Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia
Autor: | Sophia E. Maharry, Clara D. Bloomfield, Marius Bill, Sandya Liyanarachchi, Christopher C. Oakes, Chi Song, Christopher J. Walker, Albert de la Chapelle, Geoffrey L. Uy, Brian Giacopelli, James S. Blachly, Bayard L. Powell, Eunice S. Wang, Shelley Orwick, Jonathan E. Kolitz, Richard Stone, Deedra Nicolet, Kellie J. Archer, Ann-Kathrin Eisfeld, John C. Byrd, Luke K Genutis, Jessica Kohlschmidt, Dimitrios Papaioannou, Krzysztof Mrózek, Andrew J. Carroll |
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Rok vydání: | 2019 |
Předmět: |
Adult
Male 0301 basic medicine Oncology congenital hereditary and neonatal diseases and abnormalities Cancer Research medicine.medical_specialty Myeloid Adolescent Loss of Heterozygosity medicine.disease_cause Disease-Free Survival Article Loss of heterozygosity Cytogenetics Young Adult 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Internal medicine medicine Humans Aged Mutation business.industry Nuclear Proteins Chromosome Cancer Middle Aged Uniparental Disomy Prognosis medicine.disease Uniparental disomy Leukemia Myeloid Acute Leukemia 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Female Tandem exon duplication business |
Zdroj: | Clin Cancer Res |
ISSN: | 1557-3265 1078-0432 |
Popis: | Purpose:Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML.Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years.Results:We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3-internal tandem duplication (FLT3-ITD; P < 0.001), and 11p UPD with WT1 mutations (P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3-ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS.Conclusions:LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML. |
Databáze: | OpenAIRE |
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