Analysis of SNP Array Abnormalities in Patients with DE NOVO Acute Myeloid Leukemia with Normal Karyotype

Mariam Ibáñez,Eva Barragán,Inés Gómez-Seguí,José Cervera,Jorge Sellés,Rafa Andreu,María López-Pavía,Miguel Á Sanz ,Guillermo Sanz,Claudia Sargas,Esperanza Such,Joaquín Martínez‐López ,Rosa Ayala,Esther Onecha,David Hervás‐Marín ,Mireia Boluda-Navarro,Inmaculada Rapado,Alexander Neef ,Leonor Senent,Alejandra Sanjuán-Pla ,Elisa González-Romero ,Alessandro Liquori,Pau Montesinos,Marta Llop

doi:10.1038/s41598-020-61589-9

Abstract

Nearly 50% of patients with de novo acute myeloid leukemia (AML) harbor an apparently normal karyotype (NK) by conventional cytogenetic techniques showing a very heterogeneous prognosis. This could be related to the presence of cryptic cytogenetic abnormalities (CCA) not detectable by conventional methods. The study of copy number alterations (CNA) and loss of heterozygozity (LOH) in hematological malignancies is possible using a high resolution SNP-array. Recently, in clinical practice the karyotype study has been complemented with the identification of point mutations in an increasing number of genes. We analyzed 252 de novo NK-AML patients from Hospital La Fe (n = 44) and from previously reported cohorts (n = 208) to identify CCA by SNP-array, and to integrate the analysis of CCA with molecular alterations detected by Next-Generation-sequencing. CCA were detected in 58% of patients. In addition, 49% of them harbored CNA or LOH and point mutations, simultaneously. Patients were grouped in 3 sets by their abnormalities: patients carrying several CCA simultaneously, patients with mutations in FLT3, NPM1 and/or DNMT3A and patients with an amalgam of mutations. We found a negative correlation between the number of CCA and the outcome of the patients. This study outlines that CCA are present in up to 50% of NK-AML patients and have a negative impact on the outcome. CCA may contribute to the heterogeneous prognosis.

Highlights

The high resolution single-nucleotide polymorphism array (SNP-A) is a powerful tool for the study of copy number alterations (CNA), loss of heterozygosity (LOH) and chromothripsis in hematological malignancies[2,3]
In this study SNP-A, NGS and survival data were analyzed from 120 paired samples of de novo normal karyotype (NK)-acute myeloid leukemia (AML) patients to identify acquired cryptic cytogenetic abnormalities by SNP-A and to integrate analysis of cryptic cytogenetic alterations with molecular alterations detected by targeted sequencing
A detailed list of the CNA and CN-LOH found in these series is shown in Table 2 and Fig. 1

Summary

Introduction

The high resolution single-nucleotide polymorphism array (SNP-A) is a powerful tool for the study of copy number alterations (CNA), loss of heterozygosity (LOH) and chromothripsis in hematological malignancies[2,3]. Several studies have been carried out using SNP-A with www.nature.com/scientificreports the aim of improving the cytogenetic characterization of AML patients. Most of these studies have only analyzed a few dozens of patients, and those that have involved a greater number of patients, either did not analyze systematically matched sample (tumor/germline) or used low density arrays[2,3,4,5,6,7,8,9,10,11,12,13]. To extend our knowledge, we compared our SNP-A findings with data from previously published series, up to a total of 252 patients with de novo NK-AML

Methods

Results

Discussion

Conclusion