Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high-hyperdiploid B-cell acute lymphoblastic leukemia

Mireia Ramos-Muntada, Juan L. Trincado, Joan Blanco, Clara Bueno, Virginia C. Rodríguez-Cortez, Alex Bataller, Belén López-Millán, Claire Schwab, Margarita Ortega, Pablo Velasco, Maria L. Blanco, Josep Nomdedeu, Manuel Ramírez-Orellana, Alfredo Minguela, Jose L. Fuster, Esther Cuatrecasas, Mireia Camós, Paola Ballerini, Gabriele Escherich, Judith BoerMonique DenBoer, Jesús M. Hernández-Rivas, Maria J. Calasanz, Giovanni Cazzaniga, Christine J. Harrison, Pablo Menéndez, Oscar Molina

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1 Citaat (Scopus)

Samenvatting

B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer. High hyperdiploidy (HHD) identifies the most frequent cytogenetic subgroup in childhood B-ALL. Although hyperdiploidy represents an important prognostic factor in childhood B-ALL, the specific chromosome gains with prognostic value in HHD-B-ALL remain controversial, and the current knowledge about the hierarchy of chromosome gains, clonal heterogeneity and chromosomal instability in HHD-B-ALL remains very limited. We applied automated sequential-iFISH coupled with single-cell computational modeling to identify the specific chromosomal gains of the eight typically gained chromosomes in a large cohort of 72 primary diagnostic (DX, n = 62) and matched relapse (REL, n = 10) samples from HHD-B-ALL patients with either favorable or unfavorable clinical outcome in order to characterize the clonal heterogeneity, specific chromosome gains and clonal evolution. Our data show a high degree of clonal heterogeneity and a hierarchical order of chromosome gains in DX samples of HHD-B-ALL. The rates of specific chromosome gains and clonal heterogeneity found in DX samples differ between HHD-B-ALL patients with favorable or unfavorable clinical outcome. In fact, our comprehensive analyses at DX using a computationally defined risk predictor revealed low levels of trisomies +18+10 and low levels of clonal heterogeneity as robust relapse risk factors in minimal residual disease (MRD)-negative childhood HHD-B-ALL patients: relapse-free survival beyond 5 years: 22.1% versus 87.9%, P < 0.0001 and 33.3% versus 80%, P < 0.0001, respectively. Moreover, longitudinal analysis of matched DX-REL HHD-B-ALL samples revealed distinct patterns of clonal evolution at relapse. Our study offers a reliable prognostic sub-stratification of pediatric MRD-negative HHD-B-ALL patients.

Originele taal-2Engels
Pagina's (van-tot)2899-2919
Aantal pagina's21
TijdschriftMolecular Oncology
Volume16
Nummer van het tijdschrift16
DOI's
StatusGepubliceerd - aug. 2022

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