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Prevalence and clinical implications of NRAS mutations in childhood AML: a report from the Children's Oncology Group

Leukemia volume 25, pages 1039–1042 (2011)Cite this article

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Over the last several years, molecular analyses in acute myeloid leukemia (AML) have established clinical–pathological and prognostic correlations that have better defined subgroups in this heterogeneous disease and influenced risk-adapted therapeutic approaches on recent clinical trials. Genetic markers such as FLT3 internal tandem duplications (FLT3-ITD), were first identified in adults1 and subsequently in children,2 as conferring a poor prognosis. By contrast, mutations in nucleophosmin (NPM1)3, 4 and more recently, CCAAT/enhancer-binding protein alpha (CEBPA)5 have been found to be associated with improved outcomes in both adult and pediatric studies. However, despite being initially described almost 20 years ago, the prognostic implications of mutations involving the RAS proto-oncogenes, remain controversial.6 The RAS gene family is comprised of three homologues, HRAS (11p15.5), KRAS (12p12.1) and NRAS (1p13.2), all of which function as membrane-associated guanosine nucleotide phosphate-binding proteins.7 Mutations in RAS genes are frequent in AML and serve as prototypic Class I lesions, initiating key downstream hyper-proliferative signal transduction pathways.8 NRAS mutations (NRASmut) are the most common, occurring in 10–20% of AML patients. RAS mutations have been linked to leukemic progression in myelodysplastic syndrome and an inferior outcome in AML by some researchers;9, 10, 11, 12, 13 whereas other studies have reported no survival difference in AML patients harboring RAS mutations compared with those without RAS mutations.14, 15 Still other reports have suggested the presence of a RAS mutation may actually improve survival and/or response to therapy.15 Here, we report on the incidence and prognostic significance of NRASmut in a large cohort of children with AML who were treated on two recent cooperative group studies.

The presence of NRASmut was correlated with specific cytogenetic and molecular alterations in our study population. NRASmut were similarly distributed among the major cytogenetic groups (Figure 1b). Cytogenetic information was available on 563/901 (62.5%) of the de novo patients treated on CCG-2961. On COG-AAML03P1, 316/340 (93%) of patients had available cytogenetic data of which 185/316 (59%) were centrally reviewed. Of the 86 NRASmut patients, 68 had cytogenetic information available for further comparisons, of whom 17 (25%) had a normal karyotype and another 17 (25%) had abnormalities of chromosome 11q23. These frequencies were comparable to those found with wild-type NRAS. Deletions or monosomies of chromosome 7 [-7/del(7q)] were rare in patients with NRASmut (3%) and no patient with NRASmut had monosomy 5 or del (5q) (Figure 1b). NRASmut has been previously found to correlate with abnormalities of chromosomes 3 [inv(3)/t(3;3), t(3;5)]15, 16 and 16 [inv(16)/t(16;16)], 16 however, this was not found in our study. Seven percent of NRASmut were associated with t(6;9)(p23;q24) compared with only 2% of wild-type NRAS (P=0.014). However, the presence of NRASmut had no impact on the poor prognosis of patients with t(6;9)(p23;q24), who demonstrated 3-year overall survival (OS) of 0% vs 38±34% (P=0.696) and event-free survival (EFS) of 0% vs 16±32% (P=0.986) for NRASmut and wild-type patients, respectively. t(6;9)(p23;q24) translocations were frequently associated with the poor prognostic marker FLT3-ITD, even in NRASmut patients (2/5 patients with t(6;9) and NRASmut; 7/9 with t(6;9) and wild-type NRAS), in which FLT3-ITD was uncommon (see below). Correlation of NRASmut with common mutations in AML was also determined. FLT3-ITD appeared to be less common in those with NRASmut (7 vs 13%, P=0.115); whereas NPM1 mutations were significantly more common in those with NRASmut (16 vs 6%, P=0.003) compared with wild type. There was no association observed between NRASmut and CEBPA or WT1 mutations (Figure 1c). Five patients with NRASmut and WT1 mutations had a third abnormality (t(8;21), 2 patients; inv(16), 2 patients and t(9;11), 1 patient). Overall, 77 of 86 patients with NRASmut (90%) had at least one additional mutation or cytogenetic abnormality (Supplementary Figure 1).

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Acknowledgements

AAML03P1 and CCG 2961 are funded by grants U10 CA98543 and U10 CA98413. Myeloid Leukemia Reference Laboratory is supported by U10 CA114766.

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Authors and Affiliations

  1. Department of Pediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada

    J N Berman

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

    J N Berman, R B Gerbing, T A Alonzo & S Meshinchi

  3. Department of Biostatistics, University of Southern California, Los Angeles, CA, USA

    T A Alonzo

  4. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    P A Ho, K Miller & S Meshinchi

  5. Department of Pediatrics, University of Washington, Seattle, WA, USA

    P A Ho & S Meshinchi

  6. Reata Pharmaceuticals, Dallas, TX, USA

    C Hurwitz

  7. Department of Pathology, The Ohio State University, Columbus, OH, USA

    N A Heerema

  8. Department of Laboratory Medicine and Pathology, University of Minnesota Cancer Center, Minneapolis, MN, USA

    B Hirsch

  9. Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA

    S C Raimondi

  10. Department of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    B Lange

  11. Amgen Pharmaceuticals, Thousand Oaks, CA, USA

    J L Franklin

  12. Division of Hematology/Oncology/Bone Marrow Transplantation, Children′s Mercy Hospital & Clinics, Kansas City, MO, USA

    A Gamis

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Correspondence to S Meshinchi.

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Competing interests

Dr Craig Hurwitz is employed by Reatta Pharmaceuticals and Dr Janet Franklin is employed by Amgen Pharmaceuticals. The other authors declare no conflict of interest.

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Berman, J., Gerbing, R., Alonzo, T. et al. Prevalence and clinical implications of NRAS mutations in childhood AML: a report from the Children's Oncology Group. Leukemia 25, 1039–1042 (2011). https://doi.org/10.1038/leu.2011.31

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