EGAGenomicsABI_SOLID, AB 5500xl Genetic Analyzer, AB SOLiD 4 SystemOtherhttps://ega-archive.org/studies/EGAS00001001889EGAEGA study EGAS00001001889Whole exome sequencing data of germline and two independent primary leukemias of five patientsEGArestrictedgenetic susceptibilities, Networks, para Tyrosine, Family Member, Kinship, postnatal development., predisposition, Hop1, conformation, Neoplasms, postnatal development, Benign Neoplasm, jak, growth and development, Network, genetic predisposition, Tumor, Malignant, Mutations, Susceptibility, HOP, Hop, l(1)L4, IMD35, leukaemia NOS, JTK1, Life Cycle, Mood, 4, Kinase, Leucocythaemia, protein-tyrosine kinase activity, Phosphotransferase, Family Life Cycle, average, DmelCG1594, Tum-1, Genetic, Kinship Network, Genetic Predisposition, Malignancy, Research, Moods, 2-amino-3-(4-hydroxyphenyl)propanoic acid, 3-(p-Hydroxyphenyl)alanine, Tissue, Leucocythemias, Genetic Susceptibilities, blocked, Transphosphorylase, Y, l(1)hop, genetic predispositions, genetic, Neoplasias, L4, Predispositions, L Tyrosine, malignant neoplasm, Clients, Tyr, Janus kinase activity, kinase inhibitor, Malignancies, Tyrosin, Kinship Networks, Family Life Cycles, ATP Phosphotransferases, constitutitional genetic, Family, relational structural quality, ATP, Cancer, Tumors, Malignant Neoplasm, Family Research, Affects, familial, 2-Amino-3-(p-hydroxyphenyl)propionic acid, para-Tyrosine, genetic susceptibility, Client, Leukemias, Phosphotransferases, Tyrosine, Family Members, development, MT, Benign, tirosina, TYK2, inhibition of kinase activity, Neoplasm, Filiation, Genetic Predispositions, d-jak, Leucocythaemias, susceptibility, Transphosphorylases, Leucocythemia, DmHD-160, primary cancer, acute lymphoblastic leukemia (ALL), Kinases, postnatal growth, L-isomer, Benign Neoplasms, Cancers, Predisposition, Children, predispositions, malignant tumor, Susceptibilities, Malignant Neoplasms, L isomer, Life Cycles, Dm JAK, Patient, HD-160, Families, Tum, Genetic Susceptibility, msvl, l(1)G18, inherited genetic, acute lymphoblastic leukaemia (ALL), L-Tyrosine, JAK, Jak, CG1594, l(1)10Be, hereditary, growth, susceptibilities, Relatives, NeoplasiaWES, Complete Transcriptome, Leucocythemia, Complete, Complete Transcriptome Sequencing, Exome Sequencings, Complete Exome Sequencings, Complete Exome, Complete Exome Sequencing, Whole Transcriptome Sequencing, Exome, Leucocythemias, Sequencing, Leukemias, Exome Sequencing, Whole Exome, Client., Patient, Clients, Whole, Whole Exome Sequencing, leukaemia NOS, Whole Transcriptome, Transcriptome Sequencing, Leucocythaemia, Transcriptome Sequencings, LeucocythaemiasfalseWhole exome sequencing data of germline and two independent primary leukemias of five patientsThe contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2, a member of the JAK tyrosine kinase family. These mutations were located in two adjacent codons of the pseudokinase domain (p.Pro760Leu and p.Gly761Val). In silico modeling revealed that both mutations affect the conformation of this auto-regulatory domain. Consistent with this notion, both germline mutations promote TYK2 autophosphorylation and activate downstream STAT family members, which could be blocked with the JAK kinase inhibitor I. These data indicate that germline activating TYK2 mutations predispose to the development of ALL.2017-07-26 15:39:29EGAS000010018899606EGAD00001002266EGAC00001000369