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Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children

Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children


Title: Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children
Author: Mateos, Marion K.
Tulstrup, Morten
Quinn, Michael C.J.
Tuckuviene, Ruta
Marshall, Glenn M.
Gupta, Ramneek
Mayoh, Chelsea
Wolthers, Benjamin O.
Barbaro, Pasquale M.
Ruud, Ellen
... 18 more authors Show all authors
Date: 2020-05
Language: English
Scope: 15
University/Institute: Landspitali - The National University Hospital of Iceland
Series: Cancers; 12(5)
ISSN: 2072-6694
DOI: https://doi.org/10.3390/cancers12051285
Subject: Barnalæknisfræði; Bráðahvítblæði; Acute lymphoblastic leukemia; Child; Genome-wide association study; Single-nucleotide polymorphism; Venous thromboembolism; Oncology; Cancer Research
URI: https://hdl.handle.net/20.500.11815/2785

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Citation:

Mateos , M K , Tulstrup , M , Quinn , M C J , Tuckuviene , R , Marshall , G M , Gupta , R , Mayoh , C , Wolthers , B O , Barbaro , P M , Ruud , E , Sutton , R , Huttunen , P , Revesz , T , Trakymiene , S S , Barbaric , D , Tedgård , U , Giles , J E , Alvaro , F , Jonsson , O G , Mechinaud , F , Saks , K , Catchpoole , D , Kotecha , R S , Dalla-Pozza , L , Chenevix-Trench , G , Trahair , T N , Macgregor , S & Schmiegelow , K 2020 , ' Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children ' , Cancers , vol. 12 , no. 5 , 1285 . https://doi.org/10.3390/cancers12051285

Abstract:

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p < 5 × 10−8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 × 10−6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10−7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10−7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.

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Funding Information: Funding: This work was supported by the Kids Cancer Alliance (a Translational Cancer Research Centre of Cancer Institute NSW), Cancer Institute NSW (Grant ECF181430) (M.K.M.), the Anthony Rothe Memorial Trust (T.N.T. & M.K.M.), Royal Australasian College of Physicians—Kids Cancer Project Research Entry Scholarship (M.K.M.) and a Cancer Therapeutics CRC (CTx) PhD Clinician Researcher Top-Up Scholarship (M.K.M.). The authors thank the Sydney Children’s Tumour Bank Network for providing samples for this study, with support from the Cancer Council NSW, NHMRC Australia and Tour de Cure. The SNP analysis of NOPHO patients was supported by The Danish Cancer Society, The Danish Childhood Cancer Foundation, The Swedish Childhood Cancer Foundation, The Nordic Cancer Union, The Otto Christensen Foundation, University Hospital Rigshospitalet, and The Novo Nordisk Foundation. Funding Information: This work was supported by the Kids Cancer Alliance (a Translational Cancer Research Centre of Cancer Institute NSW), Cancer Institute NSW (Grant ECF181430) (M.K.M.), the Anthony Rothe Memorial Trust (T.N.T. & M.K.M.), Royal Australasian College of Physicians-Kids Cancer Project Research Entry Scholarship (M.K.M.) and a Cancer Therapeutics CRC (CTx) PhD Clinician Researcher Top-Up Scholarship (M.K.M.). The authors thank the Sydney Children?s Tumour Bank Network for providing samples for this study, with support from the Cancer Council NSW, NHMRC Australia and Tour de Cure. The SNP analysis of NOPHO patients was supported by The Danish Cancer Society, The Danish Childhood Cancer Foundation, The Swedish Childhood Cancer Foundation, The Nordic Cancer Union, The Otto Christensen Foundation, University Hospital Rigshospitalet, and The Novo Nordisk Foundation. Funding Information: Minor allele frequency as reported in dbSNP, available online at https://www.ncbi.nlm.nih.gov/snp/. NorthernSweden from the Northern Sweden Population Health Study, TWINSUK from the TwinsUK registry study, ALSPAC from the Avon Longitudinal Study of Parents and Children, Estonian from the Estonian Biocentre, GnomAD from The Genome Aggregation Database, TOPMED from the Trans-Omics for Precision Medicine (TOPMed) Program of the NIH National Heart, Lung and Blood Institute and 1000 Genomes from the International Genome Sample Resource and 1000 Genomes project. Funding Information: Acknowledgments: This work was supported by the Kids Cancer Alliance (a Translational Cancer Research Centre of Cancer Institute NSW), Cancer Institute NSW (Grant ECF181430) (M.K.M.), the Anthony Rothe Memorial Trust (T.N.T. & M.K.M.), Royal Australasian College of Physicians—Kids Cancer Project Research Entry Scholarship (M.K.M.) and a Cancer Therapeutics CRC (CTx) PhD Clinician Researcher Top-Up Scholarship (M.K.M.). The authors thank the Sydney Children’s Tumour Bank Network for providing samples for this study, with support from the Cancer Council NSW, NHMRC Australia and Tour de Cure. The SNP analysis of NOPHO patients was supported by The Danish Cancer Society, The Danish Childhood Cancer Foundation, The Swedish Childhood Cancer Foundation, The Nordic Cancer Union, The Otto Christensen Foundation, University Hospital Rigshospitalet, and The Novo Nordisk Foundation. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

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