Female survivors of childhood cancer are at risk of late effects of their cancer treatment including increased risk of premature menopause before age 40 years (1). Premature menopause causes infertility at an early age, and also is linked to other adverse health outcomes such as heart disease and osteoporosis (2). Identifying biomarkers that define risk strata for treatment-associated premature menopause may allow survivors to partake in targeted medical interventions aimed to reduce or prevent the consequences of premature menopause, such as fertility preservation procedures and prevention programs for cardiovascular diseases and osteoporosis. In this issue of the Journal, Brooke and colleagues aim to identify these potential biomarkers in a report describing the first systematic assessment of the how genetic factors may influence risk of premature menopause among childhood cancer survivors (3). The study uses data from 799 female participants in the St. Jude Lifetime Cohort Study (4) to conduct a genome-wide association study of the prevalence of clinically diagnosed premature menopause at study entry. The authors provide evidence that a high-risk haplotype upstream from Neuropeptide Y Receptor Y2 (NPY2R) associates with prevalence of premature menopause, where strongest associations are observed among participants exposed to ovarian radiotherapy. Although attenuated, the association between homozygosity for the haplotype and increased prevalence of premature menopause among survivors exposed to ovarian radiotherapy replicates in analyses using data from 1624 survivors enrolled in the Childhood Cancer Survivor Study. Additional evidence of the genetic association with premature menopause is provided through bioinformatics analyses. The authors examine genotype tissue expression (GTEx) data and find that NPY2R is most highly expressed in hypothalamus tissue, the portion of the brain that controls the release of pituitary hormones. Importantly, NPY2R regulates the gene NPY that other investigators have shown is involved in the luteinizing hormone surge before ovulation in mice (5,6). The results of the study by Brooke et al. (3) support incorporating genetic data into prediction models of treatment-associated premature menopause. However, the study has several limitations that should be addressed in future validation studies before clinical implementation into prediction models. Specifically, the control participants are on average younger than the case patients, where a large majority of the control participants are younger than age 40 years and are still at risk of developing premature menopause. To address this limitation, the authors conducted an analysis that adjusts for age at clinical assessment for premature menopause and found similar results. Future causal inferences of the association between the high-risk haplotype 'and treatment-associated premature menopause will be strengthened if the association persists as more participants develop premature menopause. Additionally, the study lacks data on the timing of premature menopause in participants. Information on how genetic variation may influence age at premature menopause would be useful for childhood cancer survivors when making fertility decisions. It is important to mention that the majority of participants are of European ancestry, potentially limiting the generalizability of the study results to other racial groups. Lastly, the study’s small sample size suggests that there may be additional variants to be identified in association with premature menopause induced by childhood cancer treatment. Identifying women at higher risk of premature menopause is valuable for a variety of reasons. Female childhood cancer survivors have more concerns about future fertility than young adults who have not been diagnosed with cancer (7). A biomarker for risk of premature menopause may help to assuage worries and empower more informed decision-making about fertility preservation. A biomarker of premature menopause risk could also be used to select appropriate prevention strategies for premature menopause–related conditions, similar to the targeted interventions currently in place for other disease conditions. For instance, clinical guidelines recommend women with specific genetic mutations (eg, BRCA1, BRCA2) be offered bilateral salpingo-oophorectomy to reduce the risk of developing ovarian cancer (8). Current fertility preservation options for children diagnosed with cancer include ovarian transposition (oophoropexy) before pelvic radiation therapy and, depending on the age of the patient, cryopreservation of embryo, oocyte, or ovarian cortex (9). An ideal biomarker of premature menopause risk would be capable of stratifying survivors into subgroups so that survivors most likely to undergo treatment-associated premature menopause might receive additional counseling and survivors at low risk might be spared unnecessary procedures and expenses. Although this study by Brooke et al. (3) has notable limitations, it provides evidence that genetic variation contributes to the development of premature menopause in female childhood cancer survivors exposed to ovarian radiotherapy. If the results of the current study are confirmed as causally associated with premature menopause, the high-risk haplotype may have clinical relevance to female childhood cancer survivors and possibly additional populations of women who receive gonadotoxic treatments for cancer prior to menopause. In general, identifying factors associated with premature menopause increases the possibility of tailoring interventions to provide the best prevention and treatment strategies to female childhood cancer survivors. Funding Dr. Warren Andersen is supported by K99 CA207848. Notes The funder had no role in the writing of the editorial or the decision to submit it for publication. The author has no conflicts of interest to disclose. References 1 Sklar CA , Mertens AC , Mitby P , et al. . Premature menopause in survivors of childhood cancer: A report from the childhood cancer survivor study . J Natl Cancer Inst. 2006 ; 98 13 : 890 – 896 . http://dx.doi.org/10.1093/jnci/djj243 Google Scholar CrossRef Search ADS PubMed 2 Shuster LT , Rhodes DJ , Gostout BS , Grossardt BR , Rocca WA. Premature menopause or early menopause: Long-term health consequences . Maturitas. 2010 ; 65 2 : 161 – 166 . Google Scholar CrossRef Search ADS PubMed 3 Brooke RJ , Im C , Wilson CL , et al. . A high-risk haplotype for premature menopause in childhood-cancer survivors exposed to gonadoxic therapy . J Natl Cancer Inst. 2018 ; 110 8 : 895 – 904 . 4 Hudson MM , Ness KK , Nolan VG , et al. . Prospective medical assessment of adults surviving childhood cancer: Study design, cohort characteristics, and feasibility of the St. Jude Lifetime Cohort study . Pediatr Blood Cancer. 2011 ; 56 5 : 825 – 836 . Google Scholar CrossRef Search ADS PubMed 5 Xu M , Hill JW , Levine JE. Attenuation of luteinizing hormone surges in neuropeptide Y knockout mice . Neuroendocrinology. 2000 ; 72 5 : 263 – 271 . http://dx.doi.org/10.1159/000054595 Google Scholar CrossRef Search ADS PubMed 6 Sahu A. Evidence suggesting that the potentiating action of neuropeptide Y on luteinizing hormone (LH)-releasing hormone-induced LH release remains unaltered in aged female rats . J Neuroendocrinol. 2000 ; 12 6 : 495 – 500 . http://dx.doi.org/10.1046/j.1365-2826.2000.00480.x Google Scholar CrossRef Search ADS PubMed 7 Langeveld NE , Grootenhuis MA , Voûte PA , de Haan RJ , van den Bos C. Quality of life, self-esteem and worries in young adult survivors of childhood cancer . Psychooncology . 2004 ; 13 12 : 867 – 881 . Google Scholar CrossRef Search ADS PubMed 8 Committee on Practice Bulletins–Gynecology, Committee on Genetics, Society of Gynecologic Oncology . Practice bulletin No 182: Hereditary breast and ovarian cancer syndrome . Obstet Gynecol. 2017 ; 130 3 : e110 – e126 . CrossRef Search ADS PubMed 9 Loren AW , Mangu PB , Beck LN , et al. . Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update . J Clin Oncol. 2013 ; 31 19 : 2500 – 2510 . http://dx.doi.org/10.1200/JCO.2013.49.2678 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
JNCI: Journal of the National Cancer Institute – Oxford University Press
Published: Aug 1, 2018
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