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Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0725 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Research Article 2 Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in 3 Cytogenetically Normal Acute Myeloid Leukemia 4 Christopher J. Walker1, Jessica Kohlschmidt1,2, Ann-Kathrin Eisfeld1, Krzysztof Mrózek1, 5 Sandya Liyanarachchi1, Chi Song3, Deedra Nicolet1,2, James S. Blachly1, Marius Bill1, 6 Dimitrios Papaioannou1, Christopher C. Oakes1, Brain Giacopelli1, Luke K. Genutis1, 7 Sophia E. Maharry1, Shelley Orwick1, Kellie J. Archer1,3, Bayard L. Powell4, Jonathan E. Kolitz5, 8 Geoffrey L. Uy6, Eunice S. Wang7, Andrew J. Carroll8, Richard M. Stone9, John C. Byrd1, 9 Albert de la Chapelle1, and Clara D. Bloomfield1 10 1The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 11 2Alliance Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, 12 Columbus, Ohio 13 3The Ohio State University Division of Biostatistics, Columbus, Ohio 14 4Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina 15 5Monter Cancer Center, Zucker School of Medicine at Hofstra/Northwell, Lake Success, New 16 York 17 6Washington University School of Medicine in St. Louis, Siteman Cancer Center, St. Louis, 18 Missouri 19 7Roswell Park Comprehensive Cancer Center, Buffalo, New York 20 8University of Alabama at Birmingham, Birmingham, Alabama 21 9Dana-Farber Cancer Institute, Boston, Massachusetts 22 Short title: UPDs, mutations, and outcome in CN-AML 23 Scientific section: Precision Medicine 1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0725 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 24 Correspondence: Christopher J. Walker, The Ohio State University Comprehensive Cancer 25 Center, 460 W 12th Ave. 894 BRT, Columbus, OH, 43210, USA; phone 614-688-4463, fax: 614- 26 685-0211; e-mail [email protected] or Dr. Clara D. Bloomfield, The Ohio State 27 University Comprehensive Cancer Center, C933 James Cancer Hospital, 460 West 10th 28 Avenue, Columbus, OH 43210-1228, phone: 614-293-7518, fax: 614-366-1637, e-mail: 29 [email protected]. 30 Support: Research reported in this publication was supported by the National Cancer Institute 31 for the National Institutes of Health under Award Numbers U10CA180821, U10CA180882, and 32 U24CA196171 (to the Alliance for Clinical Trials in Oncology); P30CA016058, U10CA180833, 33 U10CA180850, U10CA180861, U10CA180866, U10CA180867, and UG1CA233338; the 34 Leukemia Clinical Research Foundation; the Warren D. Brown Foundation; and by an allocation 35 of computing resources from The Ohio Supercomputer Center. Also supported in part by funds 36 from Novartis (CALGB-10603). The content is solely the responsibility of the authors and does 37 not necessarily represent the official views of the National Institutes of Health. 38 Conflict of Interest Disclosure Statement: The authors declare no potential conflicts of 39 interest. 40 Abstract: 249 words; main text: 2789 words; Tables: 2 Figures: 2 2 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0725 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 41 Abstract 42 Purpose: Uniparental disomy UPD is a way cancer cells duplicate a mutated gene causing loss 43 of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) 44 do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We 45 examined the prognostic significance of UPDs and frequency of LOH in CN-AML patients. 46 Experimental Design: We examined the frequency and prognostic significance of UPDs in a 47 set of 425 adult de novo CN-AML patients who were previously sequenced for 81 genes 48 typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 CN- 49 AML patients younger than 60 years. 50 Results: We detected 127 UPDs in 109 patients. Most UPDs were large and typically 51 encompassed all or most of the affected chromosome arm. The most common UPDs occurred 52 on chromosome arms 13q (7.5% of patients), 6p (2.8%) and 11p (2.8%). Many UPDs 53 significantly co-occurred with mutations in genes they encompassed, including 13q UPD with 54 FLT3-internal tandem duplication (FLT3-ITD) (P<0.001), and 11p UPD with WT1 mutations 55 (P=0.02). Among patients younger than 60 years, UPD of 11p was associated with longer 56 overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In 57 multivariable models that accounted for known prognostic markers including FLT3-ITD and WT1 58 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained 59 association with longer OS. 60 Conclusions: LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 61 13q and 11p might be useful for genetic risk stratification of CN-AML patients. 