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      The BCL2-938 C > A promoter polymorphism is associated with risk group classification in children with acute lymphoblastic leukemia

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          Abstract

          Background

          Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. While current treatment regimens achieve almost 80% overall survival, long-term side effects of chemotherapeutic agents can be severe. The functional BCL2-938C > A promoter polymorphism is known to influence the balance between survival and apoptosis of malignant hematolymphoid cells. We investigated its usefulness as a marker for treatment stratification for children with ALL.

          Methods

          We analyzed DNA from 182 children suffering from ALL in this study to determine genotypes of the−938 C > A polymorphism by “slow-down” PCR.

          Results

          ALL patients with the BCL2-938CC genotype had an approximately 3-fold higher risk of belonging to a high-risk group. Within the high-risk group, 50% of BCL2-938CC patients were classified as high-risk due to poor prednisone response whereas only 33% of patients with AC and AA genotypes were classified as high-risk for the same reason.

          Conclusions

          Our results suggest that BCL2-938C > A genotyping may be beneficial for therapy response prediction in ALL patients, and warrant examination in a larger cohort to validate its usefulness for treatment stratification of pediatric ALL patients.

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          Most cited references33

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          Treating childhood acute lymphoblastic leukemia without cranial irradiation.

          Ching-Hon Pui, Dario Campana, Deqing Pei … (2009)
          Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection. With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.) 2009 Massachusetts Medical Society
          Article 0 comments Cited 285 times – based on 0 reviews     Review now
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            Hardy-Weinberg Equilibrium Testing of Biological Ascertainment for Mendelian Randomization Studies

            Santiago Rodríguez-Pérez, Tom Gaunt, Ian N M Day (2009)
            Mendelian randomization (MR) permits causal inference between exposures and a disease. It can be compared with randomized controlled trials. Whereas in a randomized controlled trial the randomization occurs at entry into the trial, in MR the randomization occurs during gamete formation and conception. Several factors, including time since conception and sampling variation, are relevant to the interpretation of an MR test. Particularly important is consideration of the “missingness” of genotypes that can be originated by chance, genotyping errors, or clinical ascertainment. Testing for Hardy-Weinberg equilibrium (HWE) is a genetic approach that permits evaluation of missingness. In this paper, the authors demonstrate evidence of nonconformity with HWE in real data. They also perform simulations to characterize the sensitivity of HWE tests to missingness. Unresolved missingness could lead to a false rejection of causality in an MR investigation of trait-disease association. These results indicate that large-scale studies, very high quality genotyping data, and detailed knowledge of the life-course genetics of the alleles/genotypes studied will largely mitigate this risk. The authors also present a Web program (http://www.oege.org/software/hwe-mr-calc.shtml) for estimating possible missingness and an approach to evaluating missingness under different genetic models.
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              Acute lymphoblastic leukemia.

              Ching-Hon Pui, Mary Relling, James R. Downing (2004)
              Article 0 comments Cited 236 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Annette Künkele
                Anja Grosse-Lordemann
                Alexander Schramm
                Angelika Eggert
                Johannes H Schulte
                Hagen S Bachmann
                Journal
                Journal ID (nlm-ta): BMC Cancer
                Journal ID (iso-abbrev): BMC Cancer
                Title: BMC Cancer
                Publisher: BioMed Central
                ISSN (Electronic): 1471-2407
                Publication date Collection: 2013
                Publication date (Electronic): 2 October 2013
                Volume: 13
                Page: 452
                Affiliations
                [1 ]Department of Pediatric Hematology-Oncology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany
                [2 ]Institute of Pharmacogenetics, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany
                Article
                Publisher ID: 1471-2407-13-452
                DOI: 10.1186/1471-2407-13-452
                PMC ID: 3850706
                PubMed ID: 24088574
                SO-VID: 67fbcec9-3186-48db-9682-de94c4d76dfc
                Copyright © Copyright © 2013 Künkele et al.; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 20 January 2013
                Date accepted : 27 September 2013
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: pediatric all,bcl2-938c > a,risk stratification
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: pediatric all, bcl2-938c > a, risk stratification

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