TABLE 8.

Genetic susceptibility to reproductive health issues

Gene / Variant	Methods	Results	Comment / Conclusion
BRSK147 BRSK1 (BR serine/threonine kinase 1) is a serine/threonine-protein kinase that plays key role in polarization of neurons and centrosome duplication	• Single-center pilot study of 176 adult female Caucasian CCS with serum AMH levels as a marker of ovarian reserve • Studied SNPs previously reported associated with age at natural menopause: BRSK1 (rs1172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827) and TNF (rs909253)	CT genotype of rs1172822 in BRSK1 gene negatively associated with serum AMH levels (OR 3.15, 95%CI 1.35–7.32, P=0.008) and significantly associated with the predicted age at menopause (P=0.04) Other 5 SNPs not associated with serum AMH levels	Previously identified SNPs associated with age at menopause in healthy women may have an effect on onset of menopause in female CCS.
NPY2R48 NPYR2 (Neuropeptide Receptor 2 gene) belongs to a family of G-protein coupled receptors activated by a group of closely related peptide hormones. These neuropeptide Y receptors control diverse behavioral processes including appetite, circadian rhythm and anxiety. Activated neuropeptide receptors release G1 subunit from the heterotrimeric G protein complex and this in turn inhibits production of the second messenger cAMP	• GWAS of 779 female CCSs to identify SNPs associated with clinically diagnosed PM (defined as menopause <40 years) Analyses adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian RT dose • Replication using self-reported PM in 1624 survivors p in the Childhood Cancer Survivor Study (CCSS)	• PM clinically diagnosed in 30 (3.8%) participants • 13 SNPs upstream of NPY2R associated with prevalence of PM (minimum P=3.3 × 10–7 for rs9999820, all P< 10–5) • Homozygous carrier of a haplotype formed by 4/13 SNPs associated with markedly elevated PM prevalence if exposed to ovarian RT (OR 25.89, 95%CI 6.18–138.31, P=8.2 × 10–6); replicated in the independent second cohort	• NPY2R haplotype captures majority of clinically diagnosed PM cases • Evidence from bioinformatics suggests the haplotype alters regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways
ERα and ERβ49	• 51 SNP markers of 12 different haplotype blocks in the AR, ERα and ERβ genes examined in 127 CCS	• Markers of one specific haplotype block of ERα (rs2207396, rs9340958, rs9340978) associated with increased risk of azoospermia • Compared with GG genotype, patients heterozygous for A allele in rs2207396 had significantly increased risk of azoospermia [OR 3.8; 95%CI: 1.5–9.5; P=0.008], and even higher if treated with alkylating agents (OR 8.8; 95%CI 2.1–36; P=0.004)	• Genetic markers of high risk of post-treatment azoospermia may help identify boys to whom preservation of testicular tissue before cancer therapy should be offered

95%CI, 95% confidence interval; AR, androgen receptor; CCSs, childhood cancer survivors; ER, estrogen receptor; GWAS, Genome-wide association study; OR, odds ratio; PM, premature menopause; RT, radiation therapy; SNPs, single-nucleotide polymorphisms