Diversity of the juxtamembrane and TKD1 mutations (exons 13-15) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data.
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Diversity of the juxtamembrane and TKD1 mutations (exons 13-15) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data. / Schnittger, Susanne; Bacher, Ulrike; Haferlach, Claudia; Alpermann, Tamara; Kern, Wolfgang; Haferlach, Torsten.
In: GENE CHROMOSOME CANC, Vol. 51, No. 10, 10, 2012, p. 910-924.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Diversity of the juxtamembrane and TKD1 mutations (exons 13-15) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data.
AU - Schnittger, Susanne
AU - Bacher, Ulrike
AU - Haferlach, Claudia
AU - Alpermann, Tamara
AU - Kern, Wolfgang
AU - Haferlach, Torsten
PY - 2012
Y1 - 2012
N2 - In acute myeloid leukemia (AML) mutations in the juxtamembrane and tyrosine kinase 1 domain (exons 13-15) of the FLT3 gene (FLT3-ITD/LM) are heterogeneous with respect to mutation load, size, and localization. We characterized length and structure of these mutations by fragment analysis and sequencing in 689 AML which were identified among 3,365 (20.5%) newly diagnosed AML (1,803 males, 1,562 females; 15.8-91.8 years). Mutations were heterogeneous in length (median: 63, range: 3-1,236 nucleotides; nt). Most frequent were sizes of 21 (8.4%) or 24 nt (6.0%). Ninety-one different insertion sites were observed (between nt 1,788 and 1,934, according to accession "FLT3 [Ensembl/Havana merge: ENSG00000122025]" with nt 1,856 (n = 41) and 1,863 (n = 35) being most frequent. In addition, 89 different insertion end points were observed between nt 1,790 and 1,994. FLT3-mutation/wild-type ratio was available in 615 patients (median, 0.80; range 0.03-181.73). 128 Patients (20.8%) had ratios <0.3, 334 (54.3%) had ratio ?0.3 <1, 118 (19.2%) ?1, and 35 (5.7%) showed complete loss of the FLT3-wild-type allele. Overall (OS) and event-free (EFS) survival were better for FLT3-negative than FLT3mut normal karyotype patients (P = 0.078 and P = 0.004, respectively) and patients with low level FLT3-mutations had significantly longer OS and EFS compared with high level mutations (FLT3-mutation/wild-type ratio ?1) (P < 0.001 and P = 0.002, respectively). The length of the mutation had no prognostic impact. Mutations localized more 5' were associated with better outcome than more 3'mutations, but no strict association to certain functional domains was detected. In conclusion, FLT3-mutations are extremely heterogenous with mutation load being the most relevant parameter.
AB - In acute myeloid leukemia (AML) mutations in the juxtamembrane and tyrosine kinase 1 domain (exons 13-15) of the FLT3 gene (FLT3-ITD/LM) are heterogeneous with respect to mutation load, size, and localization. We characterized length and structure of these mutations by fragment analysis and sequencing in 689 AML which were identified among 3,365 (20.5%) newly diagnosed AML (1,803 males, 1,562 females; 15.8-91.8 years). Mutations were heterogeneous in length (median: 63, range: 3-1,236 nucleotides; nt). Most frequent were sizes of 21 (8.4%) or 24 nt (6.0%). Ninety-one different insertion sites were observed (between nt 1,788 and 1,934, according to accession "FLT3 [Ensembl/Havana merge: ENSG00000122025]" with nt 1,856 (n = 41) and 1,863 (n = 35) being most frequent. In addition, 89 different insertion end points were observed between nt 1,790 and 1,994. FLT3-mutation/wild-type ratio was available in 615 patients (median, 0.80; range 0.03-181.73). 128 Patients (20.8%) had ratios <0.3, 334 (54.3%) had ratio ?0.3 <1, 118 (19.2%) ?1, and 35 (5.7%) showed complete loss of the FLT3-wild-type allele. Overall (OS) and event-free (EFS) survival were better for FLT3-negative than FLT3mut normal karyotype patients (P = 0.078 and P = 0.004, respectively) and patients with low level FLT3-mutations had significantly longer OS and EFS compared with high level mutations (FLT3-mutation/wild-type ratio ?1) (P < 0.001 and P = 0.002, respectively). The length of the mutation had no prognostic impact. Mutations localized more 5' were associated with better outcome than more 3'mutations, but no strict association to certain functional domains was detected. In conclusion, FLT3-mutations are extremely heterogenous with mutation load being the most relevant parameter.
KW - Adult
KW - Humans
KW - Male
KW - Female
KW - Middle Aged
KW - Aged, 80 and over
KW - Adolescent
KW - Prognosis
KW - Survival Analysis
KW - DNA Mutational Analysis
KW - Molecular Sequence Data
KW - Alleles
KW - Gene Frequency
KW - Genetic Variation
KW - Mutagenesis, Insertional
KW - Exons
KW - fms-Like Tyrosine Kinase 3/genetics
KW - Mutation Rate
KW - Sequence Deletion
KW - Amino Acid Sequence
KW - Karyotype
KW - Leukemia, Myeloid, Acute/diagnosis/genetics/mortality
KW - Protein Structure, Tertiary/genetics
KW - Adult
KW - Humans
KW - Male
KW - Female
KW - Middle Aged
KW - Aged, 80 and over
KW - Adolescent
KW - Prognosis
KW - Survival Analysis
KW - DNA Mutational Analysis
KW - Molecular Sequence Data
KW - Alleles
KW - Gene Frequency
KW - Genetic Variation
KW - Mutagenesis, Insertional
KW - Exons
KW - fms-Like Tyrosine Kinase 3/genetics
KW - Mutation Rate
KW - Sequence Deletion
KW - Amino Acid Sequence
KW - Karyotype
KW - Leukemia, Myeloid, Acute/diagnosis/genetics/mortality
KW - Protein Structure, Tertiary/genetics
M3 - SCORING: Journal article
VL - 51
SP - 910
EP - 924
JO - GENE CHROMOSOME CANC
JF - GENE CHROMOSOME CANC
SN - 1045-2257
IS - 10
M1 - 10
ER -
