Non‐BRCA Mutations Associated with Ovarian Cancer

  • Although BRCA mutations are responsible for the majority of hereditary breast and ovarian cancers:
    • There are several other significant mutations that also carry an increased risk 
  • Hereditary breast and ovarian cancer (HBOC) syndrome:
    • Has also been associated with germline mutations in other homologous recombination repair genes, such as:
      • BARD1, BRIP1, MRE11A, NBN, RAD50, CHEK2, ATM, PALB2, RAD51C, and RAD51D
  • Partner and localizer of BRCA2 (PALB2) germline mutation:
    • Is associated with an – albeit small – increased risk of ovarian cancer compared with the general population
    • In a recent study of 1421 patients with epithelial and ovarian cancer (EOC):
      • Three (0.21%) had a germline PALB2 mutation compared with 0.05% of the control cohort of 4300 subjects
  • Similarly, BRIP1 germline mutations:
    • Were found in 0.41% to 0.9% of patients with EOC compared with 0.09% in the general population
  • In a study of 1100 German pedigrees, families with a history of gynecologic or breast cancers without BRCA1 or BRCA2 mutations:
    • Had a higher incidence of RAD51C mutations compared to the 3000 control families with no mutation carriers
    • The exact penetrance of this mutation is not known:
      • But the approximate cumulative risk of ovarian cancer in RAD51C carriers is:
        • 1% by age 49
        • 6% by age 80
      • Although these genes only confer a moderate risk for EOC, given the poor survival estimates for ovarian cancer:
        • The clinical implications for families with carriers of these mutations is great
  • Other genetic syndromes can confer increased susceptibility to breast and / or ovarian cancers:
    • Peutz‐Jeghers syndrome (PJS):
      • Which is a result of mutations in the serine / threonine kinase 11 gene (STK11, also called LKB1):
        • Is associated with the increased risk of gastrointestinal cancers
        • However, it has also been shown to confer an:
          • Increased lifetime risk of breast:
            • 32%
          • Increased lifetime risk of ovarian cancers:
            • 21%
          • Patients with PJS are at risk for:
            • Ovarian sex‐cord stromal tumors:
              • Not epithelial ovarian cancers, and they are usually diagnosed in childhood or young adulthood
  • When an identifiable mutation cannot be found in a patient with a strong family history of ovarian and / or breast cancer:
    • Our practice is to counsel women that their risk may be elevated compared with the general population but continue to discourage serial Ca‐125 levels, serial ultrasounds, and rrBSO
    • We also recommend retesting when new multigene panels are produce
  • References:
    • Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137‐1154. 
    • Kotsopoulos J, Sopik V, Rosen B, et al. Frequency of germline PALB2 mutations among women with epithelial ovarian cancer. Fam Cancer. 2017;16(1):29‐34. 
    • Ramus SJ, Song H, Dicks Ed, et al Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015;107(11). 
    • Tung N, Domchek SM, Stadler Z, et al. Counselling framework for moderate‐penetrance cancer‐susceptibility mutations. Nat Rev Clin Oncol. 2016;13(9):581‐588. 
    • vanLierMGF,WagnerA,Mathus‐VliegenEMH,etalHighcancerrisk in Peutz‐Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 2010;105(6):1258‐1264. 

#Arrangoiz #BreastSurgeon #BreastCancer #CancerSurgeon #SurgicalOncologist #CASO #Miami #CanterforAdvancedSurgicalOncology #HereditaryBreastCancer

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