TON July 2016 Vol 9 No 4 - Genetic Counseling
Cristi Radford, MS, CGC

The ability to analyze multiple genes at the same time has led to the estimate that 20% to 25% of women with ovarian cancer have an inherited mutation in a cancer-predisposing gene.1 Although this association has been noted for a while, until recently there was not enough data available to determine the lifetime ovarian cancer risk for women with a mutation in some of these genes. Therefore, it was challenging to determine which women with a mutation in a "newer" ovarian cancer risk gene should undergo risk-reducing salpingo-oophorectomy (RRSO). In February 2016, new recommendations were published suggesting that in addition to genes associated with hereditary breast and ovarian cancer syndrome and Lynch syndrome, women with mutations in BRIP1, RAD51C, and RAD51D should discuss the option of RRSO with their healthcare team.2

The most common form of inherited ovarian cancer is still believed to be due to mutations in the BRCA1 and BRCA2 genes, which are present in 10% to 15% of women with ovarian cancer.1,3,4 The risk for ovarian cancer is up to 54% and 27% with mutations in the BRCA1 and BRCA2 genes, respectively.5-7 Additionally, mutations in genes associated with Lynch syndrome (ie, MLH1, MSH2, MSH6, PMS2, EPCAM) continue to be shown to be associated with an increased risk of ovarian cancer with an upper range of 24%; the range varies depending on the gene, with some gene risks being more defined than others.8,9 In comparison, the lifetime risk of developing ovarian cancer in the general population is 1% to 2%. Lifetime risk estimates are important because they are absolute risks. The lifetime risk associated with a mutation can be compared with the general population risk to help a woman and her healthcare team determine if the benefits of RRSO outweigh the risks and side effects associated with the procedure.

Recently published data have provided some clarification of risks for mutations in PALB2, BRIP1, RAD51C, and RAD51D. Current data associated with PALB2 fail to support a high risk of ovarian cancer.10-13 However, it is important to keep in mind that an individual with a mutation in PALB2 and a strong family history of ovarian cancer may still be a candidate for RRSO based on family history and not her PALB2 mutation status. The estimated lifetime risk of ovarian cancer to age 80 years for women with a mutation in BRIP1 is 5.8%; in RAD51C, 9%; and in RAD51D, 10%.11,14,15 These lifetime risk estimates are at least triple those of the general population and, according to the most recent National Comprehensive Cancer Network Genetic/Familial High-Risk Assessment: Breast and Ovarian cancer guidelines, RRSO should be considered.2

References

1. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011;108:18032-18037.
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2016. www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf. Accessed April 4, 2016.
3. Song H, Cicek MS, Dicks E, et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014;23:4703-4709.
4. Pal T, Permuth-Wey J, Betts JA, et al. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104:2807-2816.
5. Ford D, Easton DF, Bishop DT, et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994;343:692-695.
6. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998; 62:676-689.
7. Antoniou AC, Pharoah PD, Narod S, 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. Am J Hum Genet. 2003;72:1117-1130.
8. Bonadona V, Bonaïti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304-2310.
9. Goodenberger ML, Thomas BC, Riegert-Johnson D, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet Med. 2016;18:13-19.
10. Norquist BM, Harrell MI, Brady MF, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2:482-490.
11. Ramus SJ, Song H, Dicks E, et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015 Aug 27. Epub ahead of print.
12. Kanchi KL, Johnson KJ, Lu C, et al. Integrated analysis of germline and somatic variants in ovarian cancer. Nat Commun. 2014;5:3156.
13. Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371:497-506.
14. Loveday C, Turnbull C, Ramsay E, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011;43:879-882.
15. Song H, Dicks E, Ramus SJ, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol. 2015;33:2901-2907.

Last modified: July 27, 2016