HEREDITARY BREAST AND OVARIANCANCER SYNDROME

• In the year 2018 in the United States:
  • Approximately 22 000 women received a new diagnosis of ovarian cancer, and there were 14 000 ovarian cancer deaths
• Inherited germline mutations:
  • That increase the risk for ovarian cancer:
    • Are present in approximately 7% to 25% of these women
• Hereditary breast and ovarian cancer syndrome (HBOC):
  • Is the most common genetic syndrome:
    • Linked to ovarian cancer:
      • Is associated with mutations in the BRCA genes
  • BRCA1 and BRCA2 are:
    • Tumor suppressor genes:
      • Involved in the repair of double‐stranded DNA breaks
  • Certain populations are at significantly higher risk for BRCA mutations than the general population including:
    • Ashkenazi Jewish, French Canadian, and Icelandic populations:
      • This is because of the founder effect:
        • Which causes a decrease in genetic diversity in a population that is geographically or reproductively isolated 
        • For example, in the general United States non‐Jewish population:
          • The risk of inheriting a BRCA mutation is 1 in 400 compared with theAshkenazi Jewish population, who carry an increased risk of 1 in 40
  • The inheritance pattern of the BRCA mutations is:
    • Autosomal dominant:
      • However, tumor suppressor genes are known to be recessive, requiring both copies of the gene to be affected
      • Therefore, a germline BRCA mutation is inherited in one copy of the gene, the second copy then undergoes a somatic mutation:
        • The second hit and the carrier is phenotypically affected
• The most recently estimated cumulative cancer risk by age 80 for:
  • BRCA1 carriers is:
    • 72% 
  • BRCA2 carriers is:
    • 69%
• By comparison, the lifetime risk of ovarian and breast cancer in the general population is:
  • 1.3% and 12.4%, respectively
• Furthermore, the lifetime risk for ovarian cancer in:
  • BRCA1 carriers is:
    • 44%
  • BRCA2 carriers is:
    • 17%
• BRCA carriers are also at risk for other cancers including:
  • Pancreatic, prostate, melanoma, and colon cancer
• Recently, findings by Shu et al8 suggest that BRCA1 carriers:
  • Have an increased risk for uterine papillary serous carcinoma:
    • A rare but aggressive type of uterine cancer
    • In a prospective cohort of 627 BRCA1 carriers:
      • Four women developed serious uterine cancer:
        • Which was double the expected incidence in the general population
• References:
  • Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7‐34. 
  • Noone AM, Howlader N, Krapcho M, et al. “SEER Cancer Statistics Review, 1975‐2015,” National Cancer Institute, Bethesda, MD, 2018. 
  • Morgan RD, Burghel GJ, Flaum N, et al Prevalence of germline pathogenic BRCA1/2 variants in sequential epithelial ovarian cancer cases. J Med Genet. 2019;56:301‐307. 
  • McClainMR,PalomakiGE,NathansonKL,etalAdjustingtheestimated proportion of breast cancer cases associated with BRCA1 and BRCA2 mutations: public health implications. Genet Med. 2005;7(1):28‐33. 
  • Gudmundsson J, Johannesdottir G, Bergthorsson JT, et al Different tumor types from BRCA2 carriers show wild‐type chromosome deletions on 13q12‐q13. Cancer Res. 1995;55(21):4830‐4832. 
  • Kuchenbaecker KB, Hopper JL, Barnes DR, et al Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317(23):2402‐2416. 
  • Mersch J, Jackson MA, Park M, et al Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer. 2015;121(2):269‐275. 

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