Study Links BRCA1 Gene Mutations to Diminished Ovarian Reserve

Deleterious mutations in the BRCA genes greatly enhance the risk of developing breast and ovarian cancer. In a novel finding, researchers at the New York Medical College have reported the association between the mutations in BRCA1 gene and early depletion of ovarian reserve, thereby highlighting the potential link between breast and ovarian cancer risk with infertility. The results, which highlight the importance of DNA repair in ovarian aging, were presented at the 65th Annual Meeting of the American Society for Reproductive Medicine, held at Atlanta from October 17th to 21st, 2009.

Based on earlier knock out model studies, which denoted the association between DNA repair genes and germ cell development, as well as the evidence of higher number of young women with BRCA1 mutation seeking fertility preservation, the scientists speculated that patients with this mutation have diminished ovarian reserve.

Kutluk Oktay and coworkers from the Institute for Fertility Preservation at Center for Human Reproduction, New York, conducted a secondary analysis of the prospective data obtained from 125 breast cancer patients undergoing embryo or oocyte cryopreservation. The researchers determined ovarian stimulation response in order to investigate the relationship between BRCA mutations and reduced ovarian reserve. The subjects were administered 5 mg/d letrozole and 150-300/d rFSH for ovarian stimulation, before the initiation of chemotherapy. Normal baseline ovarian reserve assessment and age <38 years were the inclusion criteria considered.

Testing for BRCA genes was performed in 57% (n=82) of the women who met the criteria. Of the 57% (n=47), BRCA+ mutation was noted in 30% (n=14), while 70% (n=33) did not possess the mutation. In those who tested positive for BRCA mutation, 9 and 4 women had BRCA1 and BRCA2 mutation, respectively, and 1 patient was reported to possess both the mutations. The other study findings are listed below.
• Mean ages were similar among BRCA+ (33.9 years), BRCA- (32.8 years), and untested patients (33.1 years)
• Rate of ovarian response was significantly poor in BRCA+ than BRCA- and untested patients (33.3% vs. 3.3% vs. 2.9%)
• Odds ratio of poor response was 28.7 in patients with BRCA+ when compared to BRCA- mutations, after controlling for confounding factors such as age, follicle stimulating hormone, and body mass index
• Mean oocyte numbers were lower in BRCA+ and BRCA1+ (7.9 and 7.4) when compared to BRCA- women
• Poor response was noted in BRCA1 but not in BRCA2 mutations (OR=38.3)

In stark contrast, few other studies reported the absence of any adverse effect of the BRCA mutation on fertility. In one such matched case-control study, Pal et al (Fertility and Sterility, 2009) analyzed 2,254 BRCA carriers and 764 noncarriers (from the same family of carriers but tested negative for the mutation). The study, which is touted to be the first epidemiologic study to determine the influence of BRCA mutations on parity and fertility, found only little or no such effect. Similar findings were also demonstrated in another recent study by Moslehi et al (American Journal of Human Biology, 2009).

According to the National Cancer Institute, around 5-10% and 10-15% of all breast and ovarian cancers, respectively, occurring in white American women are estimated to be due to inherited BRCA1 and BRCA2 mutations. With the current study results indicating the link between BRCA1 gene mutations and prematurely reduced ovarian reserve, the researchers emphasized the need for counseling such patients on their potentially greater risk for ovarian failure and infertility, and also the need for fertility preservation prior to chemotherapy. They also suggested that diminished ovarian reserve could be included as a novel part of the hereditary breast ovarian cancer syndrome.

References

1. Oktay K, Kim JY, Barad D, Babayev S. Association of BRCA1 Gene Mutations with Diminished Ovarian Reserve: A Novel Connection Between DNA Repair And Ovarian Aging in Humans. Paper presented at: Annual Meeting of the American Society for Reproductive Medicine;October 20, 2009;Atlanta.

2. Oktay K, Kim JY, Barad D, Gleicher N, Babayev S. Association of BRCA1 mutations with diminished ovarian reserve: A common genetic mechanism for breast/ovarian cancer, and infertility? Paper Presented at: Annual Meeting of the American Society of Clinical Oncology;May 29 to June 2, 2009;Orlando, Florida.

3. Pal T, Keefe D, Sun P, Narod SA; the Hereditary Breast Cancer Clinical Study Group. Fertility in women with BRCA mutations: a case-control study. Fertil Steril. 2009 Feb 5. [Epub ahead of print]

4. Moslehi R, Singh R, Lessner L, Friedman JM. Impact of BRCA mutations on female fertility and offspring sex ratio. Am J Hum Biol. 2009 Jul 29. [Epub ahead of print]

5. BRCA1 and BRCA2: Cancer Risk and Genetic Testing. National Cancer Institute. Last accessed November 20, 2009.

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