-
Something wrong with this record ?
Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE
MEM. van der Perk, L. Broer, Y. Yasui, JSE. Laven, LL. Robison, WJE. Tissing, B. Versluys, D. Bresters, GJL. Kaspers, CB. Lambalk, A. Overbeek, JJ. Loonen, CCM. Beerendonk, J. Byrne, C. Berger, E. Clemens, E. van Dulmen-den Broeder, U. Dirksen,...
Language English Country United States
Document type Journal Article, Multicenter Study
Grant support
U01 CA195547
NCI NIH HHS - United States
- MeSH
- Antineoplastic Agents, Alkylating adverse effects MeSH
- Anti-Mullerian Hormone * blood genetics MeSH
- Genome-Wide Association Study * MeSH
- Child MeSH
- Adult MeSH
- Polymorphism, Single Nucleotide * MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Neoplasms genetics drug therapy MeSH
- Ovarian Reserve * genetics drug effects radiation effects MeSH
- Cancer Survivors * MeSH
- Risk Factors MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Geographicals
- Europe MeSH
OBJECTIVE: To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SETTING: Not applicable. PATIENTS: A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0 × 10-8) and 16 genome-wide suggestive (<5.0 × 10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): -0.484 (0.091). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors.
Boyne Research Institute Bettystown Ireland
Danish Cancer Society Research Center Childhood Cancer Research Group Copenhagen Denmark
Department of Epidemiology and Cancer Control St Jude Children's Research Hospital Memphis Tennessee
Department of Epidemiology Netherlands Cancer Institute Amsterdam the Netherlands
Department of Haematology Radboud University Medical Center Nijmegen the Netherlands
Department of Obstetrics and Gynaecology Radboud University Medical Center Nijmegen the Netherlands
Department of Oncology Oslo University Hospital Oslo Norway
Department of Paediatric Oncology University Hospital Saint Etienne France
Department of Pediatric Hematology and Oncology Motol University Hospital Prague Czech Republic
Department of Reproductive Medicine University Medical Center Utrecht the Netherlands
Emma Children's Hospital Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam the Netherlands
German Cancer Research Centre DKTK Sites Duesseldorf Essen Essen Germany
Lyon University Jean Monnet University INSERM Sainbiose Saint Etienne France
Pediatrics 3 West German Cancer Centre University Hospital Essen Essen Germany
Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands
The Edmond and Lily Safra Children's Hospital Chaim Sheba Medical Center Tel Hashomer Israel
The Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc24019182
- 003
- CZ-PrNML
- 005
- 20241024111632.0
- 007
- ta
- 008
- 241015s2024 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.fertnstert.2024.05.002 $2 doi
- 035 __
- $a (PubMed)38729340
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a van der Perk, M E Madeleine $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. Electronic address: m.e.m.vanderperk@prinsesmaximacentrum.nl
- 245 10
- $a Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE / $c MEM. van der Perk, L. Broer, Y. Yasui, JSE. Laven, LL. Robison, WJE. Tissing, B. Versluys, D. Bresters, GJL. Kaspers, CB. Lambalk, A. Overbeek, JJ. Loonen, CCM. Beerendonk, J. Byrne, C. Berger, E. Clemens, E. van Dulmen-den Broeder, U. Dirksen, HJ. van der Pal, ACH. de Vries, JF. Winther, A. Ranft, SD. Fosså, D. Grabow, M. Muraca, M. Kaiser, T. Kepák, J. Kruseova, D. Modan-Moses, C. Spix, O. Zolk, P. Kaatsch, LCM. Kremer, RJ. Brooke, F. Wang, JL. Baedke, AG. Uitterlinden, AME. Bos, FE. van Leeuwen, KK. Ness, MM. Hudson, ALF. van der Kooi, MM. van den Heuvel-Eibrink, PanCareLIFE consortium
- 520 9_
- $a OBJECTIVE: To discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SETTING: Not applicable. PATIENTS: A discovery cohort of adult female childhood cancer survivors from the pan-European PanCareLIFE cohort (n = 743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nervous system or total body irradiation, or stem cell transplantation. Replication was attempted in the US-based St. Jude Lifetime Cohort (n = 391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the interindividual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions, and cyclophosphamide equivalent doses were used to quantify alkylation agent exposure. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function, and the findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0 × 10-8) and 16 genome-wide suggestive (<5.0 × 10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. On the basis of the effect allele frequency (EAF) (>0.01 if not genome-wide significant), and biologic relevance, 15 single nucleotide polymorphisms were selected for replication. None of the single nucleotide polymorphisms were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated with borderline genome-wide statistical significance (reference/effect allele: C/T; effect allele frequency: 0.04, beta (SE): -0.484 (0.091). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment because the findings of this genome-wide association study were not statistically significant replicated in the replication cohort. Suggestive evidence for the potential importance of 1 variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. Because the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity as well as fertility preservation options for childhood cancer survivors.
