@article{701dbebe8bfe43858e6bdde17184b513,
title = "Janus kinase 2 variants associated with the transformation of myeloproliferative neoplasms into acute myeloid leukemia",
abstract = "Background: Canonical Janus kinase 2 (JAK2) V617F and exon 12 mutations in myeloid neoplasms are well described. There are limited reports of other JAK2 variants of potential clinical relevance. This study was designed to survey JAK2 variants in patients with myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML) and to determine their contributions to disease pathogenesis. Methods: Next-generation sequencing of the coding region of JAK2 and 27 other genes was performed on bone marrow DNA samples. The study population was classified into 3 cohorts: chronic MPNs only (the MPN cohort); MPNs transformed into AML (the MPN>>AML cohort); and AML only, with MPN>>AML patients excluded (the AML cohort). Results: Testing was performed for 2154 patients, and non-V617F/non–exon 12 JAK2 sequence variants were identified in 114 (5.3%). They included 35 unique JAK2 variants across all functional domains. Sixteen of the 114 JAK2 variants occurred without somatic mutations in the remaining 27 genes. JAK2 variants were detected at a higher frequency in the MPN>>AML cohort (15.3%) in comparison with the MPN (4.6%; P <.001) and AML cohorts (5.2%; P <.001). Detected variants occurred at higher than expected frequencies in patients with MPNs and AML in comparison with the population, and N1108S had a significantly increased prevalence in patients with AML. A JAK2 variant in addition to JAK2 V617F (n = 13) in myelofibrosis was associated with an increased cumulative risk of transformation into AML (P =.003). Conclusions: Specific JAK2 variants detected in MPNs may be predictors for transformation into AML.",
keywords = "Janus kinase 2, acute myeloid leukemia, myeloproliferative disorders, single-nucleotide polymorphism",
author = "Benton, {Christopher B.} and Boddu, {Prajwal C.} and DiNardo, {Courtney D.} and Prithviraj Bose and Feng Wang and Rita Assi and Naveen Pemmaraju and Devendra, {K. C.} and Sherry Pierce and Keyur Patel and Marina Konopleva and Farhad Ravandi and Guillermo Garcia-Manero and Kadia, {Tapan M.} and Jorge Cortes and Kantarjian, {Hagop M.} and Michael Andreeff and Srdan Verstovsek",
note = "Funding Information: Prithviraj Bose reports grants and personal fees from Incyte Corporation, Celgene Corporation, and Blueprint Medicines Corporation and grants from Constellation Pharmaceuticals, Kartos Therapeutics, CTI BioPharma, Astellas Pharmaceuticals, and Pfizer, Inc, outside the submitted work. The other authors made no disclosures. Funding Information: A total of 3376 patients at The University of Texas MD Anderson Cancer Center (MDACC) were diagnosed either with a chronic MPN or AML between June 1989 and December 2016. They included 2215 patients with AML not transformed from MPNs, 280 with AML transformed from MPNs, and 881 with MPNs. Patient samples with mutational testing limited to exon 12 or 14 of JAK2 alone were not included. Approval was obtained from the MDACC institutional review board, and informed consent was obtained according to the Declaration of Helsinki. A total of 3376 patients at The University of Texas MD Anderson Cancer Center (MDACC) were diagnosed either with a chronic MPN or AML between June 1989 and December 2016. They included 2215 patients with AML not transformed from MPNs, 280 with AML transformed from MPNs, and 881 with MPNs. Patient samples with mutational testing limited to exon 12 or 14 of JAK2 alone were not included. Approval was obtained from the MDACC institutional review board, and informed consent was obtained according to the Declaration of Helsinki. Patients{\textquoteright} bone marrow samples were collected at the time of the MDACC referral. An NGS analysis of a panel of the coding regions of 28 leukemia-associated genes was performed with DNA extracted from the bone marrow samples. Paired-end indexed libraries were sequenced on the Illumina MiSeq platform. Exon and codon sequencing coverage for each of the genes is detailed in Supporting Table 1. The average coverage of bases per sample was 3000 with a minimum of 250 reads needed to call a somatic mutation, and the assay sensitivity was a variant allele frequency of 5% to 10% in the sample. Variants detected by the platform were classified on the basis of their allele frequency in the population, which was determined with an MDACC database in conjunction with currently available reference databases, including the Catalog of Somatic Mutations in Cancer (Wellcome Trust Sanger Institute) and the Single Nucleotide Polymorphism Database (dbSNP; National Institutes of Health). Silent mutations and common genetic polymorphisms (defined as those with a population frequency >20%) were not reported. Variants were analyzed for predicted functional effects with fathmm-MKL, MutationTaster, and Deleterious Annotation of Genetic Variants Using Neural Networks (DANN) via the VarSome platform by Saphetor. Categorical data comparisons were performed with the Fisher exact test. Frequency estimates of variants in our study population were compared against population frequencies in the Exome Aggregate Consortium database. Overall survival was measured from the time of diagnosis until death or was censored on the date of last follow-up. The survival time was estimated with the Kaplan-Meier approach. The cumulative incidence of relapse was estimated with a competing risk regression approach, with death as a competing risk factor. A P value <.05 determined statistical significance. Funding Information: This work was supported by a Leukemia Texas Supporting Grant Award and the National Institutes of Health (MD Anderson Cancer Center Support Grant P30 CA016672 and award P01 CA049639). Publisher Copyright: {\textcopyright} 2019 American Cancer Society",
year = "2019",
month = jun,
day = "1",
doi = "10.1002/cncr.31986",
language = "English (US)",
volume = "125",
pages = "1855--1866",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "11",
}
