long-term survival    . Beyond that, the presence of at least one distant metastasis, no surgery, large tumor size, and lymph node involvement have been identified as unfavorable prognostic factors and are listed here in decreasing order of hazard ratio . In sum, breast-cancer-specific ten-year survival rates approximate 70% . With regard to BRCA2-associated ovarian cancer, five-year survival rates may exceed 50%, but less than a third of affected women remain alive ten years after the initial diagnosis . It remains a matter of discussion whether female carriers of BRCA2 mutations have a worse prognosis than non-carriers who are diagnosed with the same type of tumor: So far, large-scale studies have not revealed significant differences between both groups of patients  . By contrast, the median overall survival time of men suffering from BRCA2-related prostate cancer is 3.5 years, which is significantly shorter than that of non-carriers .
BRCA2-associated BOCS is caused by pathogenic mutations in the BRCA2 gene. This gene is located on the long arm of chromosome 13 and has been classified as a tumor suppressor gene. The BRCA2 gene encodes for a protein that binds to RAD51 and promotes the assembly of RAD51 and single-stranded DNA in preparation for the repair of double-strand DNA breaks. In sum, BRCA2 is required for the maintenance of genomic stability. BRCA2 has been identified as a breast cancer susceptibility gene in 1995 . By now, more than 1,700 BRCA2 mutations have been described . It has long since been assumed that there are breast cancer cluster regions and ovarian cancer cluster regions in the BRCA2 gene. This hypothesis has finally been confirmed by Rebbeck and colleagues, who have shown that mutations in the respective regions are associated with particularly high risks for one or the other type of cancer .
The overall prevalence of BRCA2 mutations has been estimated to 0.1-0.7% of the population. However, there are considerable differences between geographical regions and ethnicities . It has been estimated that 1.5% of Ashkenazi Jews are carriers of founder mutation 6174delT, the most common one of three deleterious founder defects widely distributed in the respective population . The other two mutations affect the BRCA1 gene. In total, about 2.5% of individuals of Ashkenazi Jewish ancestry are carriers of at least one of these mutations, which account for >90% of all cases in this ethnic group  . BRCA2 founder mutations have also been detected in the Icelandic and Hungarian populations .
BRCA2-associated BOCS is inherited in an autosomal dominant manner, a fact that becomes clear when performing genealogical analyses: This pattern of inheritance is typically associated with a very high familial incidence of the disease in question. However, there may be carriers of pathogenic BRCA2 mutations who don't have a family history of breast, ovarian, or related cancer. Distinct circumstances may account for this situation. On the one hand, the penetrance of the mutated gene is incomplete, particularly in men. On the other hand, the patients' age at cancer development varies and family members may have died of non-related causes before malignancies were developed or detected .
BRCA2 is a protein-coding gene. Its gene product is involved in homologous recombination repair and is thus required for the conservative repair of double-strand DNA breaks. BRCA2-deficient cells have to resort to non-conservative forms of DNA repair, e.g., to non-homologous end joining. Non-conservative mechanisms are more likely to be associated with deletions of genetic information and thus favor the accumulation of mutations that eventually trigger cancerogenesis . BRCA2 has also been proposed to be involved in chromosome segregation, so BRCA2 deficiency may lead to chromosomal aberrations after several divisions .
First and second-degree relatives of known carriers of pathogenic BRCA2 mutations should be tested for the respective genetic defect. Beyond that, population screenings for BRCA2 mutations have been proposed for the Ashkenazi Jewish population . Because comprehensive genetic studies provide little additional benefit, such population screenings could be limited to known founder mutations .
Due to the high risks associated with BRCA2-associated BOCS, carriers should be informed about the possibility of prophylactic bilateral mastectomy and prophylactic salpingo-oophorectomy. Alternatively, they may opt for a surveillance program comprising regular clinical examination, assessment of the serum levels of tumor markers, and diagnostic imaging. Both females and males who (temporarily) opt against prophylactic surgery should be encouraged to partake in surveillance programs for the detection of breast cancer from the age of 35. The same starting age is recommended for ovarian cancer screenings; annual prostate cancer screenings should be offered to male carriers aged 45 years and older. It should be noted, though, that the sensitivity of the abovementioned techniques for the early detection of malignancies is limited. The overall risk for melanoma is low, so screenings for skin cancer should be scheduled based on the family history .
A prenatal diagnosis of BRCA2-associated BOCS is feasible but rarely demanded.
