Clinical significance of genetic aberrations in secondary acute myeloid leukemia
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2012
Authors
Milosević, Jelena D.Puda, Ana
Malcovati, Luca
Berg, Tiina
Hofbauer, Michael
Stukalov, Alexey
Klampfl, Thorsten
Harutyunyan, Ashot S.
Gisslinger, Heinz
Gisslinger, Bettina
Burjanivova, Tatiana
Rumi, Elisa
Pietra, Daniela
Elena, Chiara
Vannucchi, Alessandro M.
Doubek, Michael
Dvorakova, Dana
Robesova, Blanka
Wieser, Rotraud
Koller, Elisabeth
Suvajdžić, Nada
Tomin, Dragica
Tošić, Nataša
Colinge, Jacques
Racil, Zdenek
Steurer, Michael
Pavlović, Sonja
Cazzola, Mario
Kralovics, Robert
Article (Published version)
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The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% +/- 9.4% vs. 35.4% +/- 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mu...tant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.335.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms. Am. J. Hematol., 2012.
Source:
American Journal of Hematology, 2012, 87, 11, 1010-1016Publisher:
- Wiley, Hoboken
Funding / projects:
- Austrian Science Fund
- MPN Research Foundation [P23257-B12]
- Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano) [1005]
- Fondazione Cariplo
- AIRC [9034, MIUR-20084XBENM_002]
- Italian Society of Experimental Hematology (SIES)
- Italian Ministry of Health
- Support of human resources development using the most modern methods and forms of education at JFM CU in Martin [ITMS 26110230031]
- Rare Diseases:Molecular Pathophysiology, Diagnostic and Therapeutic Modalities and Social, Ethical and Legal Aspects (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41004)
- Austrian Science Fund (FWF) [P 23257] Funding Source: researchfish
DOI: 10.1002/ajh.23309
ISSN: 0361-8609
PubMed: 22887079
WoS: 000310246100013
Scopus: 2-s2.0-84867909136
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Institution/Community
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Milosević, Jelena D. AU - Puda, Ana AU - Malcovati, Luca AU - Berg, Tiina AU - Hofbauer, Michael AU - Stukalov, Alexey AU - Klampfl, Thorsten AU - Harutyunyan, Ashot S. AU - Gisslinger, Heinz AU - Gisslinger, Bettina AU - Burjanivova, Tatiana AU - Rumi, Elisa AU - Pietra, Daniela AU - Elena, Chiara AU - Vannucchi, Alessandro M. AU - Doubek, Michael AU - Dvorakova, Dana AU - Robesova, Blanka AU - Wieser, Rotraud AU - Koller, Elisabeth AU - Suvajdžić, Nada AU - Tomin, Dragica AU - Tošić, Nataša AU - Colinge, Jacques AU - Racil, Zdenek AU - Steurer, Michael AU - Pavlović, Sonja AU - Cazzola, Mario AU - Kralovics, Robert PY - 2012 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/590 AB - The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% +/- 9.4% vs. 35.4% +/- 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.335.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms. Am. J. Hematol., 2012. PB - Wiley, Hoboken T2 - American Journal of Hematology T1 - Clinical significance of genetic aberrations in secondary acute myeloid leukemia EP - 1016 IS - 11 SP - 1010 VL - 87 DO - 10.1002/ajh.23309 ER -
@article{ author = "Milosević, Jelena D. and Puda, Ana and Malcovati, Luca and Berg, Tiina and Hofbauer, Michael and Stukalov, Alexey and Klampfl, Thorsten and Harutyunyan, Ashot S. and Gisslinger, Heinz and Gisslinger, Bettina and Burjanivova, Tatiana and Rumi, Elisa and Pietra, Daniela and Elena, Chiara and Vannucchi, Alessandro M. and Doubek, Michael and Dvorakova, Dana and Robesova, Blanka and Wieser, Rotraud and Koller, Elisabeth and Suvajdžić, Nada and Tomin, Dragica and Tošić, Nataša and Colinge, Jacques and Racil, Zdenek and Steurer, Michael and Pavlović, Sonja and Cazzola, Mario and Kralovics, Robert", year = "2012", abstract = "The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% +/- 9.4% vs. 35.4% +/- 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.335.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms. Am. J. Hematol., 2012.", publisher = "Wiley, Hoboken", journal = "American Journal of Hematology", title = "Clinical significance of genetic aberrations in secondary acute myeloid leukemia", pages = "1016-1010", number = "11", volume = "87", doi = "10.1002/ajh.23309" }
Milosević, J. D., Puda, A., Malcovati, L., Berg, T., Hofbauer, M., Stukalov, A., Klampfl, T., Harutyunyan, A. S., Gisslinger, H., Gisslinger, B., Burjanivova, T., Rumi, E., Pietra, D., Elena, C., Vannucchi, A. M., Doubek, M., Dvorakova, D., Robesova, B., Wieser, R., Koller, E., Suvajdžić, N., Tomin, D., Tošić, N., Colinge, J., Racil, Z., Steurer, M., Pavlović, S., Cazzola, M.,& Kralovics, R.. (2012). Clinical significance of genetic aberrations in secondary acute myeloid leukemia. in American Journal of Hematology Wiley, Hoboken., 87(11), 1010-1016. https://doi.org/10.1002/ajh.23309
Milosević JD, Puda A, Malcovati L, Berg T, Hofbauer M, Stukalov A, Klampfl T, Harutyunyan AS, Gisslinger H, Gisslinger B, Burjanivova T, Rumi E, Pietra D, Elena C, Vannucchi AM, Doubek M, Dvorakova D, Robesova B, Wieser R, Koller E, Suvajdžić N, Tomin D, Tošić N, Colinge J, Racil Z, Steurer M, Pavlović S, Cazzola M, Kralovics R. Clinical significance of genetic aberrations in secondary acute myeloid leukemia. in American Journal of Hematology. 2012;87(11):1010-1016. doi:10.1002/ajh.23309 .
Milosević, Jelena D., Puda, Ana, Malcovati, Luca, Berg, Tiina, Hofbauer, Michael, Stukalov, Alexey, Klampfl, Thorsten, Harutyunyan, Ashot S., Gisslinger, Heinz, Gisslinger, Bettina, Burjanivova, Tatiana, Rumi, Elisa, Pietra, Daniela, Elena, Chiara, Vannucchi, Alessandro M., Doubek, Michael, Dvorakova, Dana, Robesova, Blanka, Wieser, Rotraud, Koller, Elisabeth, Suvajdžić, Nada, Tomin, Dragica, Tošić, Nataša, Colinge, Jacques, Racil, Zdenek, Steurer, Michael, Pavlović, Sonja, Cazzola, Mario, Kralovics, Robert, "Clinical significance of genetic aberrations in secondary acute myeloid leukemia" in American Journal of Hematology, 87, no. 11 (2012):1010-1016, https://doi.org/10.1002/ajh.23309 . .