Genetic variation in gonadal impairment in female survivors of childhood cancer: a PanCareLIFE study protocol

BMC Cancer

on behalf of the PanCareLIFE Consortium¹  Helen Campbell²  Julianne Byrne²  Dalit Modan-Moses³  Tomas Kepak⁴  Jeanette Falck Winther⁵  Linda Broer⁶  André G. Uitterlinden⁶  Sophie D Fosså⁷  Gabriele Calaminus⁸  Claire Berger⁹  Eva Clemens^1,10  Eline van Dulmen-den Broeder^1,11  Marleen van den Berg^1,11  Anne-Lotte L. F. van der Kooi^1,12  Joop S. E. Laven^1,12  Riccardo Haupt^1,13  Claudia Spix^1,14  Desiree Grabow^1,14  Melanie Kaiser^1,14  Peter Kaatsch^1,14  Oliver Zolk^1,15  Jarmila Kruseova^1,16  Andreas Ranft^1,17  Uta Dirksen^1,17  Leontien Kremer^1,18  Marry M. van den Heuvel-Eibrink^1,18 

[1] ;Boyne Research Institute;Chaim Sheba Medical Center, The Edmond and Lily Safra Children’s Hospital;Czech Republic & International Clinical Research Center (FNUSA-ICRC), University Hospital Brno;Danish Cancer Society Research Center;Department of Internal Medicine, Erasmus MC;Department of Oncology, Oslo University Hospital;Department of Paediatric Haematology and Oncology, University Children’s Hospital Bonn, University of Bonn Medical School;Department of Paediatric Oncology, University Hospital;Department of Pediatric Hematology and Oncology, Erasmus MC – Sophia Children’s Hospital;Department of Pediatric Hematology and Oncology, VU Medical Center;Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus MC – Sophia Children’s Hospital;Epidemiology and Biostatistics Unit, Istituto Giannina Gaslini;German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center;Institute of Pharmacology of Natural Products and Clinical Pharmacology, University Hospital Ulm;Motol University Hospital;Pediatrics III, West German Cancer Centre, University Hospital Essen;Princess Máxima Center for Pediatric Oncology;

关键词: Childhood cancer survivor;    Genetic variations;    SNPs;    Late effects;    GWAS;   

DOI  :  10.1186/s12885-018-4834-3

来源: DOAJ

【 摘 要 】

Abstract Background Improved risk stratification, more effective therapy and better supportive care have resulted in survival rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in susceptibility to therapy related gonadal impairment suggests a role for genetic variation. Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been performed using endocrine measurements for gonadal impairment  as the primary outcome in CCS. Methods As part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837 non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will be performed to identify novel allelic variants. The results will be validated in an independent CCS cohort. Discussion This international collaboration aims to enhance knowledge of genetic variation which may be included in risk prediction models for gonadal impairment in CCS.

【 授权许可】

Unknown