Ovarian Cancer BRCA2 Mutation Panel

BRCA2 Mutation in Ovarian Cancer risk:  
  • BRCA2 is normally involved in the repair of double-strand DNA breaks.
  • Cells with BRCA2 mutants are less capable of repair, allowing other genetic mutations to survive and grow, the type of genomic instability that cancer thrives upon.
  • Unlike BRCA1 mutations, which are exclusively associated with female breast cancer and ovarian cancer, and also confer a higher risk of pancreatic cancer, prostate cancer, male breast cancers and melanoma[1&2]
  • The life-time risk for patients with BRCA2 mutations tend to develop Epithelial Ovarian Cancer (EOC) is 10% - 27%.
  • BRCA2 gene play a key role in DNA pairing mechanism by enabling RAD51 to displace and stabilize single-stranded DNA by blocking ATP hydrolysis[3&4].
  • Mutations in BRCA2 gene may be a genetic marker for prognosis and chemotherapy response, because BRCA2 mutations are associated with longer survival than BRCA1 mutations and BRCA wild-type.
  • A patient’s BRCA status is essential as it may influence the choice of chemotherapy agents for recurrent diseases.
  • More than 50% of the High Grade Serous Epithelial Ovarian Cancer (HGSEOC) shows the dysfunction of BRCA1 or BRCA2 genes.
  • A majority of about 60% of those who were diagnosed at age >60 years were due mutation in BRCA2 gene.
  • The lifetime risk of developing an ovarian cancer is 40% to 60% in women who have BRCA1 mutation and the lifetime risk of developing ovarian cancer in women with BRCA2 mutation carries is 20%[5].
Other cancers linked to mutations in BRCA1 and BRCA2:
  • Harmful mutations in BRCA1 and BRCA2 increase the risk of several cancers in addition to breast and ovarian cancer.
  • These include fallopian tube cancer [6& 7] and peritoneal cancer [8].
  • Men with BRCA2 mutations, and to a lesser extent BRCA1 mutations, are also at increased risk of breast cancer [9] and prostate cancer [10].
  • If they are inherited from both parents, it can cause a rare form of Fanconi anemia, a syndrome that is associated with childhood solid tumors and development of acute myeloid leukemia [11&12].
  • Likewise, certain mutations in BRCA1 (also known as FANCS), if they are inherited from both parents, can cause another Fanconi anemia subtype [13].
Who should consider genetic testing for BRCA1 and BRCA2 mutations?
  • Genetic counseling is generally recommended before and after any genetic test for an inherited cancer syndrome.
  • A hereditary cancer risk assessment based on an individual’s personal and family medical history.
  • When an individual’s family history mentions the presence of the BRCA1 and BRCA2 mutation, it is recommended first to test the family member who has cancer.
  • If the cancer patient in the family is reported to have a BRCA1 or BRCA2 mutation, then other family members are advised to consider genetic test and genetic counseling, so that, they can learn more about the potential cancer risks.
  • If a woman with an unknown family history has an early-onset breast cancer or a man with an unknown family history is diagnosed with breast cancer, that individual may want to consider genetic counseling and testing for a BRCA1 or BRCA2 mutation.
  • A history of breast cancer at a young age in two or more close relatives, such as your parents, siblings or children are also recommended.
The genetic assess personal or family history factors that are associated with an increased likelihood of having a harmful mutation in BRCA1 or BRCA2, such as:
  • A first degree relative (mother, sister, or daughter) with ovarian cancer.
  • Breast cancer diagnosed before age 50 years
  • A personal history of triple negative breast cancer diagnosed at age 60 or younger
  • A personal history of breast cancer diagnosed prior to age 50, and one or more close relatives diagnosed with breast or ovarian cancer at any age.
  • Both breast and ovarian cancers in either the same woman or the same family
  • Multiple breast cancers in the family
  • Two or more primary types of BRCA1- or BRCA2-related cancers in a single family member
  • A personal history of both breast and ovarian cancers
  • A relative with a known BRCA1 or BRCA2 mutation
Reference
  1. Narod SA, Neuhausen S, Vichodez G, et al. (2008). Br J Cancer. 99(2):371-374,
  2. Ferrone CR, Levine DA, Tang LH, et al. (2009). J Clin Oncol. 27(3):433-438.
  3. Jensen RB, Carreira A, Kowalczykowski SC. (2010). Nature. 467(7316):678-683),
  4. Holloman WK. (2011). Nat Struct Mol Biol, 18(7):748-754.
  5. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. (2017). JAMA, 317(23):2402-2416)
  6. Brose MS, Rebbeck TR, Calzone KA, et al. (2002). Journal of the National Cancer Institute, 94(18):1365–1372.
  7. Finch A, Beiner M, Lubinski J, et al.. (2006) JAMA, 296(2):185–192.
  8. Levine DA, Argenta PA, Yee CJ, et al. (2003). Journal of Clinical Oncology; 21(22):4222–4227.
  9. Tai YC, Domchek S, Parmigiani G, Chen S. (2007). Journal of the National Cancer Institute, 99(23):1811–1814.
  10. Levy-Lahad E, Friedman E. (2007). British Journal of Cancer, 96(1):11–15.
  11. Howlett NG, Taniguchi T, Olson S, et al. (2002). Science, 297(5581):606–609.
  12. Alter BP. (2014). Best practice & research. Clinical Haematology, 27(3-4):214-21.
  13. Sawyer SL, Tian L, Kähkönen M, et al. (2015). Cancer Discovery, 5(2):135-142.