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Open AccessArticle

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

by
Marion K. Mateos
1,2,3,*,†,
Morten Tulstrup
4,†,
Michael CJ Quinn
5,†,
Ruta Tuckuviene
6,
Glenn M. Marshall
1,2,3,
Ramneek Gupta
7,
Chelsea Mayoh
3,
Benjamin O. Wolthers
4,
Pasquale M. Barbaro
8,9,
Ellen Ruud
10,11,
Rosemary Sutton
2,3,
Pasi Huttunen
12,
Tamas Revesz
13,
Sonata S. Trakymiene
14,
Draga Barbaric
1,
Ulf Tedgård
15,16,
Jodie E. Giles
3,
Frank Alvaro
17,18,
Olafur G. Jonsson
19,
Françoise Mechinaud
20,21,
Kadri Saks
22,
Daniel Catchpoole
23,
Rishi S. Kotecha
24,25,26,
Luciano Dalla-Pozza
27,28,
Georgia Chenevix-Trench
29,
Toby N. Trahair
1,2,3,‡,
Stuart MacGregor
5,‡ and
Kjeld Schmiegelow
4,30,‡
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
*
Author to whom correspondence should be addressed.
†
Denotes joint first authorship.
‡
Denotes joint senior authorship.
Cancers 2020, 12(5), 1285; https://doi.org/10.3390/cancers12051285
Received: 23 February 2020 / Revised: 11 May 2020 / Accepted: 14 May 2020 / Published: 19 May 2020
(This article belongs to the Special Issue Treatment of Cancer-Associated Thrombosis)
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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. View Full-Text
Keywords: acute lymphoblastic leukemia; child; genome-wide association study; single-nucleotide polymorphism; venous thromboembolism acute lymphoblastic leukemia; child; genome-wide association study; single-nucleotide polymorphism; venous thromboembolism
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MDPI and ACS Style

Mateos, M.K.; Tulstrup, M.; Quinn, M.C.; 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. 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 2020, 12, 1285. https://doi.org/10.3390/cancers12051285

AMA Style

Mateos MK, Tulstrup M, Quinn MC, Tuckuviene R, Marshall GM, Gupta R, Mayoh C, Wolthers BO, Barbaro PM, Ruud E, Sutton R, Huttunen P, Revesz T, Trakymiene SS, Barbaric D, Tedgård U, Giles JE, Alvaro F, Jonsson OG, Mechinaud F, Saks K, Catchpoole D, Kotecha RS, Dalla-Pozza L, Chenevix-Trench G, Trahair TN, MacGregor S, Schmiegelow K. 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. 2020; 12(5):1285. https://doi.org/10.3390/cancers12051285

Chicago/Turabian Style

Mateos, Marion K.; Tulstrup, Morten; Quinn, Michael C.; Tuckuviene, Ruta; Marshall, Glenn M.; Gupta, Ramneek; Mayoh, Chelsea; Wolthers, Benjamin O.; Barbaro, Pasquale M.; Ruud, Ellen; Sutton, Rosemary; Huttunen, Pasi; Revesz, Tamas; Trakymiene, Sonata S.; Barbaric, Draga; Tedgård, Ulf; Giles, Jodie E.; Alvaro, Frank; Jonsson, Olafur G.; Mechinaud, Françoise; Saks, Kadri; Catchpoole, Daniel; Kotecha, Rishi S.; Dalla-Pozza, Luciano; Chenevix-Trench, Georgia; Trahair, Toby N.; MacGregor, Stuart; Schmiegelow, Kjeld. 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 12, no. 5: 1285. https://doi.org/10.3390/cancers12051285

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