Department of Paediatric Oncology/Haematology, ErasmusMC University Medical Centre-Sophia's Children's Hospital Rotterdam, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands.
Hum Reprod. 2013 Apr;28(4):1069-76. doi: 10.1093/humrep/des472. Epub 2013 Jan 29.
Are genetic polymorphisms, previously identified as being associated with age at menopause in the healthy population, associated with ovarian reserve and predicted age at menopause in adult long-term survivors of childhood cancer?
The CT genotype of rs1172822 in the BRSK1 gene is associated with lower serum anti-Müllerian hormone (AMH) levels and a younger predicted age at menopause in adult survivors of childhood cancer.
Gonadotoxicity is a well-known late side effect of chemotherapy and radiotherapy in adult survivors of childhood cancer. In the healthy 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.
STUDY DESIGN, SIZE, DURATION: We performed a pilot study in a single-centre cohort of adult female Caucasian childhood cancer survivors (n = 176).
PARTICIPANTS/MATERIALS, SETTING, METHODS: We determined serum AMH levels (a marker of ovarian reserve) in adult survivors of childhood cancer (n = 176) 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.
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.
LIMITATIONS, REASONS FOR CAUTION: This is a pilot study showing preliminary data which must be confirmed. To confirm our findings and enlarge the project, a nationwide genome-wide association (GWA) project on the ovarian reserve in female survivors of childhood cancer should be performed, including a replication cohort.
Our findings support the hypothesis that previously identified genetic polymorphisms associated with age at menopause in healthy women may have an effect on the onset of menopause in female survivors of childhood cancer. Our study highlights a new aspect of the influences on the ovarian reserve after childhood cancer, which 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.
W.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. All other authors have nothing to disclose.
先前在健康人群中发现与绝经年龄相关的遗传多态性是否与儿童癌症成年长期幸存者的卵巢储备和预测绝经年龄相关？
BRSK1 基因中的 rs1172822 的 CT 基因型与儿童癌症成年幸存者的血清抗苗勒管激素（AMH）水平较低和预测绝经年龄较早相关。
在儿童癌症成年幸存者中，化疗和放疗的性腺毒性是众所周知的晚期副作用。在健康人群中，有几个遗传多态性与自然绝经年龄相关。目前，关于先前确定的与儿童癌症成年长期幸存者卵巢储备相关的基因座中变异对预测绝经年龄的影响的数据尚缺乏。
研究设计、大小和持续时间：我们在单中心队列的成年白种人儿童癌症幸存者（n=176）中进行了一项试点研究。
参与者/材料、地点和方法：我们测定了成年儿童癌症幸存者（n=176）的血清 AMH 水平（卵巢储备的标志物），并研究了先前报道与自然绝经年龄相关的单核苷酸多态性（SNP）：BRSK1（rs1172822）、ARHGEF7（rs7333181）、MCM8（rs236114）、PCSK1（rs271924）、IGF2R（rs9457827）和 TNF（rs909253）。使用加性遗传模型进行关联分析。进行线性回归以评估两个先前发表的绝经预测模型中显著多态性的影响。
BRSK1（BR 丝氨酸/苏氨酸激酶 1）基因中的 rs1172822 的 CT 基因型与我们队列中的血清 AMH 水平呈负相关（比值比：3.15，95%置信区间：1.35-7.32，P=0.008），与预测绝经年龄显著相关（P=0.04）。其他五个 SNP 与血清 AMH 水平无关。
局限性、谨慎的原因：这是一项初步数据的初步研究，必须加以证实。为了证实我们的发现并扩大项目范围，应该在包括复制队列的范围内，在儿童癌症女性幸存者中进行一项关于卵巢储备的全国全基因组关联（GWA）项目。
我们的研究结果支持这样的假设，即先前在健康女性中发现的与绝经年龄相关的遗传多态性可能对儿童癌症成年幸存者的绝经发作产生影响。我们的研究强调了儿童癌症后对卵巢储备产生影响的一个新方面，这应该在全国范围内的 GWA 研究中进一步研究。最终，这些信息可以帮助我们根据个体患者的遗传因素，在癌症治疗前基于遗传因素更好地进行生育力保存咨询。
W.D. 得到荷兰儿科肿瘤学中心协会（KOCR）的支持。J.S.E.L. 从以下公司获得过费用和资助（按字母顺序排列）：Ferring、Genovum、Merck-Serono、Organon、Schering Plough 和 Serono。所有其他作者均无利益冲突。
