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.