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A High-risk Haplotype for Premature Menopause in Childhood Cancer Survivors Exposed to Gonadotoxic Therapy.
Journal of the National Cancer Institute ( IF 9.9 ) Pub Date : 2018-08-01 , DOI: 10.1093/jnci/djx281
Russell J Brooke 1 , Cindy Im 2 , Carmen L Wilson 1 , Matthew J Krasin 1 , Qi Liu 2 , Zhenghong Li 1 , Yadav Sapkota 1 , WonJong Moon 1 , Lindsay M Morton 3 , Gang Wu 1 , Zhaoming Wang 1 , Wenan Chen 1 , Rebecca M Howell 4 , Gregory T Armstrong 1 , Smita Bhatia 5 , Sogol Mostoufi-Moab 6 , Kristy Seidel 7 , Stephen J Chanock 3 , Jinghui Zhang 1 , Daniel M Green 1 , Charles A Sklar 8 , Melissa M Hudson 1 , Leslie L Robison 1 , Wassim Chemaitilly 1 , Yutaka Yasui 1
Affiliation  

Background Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown. Methods Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS). Results PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 × 10-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 × 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways. Conclusions The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation.

中文翻译:

暴露于性腺毒性疗法的儿童癌症幸存者中,更年期提前的高风险单倍型。

背景儿童癌症幸存者罹患与治疗相关的更年期(PM)的风险增加,累积发生率为8.0%,但遗传因素的贡献尚不清楚。方法进行了全基因组关联分析,以鉴定参与St. Jude终生队列研究(SJLIFE)的799名儿童癌症女性幸存者中与临床诊断为PM(绝经<40岁)相关的单核苷酸多态性(SNP)。调整分析烷基化剂的环磷酰胺当量剂量和卵巢放射治疗(RT)剂量(所有P值均为双面)。使用自我报告的PM对参与儿童癌症幸存者研究(CCSS)的1624名幸存者进行了复制。结果30名(3.8%)SJLIFE参与者被临床诊断为PM。神经肽受体2基因(NPY2R)上游的13个SNP(染色体4q32.1的70 kb区)与PM患病率相关(rs9999820的最低P = 3.3×10-7,所有P <10-5)。作为由13个SNP中的4个(在普通人群中每7个中就有1个,但临床诊断为PM的SJLIFE超过50%的人所形成)的单倍型纯合子携带者,与暴露于卵巢RT的幸存者中PM患病率显着相关(奇数)比[OR] = 25.89,95%置信区间[CI] = 6.18至138.31,P = 8.2×10-6);尽管使用了自我报告的PM(OR = 3.97,95%CI = 1.67至9.41,P = .002),该发现仍在CCSS的第二个独立队列中得到了重复。来自生物信息学数据的证据表明,单倍型改变了NPY2R转录的调控,可能通过神经内分泌途径影响PM风险。结论该单倍型捕获了大多数临床诊断的PM病例,并且经过进一步验证,可能在临床上用于确定PM的最高风险幸存者,以便通过冷冻保存进行干预。
更新日期:2018-02-08
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