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Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1302
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-77625ISBN: 978-91-7519-929-0 (print)OAI: oai:DiVA.org:liu-77625DiVA: diva2:528159
Public defence
2012-05-31, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2012-05-24Bibliographically approved
List of papers
1. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells
Open this publication in new window or tab >>Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells
2008 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 47, no 4, 451-453 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells.

METHODS: Mononuclear cells were isolated from peripheral blood of healthy persons. Real-time PCR was used to detect the RFC80 variants. FITC-labelled MTX was added to cells stimulated with Candida albicans or tetanus toxoid, and the uptake of MTX was measured by flow cytometry. A FITC-conjugated monoclonal antibody against RFC was used to detect the cellular RFC expression.

RESULTS: Antigen-stimulated CD4+ T cells and B cells from individuals with the GG variant (n = 9) exhibited lower uptake of MTX than individuals expressing the AA variant (n = 8), or the GA variant (n = 8). No difference could be demonstrated between the three groups with respect to the expression of RFC by CD4+ T cells and B cells, and CD4+ T cells from individuals homozygous for the G allele exhibited lower uptake of MTX per receptor than CD4+ T cells from individuals homozygous for the A allele.

CONCLUSION: MTX is taken up more efficiently via the A allele than via the G allele. This difference between the variant forms of RFC suggests that genotyping could be relevant for determining the relevant dosage of MTX in the treatment of neoplastic and autoimmune disease.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77610 (URN)10.1093/rheumatology/ken073 (DOI)18316334 (PubMedID)
Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2017-12-07Bibliographically approved
2. The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number
Open this publication in new window or tab >>The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number
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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
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58380 (URN)10.1182/blood-2010-01-256958 (DOI)000278635900013 ()
Note
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. http://dx.doi.org/10.1182/blood-2010-01-256958 Copyright: American Society of Hematology http://www.hematology.org/Available from: 2010-08-13 Created: 2010-08-11 Last updated: 2017-12-12Bibliographically approved
3. Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia
Open this publication in new window or tab >>Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia
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2012 (English)Manuscript (preprint) (Other academic)
Abstract [en]

The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences pharmacokinetics in several anti-cancer drugs. We hypothesized that 1199G>A, 1236C>T, 2677G>A/T and 3435C>T variants of ABCB1 could affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL), since treatment includes known P-glycoprotein substrates and 3435C/T may affect methotrexate therapy.

We studied 522 Danish children with ALL treated according to NOPHO ALL92 and ALL2000 protocols, 93% of all those eligible during 1992-2007. Risk of relapse was 2.9-fold increased for 41 patients with the 1199GA variant compared to 477 with 1199GG (p=0.001), and reduced by 61% and 40%, respectively for 421 patients with the 3435CT or 3435TT variants compared to 96 with 3435CC (overall p=0.02).

Degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was higher in 71 patients with 3435TT variant (median nadirs: hemoglobin 3% and platelets 34/37% lower in3435CT/3435CC) compared to 160 patients with 3435CT/3435CC (Hemoglobin p=0.01 and platelets p<0.0001).

We observed more liver toxicity after high-dose methotrexate in 109 patients with 3435CC variant versus 3435CT/TT (Median max alanineaminotransferase: 280 versus 142/111 U/L, p=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms and efficacy and toxicity in childhood ALL.

Keyword
Acute lymphoblastic leukemia; ABCB1; MDR1; P-glycoprotein; Polymorphism; Relapse; Toxicity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77618 (URN)
Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2012-05-24Bibliographically approved
4. Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
Open this publication in new window or tab >>Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
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2012 (English)Manuscript (preprint) (Other academic)
Abstract [en]

We hypothesized that polymorphisms in folate metabolism would affect treatment effects of the folate antagonist methotrexate (MTX). We studied whether ATIC347C>T, MTHFR677C>T, MTHFR1298C>A and SHMT1-1420C>T polymorphisms influence risk of disease or efficacy and toxicity of MTX in a large population of children with acute lymphoblastic leukaemia (ALL). The children were treated after standardized Nordic protocols with 5-8 g/m2 high-dose MTX courses and long term oral maintenance therapy with weekly MTX. Ninety-four percent (n=533) of the children diagnosed during a 16 year time period were included. The study showed that the polymorphisms had no effect on risk of ALL, MTX pharmacokinetics or outcome. However after high-dose MTX treatment, patients with MTHFR677TT/MTHFR677CT had more liver toxicity than patients with MTHFR677CC (alanine transferase: 174/154 versus 115U/L, p=0.049). Patients with MTHFR1298AA had more liver toxicity than patients with MTHFR1298CC (alanine transferase: 144 versus 108 U/L, p=0.04). More bone marrow toxicity was found in patients with MTHFR1298CC compared to MTHFR1298CT / MTHFR1298AA (Nadir means: Platelets 72 versus 109/93*109/L, p=0.0001).

In conclusion this study supports that MTHFR1298C>A and MTHFR677C>T are associated with toxicity in MTX treatment and the MTHFR variants should be considered as markers for individualization of treatment in childhood ALL in combination with other pharmacogenetic markers.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77622 (URN)
Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2012-05-24Bibliographically approved

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