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a ženské pohlaví $7 D005260
- 650 12
- $a celogenomová asociační studie $7 D055106
- 650 12
- $a přežívající onkologičtí pacienti $7 D000073116
- 650 12
- $a ovariální rezerva $x genetika $x účinky léků $x účinky záření $7 D065851
- 650 _2
- $a dospělí $7 D000328
- 650 12
- $a antimülleriánský hormon $x krev $x genetika $7 D054304
- 650 12
- $a jednonukleotidový polymorfismus $7 D020641
- 650 _2
- $a mladý dospělý $7 D055815
- 650 _2
- $a alkylační protinádorové látky $x škodlivé účinky $7 D018906
- 650 _2
- $a nádory $x genetika $x farmakoterapie $7 D009369
- 650 _2
- $a rizikové faktory $7 D012307
- 650 _2
- $a dítě $7 D002648
- 650 _2
- $a mladiství $7 D000293
- 651 _2
- $a Evropa $x epidemiologie $7 D005060
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a multicentrická studie $7 D016448
- 700 1_
- $a Broer, Linda $u Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
- 700 1_
- $a Yasui, Yutaka $u Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
- 700 1_
- $a Laven, Joop S E $u Department of Obstetrics and Gynecology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
- 700 1_
- $a Robison, Leslie L $u Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
- 700 1_
- $a Tissing, Wim J E $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of pediatric oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- 700 1_
- $a Versluys, Birgitta $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- 700 1_
- $a Bresters, Dorine $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- 700 1_
- $a Kaspers, Gertjan J L $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- 700 1_
- $a Lambalk, Cornelis B $u Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- 700 1_
- $a Overbeek, Annelies $u Department of Obstetrics and Gynaecology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- 700 1_
- $a Loonen, Jacqueline J $u Department of Haematology, Radboud University Medical Center, Nijmegen, the Netherlands
- 700 1_
- $a Beerendonk, Catharina C M $u Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, the Netherlands
- 700 1_
- $a Byrne, Julianne $u Boyne Research Institute, Bettystown, Ireland
- 700 1_
- $a Berger, Claire $u Department of Paediatric Oncology, University Hospital, Saint-Etienne, France; Lyon University, Jean Monnet University, INSERM, Sainbiose, Saint-Etienne, France
- 700 1_
- $a Clemens, Eva $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- 700 1_
- $a van Dulmen-den Broeder, Eline $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- 700 1_
- $a Dirksen, Uta $u Pediatrics III, West German Cancer Centre, University Hospital Essen, Essen, Germany; German Cancer Research Centre, DKTK, Sites Duesseldorf-Essen, Essen, Germany
- 700 1_
- $a van der Pal, Helena J $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- 700 1_
- $a de Vries, Andrica C H $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- 700 1_
- $a Winther, Jeanette Falck $u Danish Cancer Society Research Center, Childhood Cancer Research Group, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health, Aarhus University and University Hospital, Aarhus, Denmark
- 700 1_
- $a Ranft, Andreas $u Pediatrics III, West German Cancer Centre, University Hospital Essen, Essen, Germany; German Cancer Research Centre, DKTK, Sites Duesseldorf-Essen, Essen, Germany
- 700 1_
- $a Fosså, Sophie D $u Department of Oncology, Oslo University Hospital, Oslo, Norway
- 700 1_
- $a Grabow, Desiree $u Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- 700 1_
- $a Muraca, Monica $u Division of Pediatric Hematology and Oncology, DOPO Clinic, IRCCS Istituto Giannina Gaslini, Via G. Gaslini, Genoa, Italy
- 700 1_
- $a Kaiser, Melanie $u Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- 700 1_
- $a Kepák, Tomáš $u University Hospital Brno, International Clinical Research Center (FNUSA-ICRC), Masaryk University, Brno, Czech Republic
- 700 1_
- $a Kruseova, Jarmila $u Department of Pediatric Hematology and Oncology, Motol University Hospital, Prague, Czech Republic
- 700 1_
- $a Modan-Moses, Dalit $u The Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer, Israel; The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- 700 1_
- $a Spix, Claudia $u Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- 700 1_
- $a Zolk, Oliver $u Institute of Clinical Pharmacology, Brandenburg Medical School Theodor Fontane, Immanuel Klinik Rüdersdorf, Neuruppin, Germany
- 700 1_
- $a Kaatsch, Peter $u Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- 700 1_
- $a Kremer, Leontien C M $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- 700 1_
- $a Brooke, Russell J $u Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
- 700 1_
- $a Wang, Fan $u Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
- 700 1_
- $a Baedke, Jessica L $u Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
- 700 1_
- $a Uitterlinden, André G $u Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
- 700 1_
- $a Bos, Annelies M E $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Reproductive Medicine, University Medical Center, Utrecht, the Netherlands
- 700 1_
- $a van Leeuwen, Flora E $u Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
- 700 1_
- $a Ness, Kirsten K $u Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
- 700 1_
- $a Hudson, Melissa M $u Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee; Division of Survivorship, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
- 700 1_
- $a van der Kooi, Anne-Lotte L F $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Obstetrics and Gynecology, Erasmus MC University Medical Center, Rotterdam, the Netherlands
- 700 1_
- $a van den Heuvel-Eibrink, Marry M $u Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Division of Child Health, Wilhelmina Children's Hospital, University Medical Center Utrecht, the Netherlands
- 710 2_
- $a PanCareLIFE consortium
- 773 0_
- $w MED00001795 $t Fertility and sterility $x 1556-5653 $g Roč. 122, č. 3 (2024), s. 514-524
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/38729340 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y - $z 0
- 990 __
- $a 20241015 $b ABA008
- 991 __
- $a 20241024111626 $b ABA008
- 999 __
- $a ok $b bmc $g 2201801 $s 1231155
- BAS __
- $a 3
- BAS __
- $a PreBMC-MEDLINE
- BMC __
- $a 2024 $b 122 $c 3 $d 514-524 $e 20240509 $i 1556-5653 $m Fertility and sterility $n Fertil Steril $x MED00001795
- GRA __
- $a U01 CA195547 $p NCI NIH HHS $2 United States
- LZP __
- $a Pubmed-20241015
