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

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. Acute myeloid leukemia (AML) is a heterogeneous disease that represents the most frequent type of acute leukemia in adults. Conventional cytogenetic studies have shown that cytogenetic alterations are frequent in AML, being useful for diagnosis, classification and prognosis purposes 1. However, almost 50% of the patients present an apparently normal karyotype (NK) by conventional cytogenetic techniques. In addition, the prognosis of these patients is very heterogeneous suggesting that cryptic alterations not detectable with such conventional methods may be able to develop the disease, having different prognostic implications. 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. Moreover, the study of matched germline/tumor tissues allows detecting acquired alterations and, therefore, those involved in the leukemogenesis. During the last decade, several studies have been carried out using SNP-A with

The Prognostic Value and Function of HOXB5 in Acute Myeloid Leukemia

“…Currently, chromosomal variations and gene mutations are considered the main factors in the pathogenesis of AML and are combined to assess the cytogenetic risk for prognostic prediction and treatment selection (Alharbi et al, 2013;Meyer and Levine, 2014;Döhner et al, 2017;Nagy et al, 2019). However, nearly 50% of AML patients harbor a normal karyotype, and some of them even lack common somatic mutations (Ibáñez et al, 2020). Thus, it is important to explore new potential factors with prognostic significance and/or roles in leukomogenesis.…”

Regions of homozygosity confer a worse prognostic impact in myelodysplastic syndrome with normal karyotype

“…Although molecular studies are becoming more and more essential for MDS diagnosis and stratification [ 2 ], SNP microarrays are valuable complementary techniques. An AML study using SNP microarrays showed that 50–100% of cases harboring deletions or ROH, in distinct myeloid genes, show point mutations of the same genes [ 13 ]. Detection of CNA and ROH is important, especially to determine the TP53 status in MDS.…”

MLPA in the initial genetic screening of patients with acute myeloid leukemia

“…The choice of methods in addition to cytogenetics depends on several factorsresources of the diagnostic or clinical entity, number of patients, recruitment, equipment, financing, and/or the possibility and practice of outsourcing such services [5]. In Bulgaria, current national healthcare politics do not provide next-generation sequencing (NGS) or single nucleotide polymorphism (SNP)-array on patients with hematological malignancies so regardless of being the most highly esteemed methods in the developed world [6][7][8][9], they remain inaccessible for most in need. This issue creates a demand for an inexpensive, yet reliable and wide-ranging option with a short turnaround time (TAT).…”