RAD51D

 

RAD51D-Related Cancer Risk

The RAD51D gene is classified as a “moderate risk” gene, meaning that there is a modestly increased risk for certain types of cancers.  Multiple studies have demonstrated an association between RAD51D pathogenic gene mutations and a risk for ovarian cancer.  Women who carry RAD51D pathogenic mutations are 4 to 12 times more likely to develop ovarian cancer than women in the general population. Data regarding a potential association between RAD51D gene mutations and breast cancer risk have been inconsistent with reports ranging from no increased risk to a risk of 3 times that of the general population.  Some studies suggest an association with triple negative breast cancer.  Further research is needed to understand the interactions of moderate risk genes and family history on lifetime cancer risk.

 

RAD51D cancer screening and risk-reducing options

The best long-term medical management for individuals who carry a mutation in the RAD51D gene is a topic of on-going research.  Healthcare providers oftentimes rely on an individual’s personal and family history to guide medical care.

  • Ovary: Depending upon personal and family history, women should discuss bilateral salpingo-oophorectomy (with or without hysterectomy) with their physicians between the ages of 45-50 years. There is no evidence that ovarian cancer screening with currently available methods (e.g. transvaginal ultrasound and CA-125 blood measurement) reduces ovarian cancer mortality.
  • Breast: Women should pursue standard clinical breast exams and mammography.  In the presence of a strong personal and/or family history of breast cancer, some women might also consider increased breast cancer surveillance with breast MRI.

 

RAD51D associated therapeutic/ treatment implications

Individuals who have a cancer diagnosis and an identified RAD51D pathogenic mutation should speak with their treating physician about the availability of targeted/ personalized treatment options.

Clinical trials evaluating different medications in individuals who have pathogenic mutations in RAD51D and/or other related genes might be available now or in the future.

 

RAD51D testing in other family members

At this point in time, testing adult family members for a moderate risk gene mutation does NOT provide the same clarity or guidance that testing for a high risk gene mutation does. This is because moderate risk gene mutations should not be assumed to be the sole explanation for a particular family’s history of cancer.  For example, a family could have additional unidentified genetic and/or non-genetic risk factors contributing to the development of cancer seen in family members.  It is recommended that family members discuss risks, benefits and limitations of genetic testing with their physician and/or genetic counselor.  If an adult family member were to test positive for the familial RAD51D gene mutation, increased cancer screening might be considered.  However, given the current lack of data regarding RAD51D gene mutations, if an adult family member were to test negative for a familial RAD51D gene mutation, that individual may still be at increased risk for cancer depending upon the family history and possibility for other genes to be playing a role.  Cancer screening should be performed in accordance with the family history until further data is available.

 

Future considerations

As research and data on cancer risk estimates continue to evolve, physicians and researchers will gain a better understanding of how a RAD51D gene mutation influences medical care.  Because the information provided to patients will almost certainly change, those with a RAD51D gene mutation are encouraged to keep in touch with their medical providers in order to receive updates.

 

References:

 

  1. Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13(9):581-8. doi: 10.1038/nrclinonc.2016.90. PubMed PMID: 27296296.
  2. Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, et al. Inherited Mutations in Women with Ovarian Carcinoma. JAMA Oncol. 2016 Apr;2(4):482-90.
  3. Slavin TP, Maxwell KN, Lilyquist J, Vijai J, Neuhausen SL, Hart SN, et al. The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer. 2017 June 9;3:22.
  4. Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC, Na J, et al. Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer. JAMA Oncol. 2017 Sep 1;3(9):1190-1196.
  5. Kurian AW, Hughes E, Handorf EA, Gutin A, Allen B, Hartman AR, et al. Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women.  JCO Precision Oncology. 2017 June 27;1:1-12.
  6. Loveday C, Turnbull C, Ramsay E, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 2011; 43: 879-82.
  7. Pelttari LM, Kiiski J, Nurminen R, et al. A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer. J Med Genet 2012; 49: 429-32.
  8. Song, H. et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. Clin. Oncol. 33, 2901–2907 (2015).
  9. Thompson ER, Rowley SM, Sawyer S, et al: Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer. PLoS One 8:e54772, 2013