Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00085124 NCT00742625 NCT00651261 NCT00006363 NCT00900224 NCT00048958 NCT00899223 NCT00003190.

Conflict of interest statement

Conflict of Interest Disclosure Statement: The authors declare no potential conflicts of interest.

©2019 American Association for Cancer Research.

Figures

Figure 1.

Uniparental disomies (UPDs) in 425 adult patients with de novo cytogenetically normal acute myeloid leukemia. Each orange line represents a single UPD in a single patient. The locations of recurrently mutated genes (mutated in at least 2% of patients) are shown.

Figure 2.

Associations between uniparental disomies (UPDs) and outcome in younger patients (aged A, Overall survival of patients with and without 11p UPD. B, Overall survival and C, disease-free survival of patients with and without 13q UPD. D, Disease-free survival of patients who have FLT3 internal tandem duplications (FLT3-ITD) and either harbor 13q UPD or do not.