Genetic variation may modify ovarian reserve in female childhood cancer survivors

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 498-531-Female Repro Endocrinology & Case Reports
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-504
Wendy van Dorp*1, Marry M. van den Heuvel-Eibrink2, Lisette Stolk1, Rob Pieters2, Andre Uitterlinden3, Jenny A. Visser3 and Joop S E Laven4
1Erasmus MC University Medical Center, Rotterdam, Netherlands, 2Erasmus MC University Medical Center - Sophia's Children's Hospital Rotterdam, 3Erasmus MC, Rotterdam, Netherlands, 4Erasmus Medical Center, Rotterdam, Netherlands
Objective: Gonadotoxicity is a well known late side effect of chemotherapy and radiotherapy in adult survivors of childhood cancer. In the general population, several genetic polymorphisms are associated with age at natural menopause. Currently, data on the impact of previously identified variants in gene loci associated with ovarian reserve in adult long-term survivors of childhood cancer are lacking. The aim of this pilot study was to evaluate whether the genetic polymorphisms known to be associated with menopause in the general population were associated with serum Anti-Mullerian Hormone (AMH) levels (as marker for ovarian reserve) in adult long-term childhood cancer survivors, and to evaluate the association between AMH and the predicted age at menopause of two prediction models. 

Patients: We performed a pilot study in a single centre cohort of adult female Caucasian childhood cancer survivors (n=176), determined serum AMH levels (a marker of ovarian reserve) and studied single nucleotide polymorphisms (SNPs) previously reported to be associated with age at natural menopause: BRSK1 (rs1172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827) and TNF (rs909253). Association analysis was performed using the additive genetic model. Linear regression was conducted to assess the effect of significant polymorphisms in two previously published menopause prediction models.

Results: The CT genotype of rs1172822 in the BRSK1 (BR serine/ threonine kinase 1) gene was negatively associated with serum AMH levels in our cohort (Odds Ratio=3.15, 95% Confidence Interval 1.35-7.32, p=0.008) and significantly associated with the predicted age at menopause (p=0.04). The other five SNPs were not associated with serum AMH levels.

Conclusion: Our findings support the idea that previously identified polymorphisms that are associated with the age at menopause in the general population may also have an effect on menopause onset in female CCS. This pilot study appears to show a new aspect of the influence of genetic variants on ovarian reserve following treatment of childhood cancer and should be investigated further in a nationwide GWA study. Eventually, this information can help us to improve counselling on fertility preservation prior to cancer treatment, based on genetic factors in individual patients.

Disclosure: JSEL: Researcher, Ferring Pharmaceuticals, Researcher, Merck BV, Founder, Genovum. Nothing to Disclose: WV, MMV, LS, RP, AU, JAV

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