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      Germline Genetic Variation in ETV6 and Risk of Childhood Acute Lymphoblastic Leukemia: a Systematic Genetic Study

      research-article
      Author(s): , MD a , b , , MD c , , PhD d , a , e , , PhD a , , PhD f , , PhD a , , PhD g , , PhD g , , MS c , , PhD h , , PhD i , , MD j , , MD k , , MD, PhD l , , MD m , , MD n , , MD, PhD b , , PhD d , , BA d , , PhD o , , PhD p , , MS p , , MD c , h , q , , MBBS, MD h , q , , PharmD a , q , , PhD d , , MD r , , PharmD a , q , , MD c , , MD s , , PhD a
      Publication date (Electronic):
      Journal: The Lancet. Oncology

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          Abstract

          Background

          Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukemia (ALL). Recent studies identified germline ETV6 variations associated with marked familial clustering of hematologic malignancies, pointing to this gene as a potentially important genetic determinant for ALL susceptibility. The aims of the current study are to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contribute to the overall risk of childhood ALL.

          Methods

          Whole-exome sequencing of an index family with multiple cases of ALL was performed to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in 4,405 children from the Children's Oncology Group (COG) and St. Jude Children's Research Hospital frontline ALL trials. Patients were included in this study on the basis of their enrollment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterized bioinformatically and correlated with clinical and demographic features in 2,021 children with ALL.

          Findings

          We identified a novel nonsense ETV6 variant (p.R359X) with a high penetrance of familial ALL. Subsequent targeted sequencing of ETV6 in 4,405 childhood ALL cases discovered 31 exonic variants (4 nonsense, 21 missense, 1 splice site, and 5 frame shift variants) that are potentially related to ALL risk in 35 cases (0.79%). Fifteen (48%) of the 31 ALL-related ETV6 variants clustered in the ETS domain and predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukemia diagnosis than others (10.2 years [IQR 5.3-13.8] vs 4.7 years [IQR 3.0-8.7], P=0.017). The hyperdiploid leukemia karyotype was strikingly overrepresented in ALL cases harboring germline ETV6 risk variants compared to the wildtype group (9 of 14 cases [64.3%] vs 538 of 2,007 cases [26.8%]; P=0.0050).

          Interpretation

          Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL.

          Funding

          This study was supported by the National Institutes of Health and by the American Lebanese Syrian Associated Charities.

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          Most cited references32

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          Clinical effect of point mutations in myelodysplastic syndromes.

          Rafael Bejar, Kristen Stevenson, Omar Abdel-Wahab … (2011)
          Myelodysplastic syndromes are clinically heterogeneous disorders characterized by clonal hematopoiesis, impaired differentiation, peripheral-blood cytopenias, and a risk of progression to acute myeloid leukemia. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems. We used a combination of genomic approaches, including next-generation sequencing and mass spectrometry-based genotyping, to identify mutations in samples of bone marrow aspirate from 439 patients with myelodysplastic syndromes. We then examined whether the mutation status for each gene was associated with clinical variables, including specific cytopenias, the proportion of blasts, and overall survival. We identified somatic mutations in 18 genes, including two, ETV6 and GNAS, that have not been reported to be mutated in patients with myelodysplastic syndromes. A total of 51% of all patients had at least one point mutation, including 52% of the patients with normal cytogenetics. Mutations in RUNX1, TP53, and NRAS were most strongly associated with severe thrombocytopenia (P<0.001 for all comparisons) and an increased proportion of bone marrow blasts (P<0.006 for all comparisons). In a multivariable Cox regression model, the presence of mutations in five genes retained independent prognostic significance: TP53 (hazard ratio for death from any cause, 2.48; 95% confidence interval [CI], 1.60 to 3.84), EZH2 (hazard ratio, 2.13; 95% CI, 1.36 to 3.33), ETV6 (hazard ratio, 2.04; 95% CI, 1.08 to 3.86), RUNX1 (hazard ratio, 1.47; 95% CI, 1.01 to 2.15), and ASXL1 (hazard ratio, 1.38; 95% CI, 1.00 to 1.89). Somatic point mutations are common in myelodysplastic syndromes and are associated with specific clinical features. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors. (Funded by the National Institutes of Health and others.).
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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
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              Biology, risk stratification, and therapy of pediatric acute leukemias: an update.

              Ching-Hon Pui, William Carroll, Soheil Meshinchi … (2011)
              We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of research. A review of English literature on childhood acute leukemias from the past 5 years was performed. Contemporary treatments have resulted in 5-year event-free survival rates of approximately 80% for childhood ALL and almost 60% for pediatric AML. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and the vast majority of AML cases can be classified according to specific genetic abnormalities. Cooperative mutations involved in cell differentiation, cell cycle regulation, tumor suppression, drug responsiveness, and apoptosis have also been identified in many cases. The development of new formulations of existing drugs, molecularly targeted therapy, and immunotherapies promises to further advance the cure rates and improve quality of life of patients. The application of new high-throughput sequencing techniques to define the complete DNA sequence of leukemia and host normal cells and the development of new agents targeted to leukemogenic pathways promise to further improve outcome in the coming decade.
              Article 0 comments Cited 242 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100957246
                Journal ID (pubmed-jr-id): 27004
                Journal ID (nlm-ta): Lancet Oncol
                Journal ID (iso-abbrev): Lancet Oncol.
                Title: The Lancet. Oncology
                ISSN (Print): 1470-2045
                ISSN (Electronic): 1474-5488
                Publication date Nihms-submitted: 23 November 2015
                Publication date (Electronic): 28 October 2015
                Publication date (Print): December 2015
                Publication date PMC-release: 01 December 2016
                Volume: 16
                Issue: 16
                Pages: 1659-1666
                Affiliations
                [a ]Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
                [b ]Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan
                [c ]Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
                [d ]Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
                [e ]Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan
                [f ]Department of Biostatistics, College of Medicine, Public Health & Health Professions, University of Florida, Gainesville, Florida, USA
                [g ]Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
                [h ]Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
                [i ]Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, and Departments of Pathology and Pediatrics, Ohio State University, Columbus, Ohio, USA
                [j ]Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA
                [k ]Maine Children's Cancer Program, Scarborough, Maine, USA
                [l ]Department of Pediatrics, Duke University, Durham, North Carolina, USA
                [m ]Cook Children's Medical Center, Ft. Worth, Texas, USA
                [n ]Pediatric Hematology Oncology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
                [o ]Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
                [p ]McDonnell Genome Institute, Washington University School of Medicine, St Louis, Missouri, USA
                [q ]Hematological Malignancies Program, Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
                [r ]Department of Pediatrics and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
                [s ]Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, California, USA
                Author notes
                Correspondence: Jun J. Yang, PhD, Hematologic Malignancies Program, Pharmaceutical Sciences, St. Jude Children's Research Hospital, MS313, 262 Danny Thomas Place Memphis, Tennessee 38105-3678, jun.yang@ 123456stjude.org , Phone: (901)595-2517
                [*]

                These authors contributed equally

                Article
                Manuscript ID: NIHMS737731
                DOI: 10.1016/S1470-2045(15)00369-1
                PMC ID: 4684709
                PubMed ID: 26522332
                SO-VID: a719d0f5-f0f2-4af9-8bc1-789d895a70cf
                License:

                This manuscript version is made available under the CC BY-NC-ND 4.0 license.

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                ScienceOpen disciplines: Oncology & Radiotherapy
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                ScienceOpen disciplines: Oncology & Radiotherapy

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