Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children

Marion K Mateos; Morten Tulstrup; Michael Cj Quinn; Ruta Tuckuviene; Glenn M Marshall; Ramneek Gupta; Chelsea Mayoh; Benjamin O Wolthers; Pasquale M Barbaro; Ellen Ruud; Rosemary Sutton; Pasi Huttunen; Tamas Revesz; Sonata S Trakymiene; Draga Barbaric; Ulf Tedgård; Jodie E Giles; Frank Alvaro; Olafur G Jonsson; Françoise Mechinaud; Kadri Saks; Daniel Catchpoole; Rishi S Kotecha; Luciano Dalla-Pozza; Georgia Chenevix-Trench; Toby N Trahair; Stuart MacGregor; Kjeld Schmiegelow

doi:10.3390/cancers12051285

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 (Basel). 2020 May 19;12(5):1285. doi: 10.3390/cancers12051285.

Authors

Marion K Mateos^{1

2

3}, Morten Tulstrup⁴, Michael Cj Quinn⁵, Ruta Tuckuviene⁶, Glenn M Marshall^{1

2

3}, Ramneek Gupta⁷, Chelsea Mayoh³, Benjamin O Wolthers⁴, Pasquale M Barbaro^{8

9}, Ellen Ruud^{10

11}, Rosemary Sutton^{2

3}, Pasi Huttunen¹², Tamas Revesz¹³, Sonata S Trakymiene¹⁴, Draga Barbaric¹, Ulf Tedgård^{15

16}, Jodie E Giles³, Frank Alvaro^{17

18}, Olafur G Jonsson¹⁹, Françoise Mechinaud^{20

21}, Kadri Saks²², Daniel Catchpoole²³, Rishi S Kotecha^{24

25

26}, Luciano Dalla-Pozza^{27

28}, Georgia Chenevix-Trench²⁹, Toby N Trahair^{1

2

3}, Stuart MacGregor⁵, Kjeld Schmiegelow^{4

30}

Affiliations

¹ Kids Cancer Centre, Sydney Children's Hospital Randwick, Sydney, NSW 2031, Australia.
² School of Women and Children's Health, University of New South Wales (UNSW), Sydney, NSW 2052, Australia.
³ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia.
⁴ Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, 2100 Copenhagen, Denmark.
⁵ Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia.
⁶ Department of Pediatrics, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark.
⁷ Department of Health Technology, Technical University of Denmark, 2800 Kongens Lyngby, Denmark.
⁸ Children's Medical Research Institute, University of Sydney, Westmead, Sydney, NSW 2145, Australia.
⁹ Queensland Children's Hospital, Brisbane, QLD 4101, Australia.
¹⁰ Department of Pediatric Hematology and Oncology, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, 0424 Oslo, Norway.
¹¹ Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0318 Oslo, Norway.
¹² Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, New Children's Hospital, Helsinki University Hospital, Stenbäckinkatu 9, 00290 Helsinki, Finland.
¹³ Women's and Children's Hospital, North Adelaide, SA 5006, Australia.
¹⁴ Children's Hospital, Affiliate of Vilnius University Hospital Santaros Klinikos, Santariškių Str. 7, LT-08406 Vilnius, Lithuania.
¹⁵ Department of Pediatric Hematology and Oncology, Skåne University Hospital, Lasarettsgatan 48, 221 85 Lund, Sweden.
¹⁶ Department of Clinical Sciences Lund, Pediatrics, Lund University, Sölvegatan 19, BMC F12 Lund, Sweden.
¹⁷ John Hunter Children's Hospital, Newcastle, NSW 2305, Australia.
¹⁸ School of Medicine and Public Health, University of Newcastle, University Drive Callaghan, Newcastle, NSW 2308, Australia.
¹⁹ Children's Hospital, Barnaspitali Hringsins, Landspitali University Hospital, Hringbraut 101, 101 Reykjavik, Iceland.
²⁰ The Royal Children's Hospital, Parkville, Melbourne, VIC 3052, Australia.
²¹ Unite Hematologie Immunologie, Hopital universitaire Robert-Debre, 75019 Paris, France.
²² Department of Hematology and Oncology, Tallinn Children's Hospital, 13419 Tallinn, Estonia.
²³ Tumour Bank, Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead Sydney, NSW 2145, Australia.
²⁴ Perth Children's Hospital, Nedlands, Perth, WA 6009, Australia.
²⁵ Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Nedlands Perth, WA 6009, Australia.
²⁶ School of Pharmacy and Biomedical Sciences, Curtin University, Bentley, Perth, WA 6102, Australia.
²⁷ Cancer Centre for Children, The Children's Hospital at Westmead, Westmead, Sydney, NSW 2145, Australia.
²⁸ Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, Sydney, NSW 2145, Australia.
²⁹ Cancer Genetics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia.
³⁰ Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.

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.

Keywords: acute lymphoblastic leukemia; child; genome-wide association study; single-nucleotide polymorphism; venous thromboembolism.

Grants and funding

MC_PC_19009/MRC_/Medical Research Council/United Kingdom