Onco-fertility and personalized testing for potential for loss of ovarian reserve in patients undergoing chemotherapy: proposed next steps for development of genetic testing to predict changes in ovarian reserve

John Yeh,Bei Sun

doi:10.1186/s40738-021-00105-7

Abstract

Women of reproductive age undergoing chemotherapy face the risk of irreversible ovarian insufficiency. Current methods of ovarian reserve testing do not accurately predict future reproductive potential for patients undergoing chemotherapy. Genetic markers that more accurately predict the reproductive potential of each patient undergoing chemotherapy would be critical tools that would be useful for evidence-based fertility preservation counselling. To assess the possible approaches to take to develop personalized genetic testing for these patients, we review current literature regarding mechanisms of ovarian damage due to chemotherapy and genetic variants associated with both the damage mechanisms and primary ovarian insufficiency. The medical literature point to a number of genetic variants associated with mechanisms of ovarian damage and primary ovarian insufficiency. Those variants that appear at a higher frequency, with known pathways, may be considered as potential genetic markers for predictive ovarian reserve testing. We propose developing personalized testing of the potential for loss of ovarian function for patients with cancer, prior to chemotherapy treatment. There are advantages of using genetic markers complementary to the current ovarian reserve markers of AMH, antral follicle count and day 3 FSH as predictors of preservation of fertility after chemotherapy. Genetic markers will help identify upstream pathways leading to high risk of ovarian failure not detected by present clinical markers. Their predictive value is mechanism-based and will encourage research towards understanding the multiple pathways contributing to ovarian failure after chemotherapy.

Highlights

The probability of premenopausal women to develop any type of invasive cancer is approximately 6%, among which breast cancer is the most common [1]
Due to the ethnic-group specific nature of current studies, we propose a trial 7-gene panel encompassing variants that appear at a high frequency specific to the ethnic group of the patient
Recent sequencing studies have identified several genetic variants such as newborn ovary homeobox protein (NOBOX), Folliculogenesis specific BHLH transcription factor (FIGLA), SOHLH1, SOHLH2, FOXO3 and helicase for meiosis 1 (HFM1) that appear in high frequency in patients with primary ovarian insufficiency (POI)

Summary

Introduction

The probability of premenopausal women to develop any type of invasive cancer is approximately 6%, among which breast cancer is the most common [1]. A missense variant of NANOS3 was identified in a study of Chinese women with primary ovarian insufficiency, and the level of NANOS3 protein was shown to correlate with the number of primordial germ cells [66]. Genes in follicular activation and development Animal and clinical studies have shown that genetic mutations involved in follicular activation process are associated with primary ovarian failure and likely an increased susceptibility to ovarian failure after chemotherapy [13–15].

Results

Conclusion