E Clemens1, A L F van der Kooi2, L Broer3, E van Dulmen-den Broeder4, H Visscher5, L Kremer6, W Tissing7, J Loonen8, C M Ronckers6, S M F Pluijm9, S J C M M Neggers10, O Zolk11, T Langer12, A Am Zehnhoff-Dinnesen13, C L Wilson14, M M Hudson14, B Carleton15, J S E Laven16, A G Uitterlinden3, M M van den Heuvel-Eibrink17. 1. Department of Pediatric Hematology and Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. Electronic address: e.clemens@erasmusmc.nl. 2. Department of Pediatric Hematology and Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Gynecology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands. 3. Department of Internal Medicine, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands. 4. Department of Pediatric Hematology and Oncology, VU Medical Center, Amsterdam, The Netherlands. 5. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Pediatrics, Antwerp University Hospital, Antwerp, Belgium. 6. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Pediatrics, Academic Medical Center - Emma Children's Hospital, Amsterdam, The Netherlands. 7. Department of Pediatric Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 8. Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands. 9. Department of Pediatric Hematology and Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. 10. Department of Pediatric Hematology and Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands; Department of Medicine, Section endocrinology, Erasmus MC, Rotterdam, The Netherlands. 11. Institute of Pharmacology of Natural Products and Clinical Pharmacology, University Hospital Ulm, Germany. 12. Pediatric Oncology, University Hospital for Children and Adolescents, Lübeck, Germany. 13. Department of Phoniatrics and Pedaudiology, University of Münster, Münster, Germany. 14. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. 15. BC Children's Hospital, Vancouver, Canada. 16. Department of Gynecology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands. 17. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Abstract
INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.
INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.
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