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RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia

Leukemia volume 18, pages 685–692 (2004)Cite this article

Abstract

Activating mutations in the RAS oncogenes are among the most common genetic alterations in human cancers, including patients with acute lymphoblastic leukemia (ALL). We sought to define the frequency and spectrum, and possible prognostic importance, of N- and K-RAS mutations in children with ALL treated with contemporary therapy. Leukemic blast DNA from 870 children was analyzed for the presence of activating mutations in the N- or K-RAS oncogenes using a sensitive mutation detection algorithm. RAS mutations were present in the blasts of 131 (15.1%) pediatric ALL patients. The spectrum of mutations included 81 (9.3%) mutations of codons 12/13 of N-RAS, 12 (1.4%) mutations of codon 61 of N-RAS, 39 (4.5%) mutations of codons 12/13 of K-RAS, and 2 (0.2%) mutations of codon 61 of K-RAS. The presence of N- or K-RAS mutations was not associated with white blood cell count at diagnosis, sex, race, extramedullary testicular involvement, central nervous system disease, or NCI/CTEP ALL Risk Group. Patients with an exon 1 K-RAS mutation (codons 12/13) were significantly younger at diagnosis (P=0.001) and less frequently B-lineage phenotype (P=0.01). RAS mutation status did not predict overall survival, event-free survival and disease-free survival. While N- and K-RAS mutations can be identified in 15% of children with newly diagnosed ALL, they do not represent a significant risk factor for outcome using contemporary chemotherapy regimens.

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Acknowledgements

This work was supported by National Institutes of Health award R01 ES07819 to LLR and by support to the University of Minnesota from the Children's Cancer Research Fund. Samples were obtained with the assistance of the Cooperative Human Tissue Network. Contributing Children's Oncology Group investigators, institutions and grant numbers are provided in the appendix.

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Authors and Affiliations

  1. Children's Hospital Medical Center, Cincinnati, OH, USA

    J P Perentesis

  2. City of Hope National Medical Center, Duarte, CA, USA

    S Bhatia

  3. Children's Hospital Central California, Madera, CA, USA

    E Boyle

  4. University of Minnesota Cancer Center, Minneapolis, MN, USA

    Y Shao, X Ou Shu, W Kiffmeyer, J Envall-Fox & L L Robison

  5. Health Care Research Center, Mason, OH, USA

    M Steinbuch

  6. USC Keck School of Medicine, Los Angeles, CA, USA

    H N Sather

  7. Children's Oncology Group, Arcadia, CA, USA

    H N Sather

  8. Childrens Hospital Los Angeles, Los Angeles, CA, USA

    P Gaynon

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Correspondence to J P Perentesis.

Appendix

Appendix

The following lists the principal investigators from the Children's Cancer Group, their institutions, and the grants that supported them in this work: W Archie Bleyer, Anita Khayat, Harland Sather, Mark Krailo, Jonathan Buckley, Daniel Stram, and Richard Sposto, Group Operations Center, Grant CA13539; Raymond Hutchinson, University of Michigan Medical Center, Ann Arbor, CA02971; Katherine Matthay, University of California Medical Center, San Francisco, CA17829; Paul Gaynon, University of Wisconsin Hospital, Madison, CA05436; Ronald Chard, Children's Hospital and Medical Center, Seattle, WA, CA10382; Susan Shurin, Rainbow Babies and Children's Hospital, Cleveland, OH, CA20320, Gregory Reaman, Children's National Medical Center, Washington, DC, CA03888; Edward Baum, Children's Memorial Hospital, Chicago, IL, CA07431; Jorge Ortega, Children's Hospital of Los Angeles, CA, CA02649; Frederick Ruymann, Children's Hospital of Columbus, OH, CA03750; Sergio Piomelli, Columbia Presbyterian College of Physicians and Surgeons, New York, NY, CA03526; Joseph Mirro, Children's Hospital of Pittsburgh, PA, CA36015; John Lukens, Vanderbilt University School of Medicine, Nashville, TN, CA26270; Lawrence Wolff, Doernbecher Memorial Hospital for Children, Portland, OR, CA26044; William Woods, University of Minnesota Health Sciences Center, Minneapolis, CA07306; Thomas Williams, University of Texas Health Sciences Center, San Antonio, CA36004; Anna Meadows, Children's Hospital of Philadelphia, PA, CA11796; Peter Steinherz, Memorial Sloan-Kettering Cancer Center, New York, NY, cA42764; Philip Breitfeld, James Whitcomb Riley Hospital for Children, Indianapolis, IN, CA13809; Mark Greenerg, Hospital for Sick Children, Toronto, Ont., Canada; Richard O'Brien, University of Utah Medical Center, Salt Lake City, CA10198; Harvey Cohen, Strong Memorial Hospital, Rochester, NY, CA11174; Cristopher Fryer, University of British Columbia, Vancouver, Canada, CA29013; Robert Wells, Children's Hospital Medical Center, Cincinnati, OH, CA26126; Jerry Finklestein, Harbor/UCLA and Miller Children's Medical Center, Torrance/Long Beach, CA, CA14560; Stephen Feig, University of California Medical Center, Los Angeles, CA27678; Raymond Tannous, University of Iowa Hospitals and Clinics, Iowa City, CA29314; Lorrie Odom, Children's Hospital of Denver, CO, CA28851; Gerald Gilchrist, Mayo Clinic and Foundation, Rochester, MN, CA28882; Dorothy Barnard, Izaak Walton Killam Hospital for Children, Halifax, Nova Scotia, Canada; Joseph Wiley, University of North Carolina, Chapel Hill; Milton Donaldson, University of Medicine and Dentistry of New Jersey, Camden; Maxine Hetherington, Children's Mercy Hospital Kansas City, MO; Peter Coccia, University of NebRASka Medical Center, Omaha; Donald Norris, Cleveland Clinic Foundation, OH; F Leonard Johnson, Wyler Children's Hospital, Chicago, IL; R Beverly Raney, MD Anderson Cancer Center, Houston, TX; David Baker, Princess Margaret Hospital, Perth, Western Australia; Jean Sanders, Fred Hutchinson Cancer Research Center, Seattle, WA; Aaron Rausen, New York University Medical Center, NY; Mitchell Cairo, Children's Hospital of Orange County, CA.

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Perentesis, J., Bhatia, S., Boyle, E. et al. RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia. Leukemia 18, 685–692 (2004). https://doi.org/10.1038/sj.leu.2403272

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