Hyperdiploidy: the longest known, most prevalent, and most enigmatic form of acute lymphoblastic leukemia in children

Abstract

Hyperdiploidy is the largest genetic entity B-cell precursor acute lymphoblastic leukemia in children. The diagnostic hallmark of its two variants that will be discussed in detail herein is a chromosome count between 52 and 67, respectively. The classical HD form consists of heterozygous di-, tri-, and tetrasomies, whereas the nonclassical one (usually viewed as “duplicated hyperhaploid”) contains only disomies and tetrasomies. Despite their apparently different clinical behavior, we show that these two sub-forms can in principle be produced by the same chromosomal maldistribution mechanism. Moreover, their respective array, gene expression, and mutation patterns also indicate that they are biologically more similar than hitherto appreciated. Even though in-depth analyses of the genomic intricacies of classical HD leukemias are indispensable for the elucidation of the disease process, the ensuing results play at present surprisingly little role in treatment stratification, a fact that can be attributed to the overall good prognoses and low relapse rates of the concerned patients and, consequently, their excellent treatment outcome. Irrespective of this underutilization, however, the detailed genetic characterization of HD leukemias may, especially in planned treatment reduction trials, eventually become important for further treatment stratification, patient management, and the clinical elucidation of outcome data. It should therefore become an integral part of all upcoming treatment studies.

Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL

“…Moreover, there is no clear agreement on the optimal method of defining high hyperdiploidy and its subgroups. 27 Traditional definition of hyperdiploidy using chromosome number using conventional G-banded karyotypic profiling requires a high level of technical expertise, with varying degrees of availability across hospitals. 11 DNA index (DI), which is a surrogate measure of the amount of DNA inside leukemic cells, 28 can be performed more quickly and with greater technical ease 29 ; however, it cannot identify individual chromosome gain or loss.…”

“…11 DNA index (DI), which is a surrogate measure of the amount of DNA inside leukemic cells, 28 can be performed more quickly and with greater technical ease 29 ; however, it cannot identify individual chromosome gain or loss. 27,30 Overall, the utility of these methods for the diagnosis of hyperdiploidy and its subgroups have not yet been directly compared. Therefore, the clinical question of which method is the most optimal for defining hyperdiploidy for low-risk stratification?…”

Optical Genome Mapping Identifies Novel Recurrent Structural Alterations in Childhood ETV6::RUNX1+ and High Hyperdiploid Acute Lymphoblastic Leukemia

“…For instance, studies by Enshaei et al 4 and others highlighted that specific copy number (CN) patterns of HD leukemia may influence prognosis and enable further subclassification in low and poor-risk groups. 1 According to the 2-step model of childhood leukemogenesis, both lesions are acquired in utero during fetal hematopoiesis, and postnatally acquired secondary genetic hits are required for the development of overt disease. 5 Thus, a distinct constellation of secondary structural variants (SVs) and single-nucleotide variants (SNVs) together with the entity-defining key lesion likely drive the leukemic process.…”

“…The 2 most frequent genetic subtypes, encompassing 50%-55% of all childhood BCP-ALL cases are ETV6::RUNX1-translocated (t [12;21] [p13;q22]) BCP-ALL and classical hyperdiploid (HD) BCP-ALL, harboring about 51-67 chromosomes per leukemic cell and comprise heterozygous di-, tri-, and tetrasomies. 1 Both genetic entities usually have excellent therapy responses. Their good outcomes may identify them as candidates for therapy reduction 2 ; however, ≈20% of patients experience a relapse, partly with unknown reason, in a subset of initially diagnosed standard-risk 1 Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University and University Hospital Dusseldorf, Germany 2 Dusseldorf School of Oncology (DSO), Medical Faculty, Heinrich-Heine University, Dusseldorf, Germany patients.…”

Chromosomal Gains as a Favorable Prognostic Factor in Pediatric ALL

“…1 High hyperdiploidy, classically defined as 51-67 chromosomes (Fig 1), constitutes the largest genetic subtype of pediatric ALL and is associated with a superior prognosis. [1][2][3] Genetically, it is characterized by gains of specific chromosomes, with extra copies of chromosomes X, 4, 6, 10, 14, 17, 18, and 21 seen in more than 70% of the cases. The remaining chromosomes are also gained in subsets of cases, but at lower frequencies.…”