TY - JOUR

T1 - Cost-effective multiplexing before capture allows screening of 25 000 clinically relevant SNPs in childhood acute lymphoblastic leukemia

AU - Wesolowska, Agata

AU - Gautier, Laurent

AU - Weinhold, Nils

AU - Audouze, Karine Marie Laure

AU - Brunak, S.

AU - Sicheritz-Ponten, T.

AU - Gupta, R.

AU - Dalgaard, M.D.

AU - Nielsen, B.F.

AU - Leffers, H.

AU - Borst, L.

AU - Helt, L.R.

AU - Nersting, J.

AU - Schmiegelow, K.

AU - Bak, M.

AU - Tommerup, N.

PY - 2011/6/1

Y1 - 2011/6/1

N2 - Genetic variants, including single-nucleotide polymorphisms (SNPs), are key determiners of interindividual differences in treatment efficacy and toxicity in childhood acute lymphoblastic leukemia (ALL). Although up to 13 chemotherapeutic agents are used in the treatment of this cancer, it remains a model disease for exploring the impact of genetic variation due to well-characterized cytogenetics, drug response pathways and precise monitoring of minimal residual disease. Here, we have selected clinically relevant genes and SNPs through literature screening, and on the basis of associations with key pathways, protein-protein interactions or downstream partners that have a role in drug disposition and treatment efficacy in childhood ALL. This allows exploration of pathways, where one of several genetic variants may lead to similar clinical phenotypes through related molecular mechanisms. We have designed a cost-effective, high-throughput capture assay of ∼25 000 clinically relevant SNPs, and demonstrated that multiple samples can be tagged and pooled before genome capture in targeted enrichment with a sufficient sequencing depth for genotyping. This multiplexed, targeted sequencing method allows exploration of the impact of pharmacogenetics on efficacy and toxicity in childhood ALL treatment, which will be of importance for personalized chemotherapy. © 2011 Macmillan Publishers Limited All rights reserved.

AB - Genetic variants, including single-nucleotide polymorphisms (SNPs), are key determiners of interindividual differences in treatment efficacy and toxicity in childhood acute lymphoblastic leukemia (ALL). Although up to 13 chemotherapeutic agents are used in the treatment of this cancer, it remains a model disease for exploring the impact of genetic variation due to well-characterized cytogenetics, drug response pathways and precise monitoring of minimal residual disease. Here, we have selected clinically relevant genes and SNPs through literature screening, and on the basis of associations with key pathways, protein-protein interactions or downstream partners that have a role in drug disposition and treatment efficacy in childhood ALL. This allows exploration of pathways, where one of several genetic variants may lead to similar clinical phenotypes through related molecular mechanisms. We have designed a cost-effective, high-throughput capture assay of ∼25 000 clinically relevant SNPs, and demonstrated that multiple samples can be tagged and pooled before genome capture in targeted enrichment with a sufficient sequencing depth for genotyping. This multiplexed, targeted sequencing method allows exploration of the impact of pharmacogenetics on efficacy and toxicity in childhood ALL treatment, which will be of importance for personalized chemotherapy. © 2011 Macmillan Publishers Limited All rights reserved.

UR - http://www.scopus.com/inward/record.url?scp=79958123991&partnerID=8YFLogxK

U2 - 10.1038/leu.2011.32

DO - 10.1038/leu.2011.32

M3 - Journal article

C2 - 21415851

VL - 25

SP - 1001

EP - 1006

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 6

ER -