BRCA2-associated BOCS is a hereditary cancer syndrome related to high risks for breast and ovarian cancer including fallopian tube and primary peritoneal malignancies. Furthermore, carriers of pathogenic mutations in the BRCA2 gene have greatly increased risks for prostate cancer and pancreatic cancer. Their risk for cutaneous and uveal melanoma is moderately elevated when compared to the general population. BRCA2-associated BOCS is inherited in an autosomal dominant manner. The relatively high penetrance of the mutated gene justifies regular examinations in the scope of surveillance programs and even prophylactic surgery, so it is highly recommended to perform a thorough familial workup, to identify affected kindreds and family members at risk. Molecular genetic studies are required to diagnose BRCA2-associated BOCS .
The causes of cancer remain unknown in the majority of cases, but some patients are genetically predisposed to the development of malignancies. They may have inherited mutated genes from either of their parents and thus become prone to certain types of tumors. If this is the case, they suffer from a hereditary cancer syndrome. BRCA2-associated hereditary breast and ovarian cancer syndrome (BOCS) is one of the most common ones. It is related to mutations in a gene named BRCA2 and renders affected individuals highly susceptible to breast cancer, ovarian cancer including fallopian tube and primary peritoneal malignancies, prostate cancer, pancreatic cancer, and melanoma. BRCA2 mutations can be detected by molecular genetic studies at any age, so BRCA2-associated BOCS can be diagnosed before the development of any tumor.
Because BRCA2-associated BOCS is inherited, patients who carry pathogenic variants of the BRCA2 gene usually have a family history of cancer. They tend to develop cancer at rather young ages, often before turning 50 years old. With regard to female patients, their lifetime risk for malignancies of the breast and ovaries may be as high as 84%, so they are generally recommended prophylactic surgery. Risk-reducing bilateral mastectomy and salpingo-oophorectomy greatly improve their survival. Men's lifetime risks for breast and prostate cancer are significantly increased, too, and amount to 9 and 15%, respectively. Therefore, male carriers of BRAC2 mutations are highly recommended to undergo regular examinations. In sum, every possible effort should be made to avoid the development of malignancies and to diagnose cancer during early stages of the disease to improve the patients' prognosis.
- Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
- Rebbeck TR, Friebel TM, Friedman E, et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018.
- Fountzilas C, Kaklamani VG. Multi-gene Panel Testing in Breast Cancer Management. Cancer Treat Res. 2018; 173:121-140.
- Toss A, Tomasello C, Razzaboni E, et al. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. Biomed Res Int. 2015; 2015:341723.
- Schmidt MK, van den Broek AJ, Tollenaar RA, et al. Breast Cancer Survival of BRCA1/BRCA2 Mutation Carriers in a Hospital-Based Cohort of Young Women. J Natl Cancer Inst. 2017; 109(8).
- McLaughlin JR, Rosen B, Moody J, et al. Long-term ovarian cancer survival associated with mutation in BRCA1 or BRCA2. J Natl Cancer Inst. 2013; 105(2):141-148.
- Cserni G, Chmielik E, Cserni B, Tot T. The new TNM-based staging of breast cancer. Virchows Arch. 2018.
- Zeppernick F, Meinhold-Heerlein I. The new FIGO staging system for ovarian, fallopian tube, and primary peritoneal cancer. Arch Gynecol Obstet. 2014; 290(5):839-842.
- Metcalfe K, Lynch HT, Foulkes WD, et al. Effect of Oophorectomy on Survival After Breast Cancer in BRCA1 and BRCA2 Mutation Carriers. JAMA Oncol. 2015; 1(3):306-313.
- Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002; 346(21):1616-1622.
- Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012; 30(21):2654-2663.
- Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017; 355(6330):1152-1158.
- Gallagher DJ, Gaudet MM, Pal P, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res. 2010; 16(7):2115-2121.
- Thorne H, Willems AJ, Niedermayr E, et al. Decreased prostate cancer-specific survival of men with BRCA2 mutations from multiple breast cancer families. Cancer Prev Res (Phila). 2011; 4(7):1002-1010.
- Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995; 378(6559):789-792.
- Rebbeck TR, Mitra N, Wan F, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. Jama. 2015; 313(13):1347-1361.
- Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996; 14(2):185-187.
- Lieberman S, Lahad A, Tomer A, Cohen C, Levy-Lahad E, Raz A. Population screening for BRCA1/BRCA2 mutations: lessons from qualitative analysis of the screening experience. Genet Med. 2017; 19(6):628-634.
- Petrucelli N, Mange S, Fulbright JL, Dohany L, Zakalik D, Duquette D. To reflex or not: additional BRCA1/2 testing in Ashkenazi Jewish individuals without founder mutations. J Genet Couns. 2015; 24(2):285-293.
- Godet I, Gilkes DM. BRCA1 and BRCA2 mutations and treatment strategies for breast cancer. Integr Cancer Sci Ther. 2017; 4(1).