EC Microbiology

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is primarily associated with germline mutations in the BRCA1 and BRCA2 genes, which play a critical role in repairing DNA double-strand breaks through homologous recombination [1,2]. Mutations in these genes compromise genomic stability, resulting in significantly increased lifetime risks of breast and ovarian cancers. BRCA1 mutations are often linked to aggressive triple-negative breast cancers, whereas BRCA2 mutations are associated with hormone receptor-positive tumors [3,4]. This systematic review synthesizes evidence on the molecular mechanisms, epidemiology, clinical manifestations, and therapeutic approaches for BRCA related cancers. Findings indicate that mutation carriers face earlier onset of disease, distinct tumor subtypes, and differential responses to targeted therapies, particularly PARP inhibitors [5,6]. Despite major advances in genetic testing and personalized treatment, challenges remain, including limited access to testing in low- and middle- income countries, underrepresentation of diverse populations, and uncertainties surrounding variants of uncertain significance (VUS) [7,8]. Recommendations emphasize the expansion of genetic testing and counseling, population specific research, personalized surveillance, and broader access to targeted therapies. Overall, understanding BRCA1 and BRCA2 mutations bridges molecular research and clinical practice, enabling precision medicine approaches that improve early detection, risk reduction, and treatment outcomes for individuals affected by hereditary cancers [1-8].

 Keywords: BRCA1; BRCA2; Hereditary Breast Cancer; Ovarian Cancer; DNA Repair; PARP Inhibitors; Genetic Counseling; Hereditary Cancer Syndromes

1. Miki Y., et al. “A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1”. Science 5182 (1994): 66-71.
2. Wooster R., et al. “Identification of the breast cancer susceptibility gene BRCA2”. Nature 6559 (1995): 789-792.
3. Roy R., et al. “BRCA1 and BRCA2: Different roles in a common pathway of genome protection”. Nature Reviews Cancer1 (2012): 68-78.
4. Venkitaraman AR. “Cancer susceptibility and the functions of BRCA1 and BRCA2”. Cell2 (2002): 171-182.
5. Kuchenbaecker KB., et al. “Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers”. JAMA23 (2017): 2402-2416.
6. Easton DF., et al. “Gene-panel sequencing and the prediction of breast-cancer risk”. New England Journal of Medicine 23 (2015): 2243-2257.
7. Foulkes WD., et al. “Triple-negative breast cancer”. New England Journal of Medicine20 (2010): 1938-1948.
8. Lord CJ and Ashworth A. “PARP inhibitors: Synthetic lethality in the clinic”. Science6330 (2017): 1152-1158.
9. Moore K., et al. “Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer”. New England Journal of Medicine26 (2018): 2495-2505.
10. Rebbeck TR., et al. “Mutational spectrum in a global study of BRCA1 and BRCA2”. Human Mutation5 (2018): 593-620.
11. Antoniou AC., et al. “Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies”. American Journal of Human Genetics 5 (2003): 1117-1130.
12. Daly MB., et al. “Genetic/familial high-risk assessment: Breast, ovarian, and pancreatic, version 3.2023”. Journal of the National Comprehensive Cancer Network2 (2023): 168-214.
13. Struewing JP., et al. “The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews”. New England Journal of Medicine12 (1995): 745-749.
14. Mavaddat N., et al. “Cancer risks for BRCA1 and BRCA2 mutation carriers: Results from prospective analysis of EMBRACE”. Journal of the National Cancer Institute 11 (2010): 812-822.
15. Leongamornlert DA., et al. “Germline BRCA1 mutations increase prostate cancer risk”. British Journal of Cancer10 (2012): 1697-1701.
16. Richards S., et al. “Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation”. Genetics in Medicine5 (2015): 405-424.
17. Fong PC., et al. “Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers”. New England Journal of Medicine2 (2009): 123-134.
18. Lord CJ and Ashworth A. “Mechanisms of resistance to therapies targeting BRCA-mutant cancers”. Nature Medicine11 (2013): 1381-1388.
19. Eccles DM., et al. “BRCA1 and BRCA2 genetic testing - pitfalls and recommendations”. Journal of Clinical Pathology7 (2015): 531-536.
20. Snyder H. “Literature review as a research methodology: An overview and guidelines”. Journal of Business Research 104 (2019): 333-339.
21. World Medical Association. “WMA Declaration of Helsinki - Ethical principles for medical research involving human subjects”. Journal of the American Medical Association20 (2013): 2191-2194.