Mutational analysis of JAK2, CBL, RUNX1, and NPM1 genes in familial aggregation of hematological malignancies
- 638 Downloads
Familial aggregation of hematological malignancies has been reported highlighting inherited genetic predisposition. In this study, we targeted four candidate genes: JAK2 and RUNX1 genes assuring a prominent function in hematological process and CBL and NPM1 as proto-oncogenes. Their disruption was described in several sporadic hematological malignancies. The aim of this study is to determine whether JAK2, CBL, RUNX1, and NPM1 germline genes mutations are involved in familial hematological malignancies. Using direct sequencing, we analyzed JAK2 (exons 12 and 14); CBL (exons 7, 8 and 9); NPM1 (exon 12) and the entire RUNX1 in 88 independent families belonging to Tunisian and French populations. Twenty-one sporadic acute leukemias were included in this study. We reported a heterozygous intronic c.1641 + 6 T > C JAK2 variant (rs182123615) found in two independent familial cases diagnosed with gastric lymphoma and Hodgkin lymphoma. The in silico analysis suggested a potential impact on splicing, but the functional splicing minigene reporter assay on rs182123615 variant showed no aberrant transcripts. In one sporadic acute myeloblastic leukemia, we reported an insertion 846 in. TGTT in exon 12 of NPM1 gene that may impact the normal reading frame. The rs182123615 JAK2 variant was described in several contexts including myeloproliferative neoplasms and congenital erythrocytosis and was supposed to be pathogenic. Through this current study, we established the assessment of pathogenicity of rs182123615 and we classified it rather as rare polymorphism.
KeywordsJAK2 CBL RUNX1 NPM1 Familial hematological malignancies
This work was supported by la Société Française d’Hématologie, le groupe Génétique et Cancer and Institut National du Cancer (INCa) and the Ministère de l’Enseignement Supérieur et de la Recherche Scientifique Tunisie. It is a part of the GenHem INSERM/DGRS project. We are grateful for the English correction and assistance provided by Mouna Bouali.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 12.Preudhomme C, Warot-Loze D, Roumier C, Grardel-Duflos N, Garand R, Lai JL et al (2000) High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood 96(8):2862–2871PubMedGoogle Scholar
- 17.Dunbar AJ, Gondek LP, O’Keefe CL, Makishima H, Rataul MS, Szpurka H et al (2008) 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygousmutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res 68(24):10349–10357CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Browne G, Taipaleenmäki H, Bishop NM, Madasu SC, Shaw LM, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2015) Runx1 is associated with breast cancer progression in MMTV-PyMT transgenic mice and its depletion in vitro inhibits migration and invasion. J Cell Physiol 230(10):2522–32CrossRefPubMedGoogle Scholar
- 34.Marcinkowska-Swojak M, Handschuh L, Wojciechowski P, Goralski M, Tomaszewski K, Kazmierczak M et al (2016) Simultaneous detection of mutations and copy number variation of NPM1 in the acute myeloid leukemia using multiplex ligation-dependent probe amplification. Mutat Res 4:14–26CrossRefGoogle Scholar
- 35.dos Santos MT, Mitne-Neto M, Miyashiro K, Chauffaille Mde L, Rizzatti EG (2014) Molecular genetic tests for JAK2V617F, Exon12_JAK2 and MPLW515K/L are highly informative in the evaluationof patients suspected to have BCR-ABL1-negative myeloproliferative neoplasms. J Clin Pathol 67(2):176–184CrossRefPubMedPubMedCentralGoogle Scholar