ICARE Newsletter Winter 2016

What Is the Risk for Ovarian Cancer Among Women with Mutations in Newer Ovarian Cancer Genes?

The most common form of inherited ovarian cancer is due to mutations in the BRCA1 and BRCA2 genes, which are present in 10-15% of women with ovarian cancer and lead to an ovarian cancer risk of up to 44% and 27%, respectively.  Another set of genes known to raise ovarian cancer risks are the mismatch repair genes (i.e., MLH1, MSH2, MSH6, PMS2, EPCAM) which lead to Lynch Syndrome.  Mutations in these genes result in a lifetime risk of ovarian cancer in the range of 10-12%. 

Technological advances that make it possible to test for multiple inherited cancer genes at the same time have led to the suggestion that 20-25% of women with ovarian cancer may have an inherited mutation in a cancer predisposing gene.1  There have been several inherited cancer genes identified among women with ovarian cancer (e.g., RAD51C, RAD51D, BRIP1), however it has only recently become possible to gather enough information to tell us how high the lifetime ovarian cancer risk may be for women with mutations in some of these genes.

It is important to figure out the level of ovarian cancer risk to determine whether removal of the ovaries for risk reduction is appropriate. Generally, a lifetime risk in the range of ~10% is reasonable to consider risk-reducing salpingo-oophorectomy (i.e., removal of the ovaries and fallopian tubes). The lifetime risk for developing ovarian cancer among women in the general population is between 1-2%.

Recently published data has provided some clarification of risks for mutations in the ovarian cancer genes outlined in the table, where an association with ovarian cancer has been suspected:

Gene Risk Estimated Lifetime Risk by age 80
RAD51C 5-6 fold2,3,4 to 16 fold5 ~9%3
RAD51D 6-12 fold4,5,6,7 10%7
BRIP1 3-9 fold6,8,9 5.8%8
PALB2 Current data fails to clearly support a high risk for ovarian cancer6,8,10,11

This new information will help individuals with mutations in these genes and their providers determine an individualized cancer risk management plan.

1Walsh T et al. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. PMID: 22006311
2Pelttari LM et al. Hum Mol Genet. 2011 Aug 15;20(16):3278-88. PMID: 21616938
3Loveday C. Nat Genet. 2012 Apr 26; 44(5):475-6 PMID: 22538716
4Song H et al. J Clin Oncol. 2015 Sep 10;33(26):2901-7. Epub 2015 Aug 10. PMID: 26261251
5Pelttari LM et al. J Med Genet. 2012 Jul;49(7):429-32. PMID: 22652533
6Norquist BM et al. JAMA Oncol. 2015 Dec 30:1-9. PMID: 26720728
7Loveday C. Nat Genet. 2011 Aug 7;43(9):879-82. PMID: 21822267
8Ramus SJ et al. J Natl Cancer Inst. 2015 Aug 27;107(11). PMID: 26315354
9Rafnar T et al. Nat Genet. 2011 Oct 2;43(11):1104-7. PMID: 21964575
10Kanchi KL et al. Nat Commun. 2014;5:3156. PMID: 24448499
11Antoniou AC et al. N Engl J Med. 2014 Aug 7;371(6):497-506. PMID: 25099575.

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