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Myelodysplastic syndrome

Landscape of RAS pathway mutations in patients with myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a study of 461 molecularly annotated patients

Leukemia volume 35, pages 644–649 (2021)Cite this article

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RAS pathway mutations are driver mutations in several cancers including myeloid neoplasms. In particular, in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes, RAS pathway mutations are associated with a proliferative phenotype, increased rates of leukemic transformation (LT) and adverse outcomes [1, 2]. In fact, juvenile myelomonocytic leukemia (JMML), a pediatric MDS/MPN overlap syndrome, is a bona fide RASopathy, with germline and somatic mutations in RAS pathway genes giving rise to disease [3]. Whole genome and exome sequencing (WES) studies in MDS/MPN overlap syndromes, including chronic myelomonocytic leukemia (CMML), have shown recurrent somatic mutations involving NRAS, CBL, KRAS, PTPN11, and NF1 [4]. In CMML, RAS pathway mutations are seen in 30% of patients and are commonly associated with MPN-CMML, increased rate of LT and shortened survival [5]. We carried out this study in patients with MDS/MPN overlap neoplasms to (i) define the prevalence and phenotypic correlates of RAS pathway mutations and (ii) assess the prognostic impact of RAS pathway mutations, including individual RAS pathway mutations.

After approval by the Mayo Clinic (Rochester, MN, USA) institutional review board, patients with World Health Organization (WHO)-defined MDS/MPN overlap neoplasms were included in the study [6]. The bone marrow (BM) morphology, cytogenetics and 2016 WHO diagnoses were retrospectively reviewed and all patients underwent targeted next generation sequencing (NGS) for 29 myeloid-relevant genes, obtained on BM mononuclear cells, at diagnosis, or at first referral, by previously described methods [7]. The performance statistics for the NGS assay include minimum depth coverage of 250×, along with a sensitivity of 5% variant allele fraction (VAF) for single base substitutions and insertion/deletion events. Patients were included in this study at first referral only if their diagnosis was within 6 months of referral and provided they had not been treated with disease modifying agents, especially hypomethylating agents (HMA). Prior use of hydroxyurea, erythropoiesis stimulating agents and transfusions were allowed. Germline mutational status in JMML was confirmed by sequencing skin fibroblast-derived DNA. For the purposes of this study, NRAS, CBL, KRAS, and PTPN11 mutations were considered as RAS pathway mutations (given the low frequency, NF1 was not included in the NGS panel). All variants were manually curated to assess pathogenicity. Statistical analyses considered clinical and laboratory parameters obtained at the time of diagnosis or first referral. Continuous variables were presented as median (range) and categorical variables as frequency (percentage). Differences in the distribution of continuous variables between categories were compared by the Mann-Whitney test. Categorical variables were compared using the χ2 test. Overall survival (OS) analysis was computed from the date of diagnosis or first referral to date of death (uncensored) or last contact (censored). Date of LT replaced the date of death, as the uncensored variable, for estimating leukemia-free survival (LFS). The Kaplan–Meier method was used to prepare both OS and LFS curves, which were compared by the log-rank test. The Benjamini–Hochberg correction was used for multiple hypothesis testing (Supplemental methods), with p-values marked with an asterisk identifying those that remained statistically significant after correction to limit the false discovery rate to 5%. Unadjusted p-values were also provided to emphasize potential significance/trend.

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Fig. 1: Germline and somatic RAS pathway mutations in MDS/MPN overlap neoplasms and their impact on overall and leukemia-free survival.

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Acknowledgements

Current publication is supported by a grant from the Henry J. Predolin Foundation for Research in Leukemia, Mayo Clinic, Rochester, MN, USA.

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Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Ajinkya Buradkar, Evandro Bezerra, Giacomo Coltro, Terra L. Lasho, Christy M. Finke, Naseema Gangat, Ryan M. Carr, Moritz Binder, Abhishek A. Mangaonkar, Ayalew Tefferi & Mrinal M. Patnaik

  2. Haematology Unit, Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy

    Giacomo Coltro

  3. CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, AOU Careggi, Firenze, Italy

    Giacomo Coltro

  4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Rhett Ketterling

  5. Division of Pediatric Hematology-Oncology, Mayo Clinic, Rochester, MN, USA

    Shakila Khan & Vilmarie Rodriguez

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  1. Ajinkya Buradkar
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Correspondence to Mrinal M. Patnaik.

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Buradkar, A., Bezerra, E., Coltro, G. et al. Landscape of RAS pathway mutations in patients with myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a study of 461 molecularly annotated patients. Leukemia 35, 644–649 (2021). https://doi.org/10.1038/s41375-020-0889-7

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