ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 9.8 | DOI: 10.1530/ey.18.9.8

Hum Reprod. 2021; 36: 1120–1133.

This multi-centre retrospective cohort study identifies that common genetic variants in DNA repair genes modify the damage induced by alkylating agents on ovarian function, as assessed by low AMH levels.

Alkylating agents are known to induce apoptosis of cancer cells by damaging DNA replication and transcription and inhibiting cellular metabolism (1). Previous studies in female childhood cancer survivors (CCS) showed that alkylating agents are strongly associated with reduced ovarian function, as measured by low anti-Mullerian hormone (AMH) levels. However, there is wide inter-individual variability in the detrimental effect of alkylating agents on adult ovarian function. Genetic variants in genes involved in DNA repair may be responsible for this variability.

This study reports a strong modifying effect of the G allele of the common single-nucleotide polymorphism rs11668344 in BRSK1 gene (rs11668344 A>G) on the ovarian toxicity induced by alkylating agents. The modifying impact results in 2.5-fold increased odds of gonadotoxicity in CCS carrying one G allele, and 3-fold increased odds in CCS carrying two G alleles, compared to CCS without this allele. The BR Serine/Threonine Kinase 1 (BRSK1) gene is recognized to be involved in DNA damage checkpoint response. The efficiency of the DNA damage sensing and repair system is crucial when treatments with alkylating agents corresponding to a high cyclophosphamide equivalent dose (CED) are needed. Due to a less efficient response to DNA damage, cancer patients carrying the G allele of rs11668344 in BRSK1 may experience increased risk of gonadotoxicity.

To our knowledge, this is the first study to report a specific genetic factor that influences the damaging effects of chemotherapy on long-term ovarian function. The identification of genetic markers that can predict the extent of gonadal damage induced by alkylating agents can potentially inform the development of risk prediction models. Fertility preservation programs, including ovarian tissue cryopreservation, would benefit from personalized counselling directed to adolescent and young adults identified to be at high risk of gonadotoxicity.

Reference: 1. Fu D, Calvo JA, Samson LD. Balancing repair and tolerance of DNA damage caused by alkylating agents. Nat Rev Cancer 2012; 12: 104–20.

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