3 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0725 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 62 Statement of Translational Relevance 63 Acquired uniparental disomy (UPD) is recognized as a common mechanism by which cancer 64 cells can achieve homozygous mutations in oncogenes or tumor suppressor genes. UPDs 65 frequently occur in cytogenetically normal acute myeloid leukemia (CN-AML) patients, and 66 specific UPDs are reportedly associated with patient outcome. Our study reports the largest CN- 67 AML patient set screened for UPDs, to our knowledge. Consistent with previous reports, we 68 found that UPDs often co-occur with mutations in genes they encompass resulting in loss of 69 heterozygosity, including UPD of 13q with FLT3 internal tandem duplication and UPD of 11p 70 with WT1 mutations. In the CN-AML patients younger than 60 years, we found UPD of 13q and 71 UPD of 11p were associated with shorter and longer survival, respectively, even in multivariable 72 models that accounted for known prognostic markers. These results imply that genetic risk 73 stratification of younger CN-AML patients could be improved by the inclusion of UPD testing. 4 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0725 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 74 Introduction 75 Acute myeloid leukemia (AML) is a genetically heterogeneous disease. The prognosis of AML 76 patients is strongly influenced by chromosomal aberrations and gene mutations, and patients 77 are prognostically stratified based on the results of gene sequencing and cytogenetic analysis 78 (1-3). Although genetic risk stratification of AML patients has been well-studied, there remains 79 room for improvement, especially for the cytogenetically normal (CN) group which comprises 80 40-45% of adult patients. For CN-AML patients, the 2017 European LeukemiaNet (ELN) genetic 81 risk stratification guidelines are determined entirely by gene mutations (i.e. mutation of NPM1, 82 RUNX1, ASXL1 and TP53; bi-allelic CEBPA mutations; and FLT3-internal tandem duplication 83 [ITD] allelic ratio). 84 CN-AML patients by definition do not have chromosomal abnormalities detectable by 85 karyotyping (3), but these patients often harbor acquired uniparental disomies (UPDs, also 86 called copy-neutral loss of heterozygosity) (4-10), which are somatic losses of a chromosome or 87 segment with duplication of the homologous chromosome or segment. In cancer development 88 UPDs have been shown to mediate loss of heterozygosity (LOH) of mutated oncogenes and 89 tumor suppressor genes by duplicating the mutant alleles thus resulting in homozygous 90 mutations. 91 The prognostic relevance of UPD in CN-AML has not been adequately investigated, although 92 there is evidence that specific UPDs can impact AML patient outcome (11-20). To better define 93 the utility of UPDs for prognostic risk stratification of CN-AML patients, we herein screened a 94 large cohort of adult de novo CN-AML patients for UPDs and investigated their associations with 95 patient survival and relationship with recurrent gene mutations. 5 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 2, 2019; DOI: 10.1158/1078-0432.CCR-19-0725 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 96 Materials and Methods 97 Patients and cytogenetic analysis 98 Studies were conducted using samples obtained from a cohort of 425 adults with de novo AML 99 aged 17-79 years (median 52 years), with 315 patients younger than 60 years. Patients with 100 acute promyelocytic leukemia, AML secondary to myelodysplastic syndromes, or therapy- 101 related AML, and patients who received allogeneic hematopoietic stem cell transplantation in 102 first complete remission (CR) were not included in the study. This study was limited to patients 103 with CN-AML. Pretreatment cytogenetic analyses of bone marrow samples of all patients were 104 performed by the Cancer and Leukemia Group B (CALGB)-approved institutional laboratories 105 using short-term (24-48 hours) unstimulated cultures, and all karyotypes were centrally 106 reviewed (21). In each case, ≥20 metaphase cells were analyzed and no clonal abnormality was 107 found. All patients were similarly treated on CALGB trials (21-33) and did not die within 30 days 108 (see Supplementary Methods for details).
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