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The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number
University of Copenhagen, Denmark.
Rigshospital, Copenhagen, Denmark.
Bispebjerg Hospital.
Rigshospital, Copenhagen, Denmark.
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2010 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, no 23, 4671-4677 p.Article in journal (Refereed) Published
Abstract [en]

The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G greater than A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (platelet 73 vs 99/105 x 10(9)/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G greater than A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.

Place, publisher, year, edition, pages
American Society of Hematology , 2010. Vol. 115, no 23, 4671-4677 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-58380DOI: 10.1182/blood-2010-01-256958ISI: 000278635900013OAI: diva2:343304
Original Publication: Jannie Gregers, Ib Jarle Christensen, Kim Dalhoff, Birgitte Lausen, Henrik Schroeder, Steen Rosthoej, Niels Carlsen, Kjeld Schmiegelow and Curt Peterson, The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number, 2010, Blood, (115), 23, 4671-4677. Copyright: American Society of Hematology from: 2010-08-13 Created: 2010-08-11 Last updated: 2012-05-24Bibliographically approved
In thesis
1. Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate
Open this publication in new window or tab >>Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Childhood acute lymphoblastic leukaemia is the most common type of cancer in children. Improvement in treatment has increased survival to approximately 85 per cent. Pharmacogenetics can influence the disposition of anticancer agents and can ideally be used as tool to further improve treatment based on the individual child’s pharmacogenetic profile.

The hypothesis in this thesis was that polymorphisms in genes responsible for MTX influx (SLC19A1), efflux (ABCB1, studies with MTX monotherapy have demonstrated effect of variations in this gene) or other MTX pathways (ATIC, MTHFR and SHMT) could have impact on efficacy in childhood acute lymphoblastic leukaemia.

The uptake of MTX and impact of SLC19A1 80G>A was investigated in vitro and showed that SLC19A1 80GG had decreased uptake in CD+ T cells and B cells caused by reduced capacity on receptor-to-receptor basis.

In more than 500 patients the clinical effect of SLC19A1 80G>A genotype was evaluated and showed that patients with the SLC19A1 80AA had better survival, more bone marrow toxicity, but less liver toxicity than patients with SLC19A1 80GG or 80GA variants. Furthermore, it was demonstrated that SLC19A1 80G>A interacts with chromosome 21 copy number in the leukemic clone.

The clinical impact of ABCB1 1199G>A, 1236C>T, 2677G<T/A and 3435C>T on the treatment was evaluated. Patients with either the 1199GA or the 3435CC variant had increased risk of relapse compared to patients with the 1199GG or 3435CT/TT variants, respectively. Toxicity was also affected by the ABCB1 polymorphisms.

No association between polymorphisms in the ATIC, MTHFR and SHMT genes and outcome was seen. However the 677C>T and 1298 C>A in the MTHFR gene were associated with toxicity.

The genotype frequencies between healthy donors and patients were compared, but no association to risk of developing cancer was seen in the investigated polymorphisms.

The results in this thesis emphasise the importance of including pharmacogenetic markers in attempts to improve outcome and reduced side effects in childhood ALL.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 83 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1302
National Category
Pharmaceutical Sciences
urn:nbn:se:liu:diva-77625 (URN)978-91-7519-929-0 (ISBN)
Public defence
2012-05-31, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2012-05-24Bibliographically approved

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