NGS profiling refines prognosis and identifies targetable mutations in Mexican pediatric preB-ALL
Investigators analyzed a custom NGS exome panel, chromosomal microarrays, and fusion assays in 73 Mexican children with B-cell precursor acute lymphoblastic leukemia. The molecular screening reduced the unclassified preB-ALL cohort from 63% to 37% by identifying Tier 1 diagnostic variants, while 37% of cases carried intermediate to adverse prognostic markers such as CRLF2 fusions and IKZF1 or TP53 mutations. Nearly one in five patients harbored Tier 2 variants actionable with JAK-STAT or RAS-MAPK inhibitors, and 10% presented potential germline predisposition variants in BRCA1/2 or CHEK2. These findings demonstrate that routine genomic profiling can improve risk stratification, guide targeted therapy selection, and trigger genetic counseling in resource-limited pediatric oncology settings.
The original study
Genomic profiling of Mexican patients with B-cell precursor acute lymphoblastic leukemia reveals clinically significant somatic and potential germline variants.
- Authors
- Martínez Anaya D, Juárez-Velázquez MDR, Juárez Figueroa U, Dean M, Salas Labadía C, Valladares Coyotecatl M, et al.
- Journal
- The journal of pathology. Clinical research
- Type
- Journal Article
- PMID
- 42552995
Original abstract
B-cell precursor acute lymphoblastic leukemia (preB-ALL) is characterized by pathogenic variants currently used in precision oncology. However, the mutational landscape of Mexican children with preB-ALL has not yet been thoroughly explored and defined in terms of the clinical significance. We used a custom-designed next-generation sequencing exome panel, along with high-resolution chromosome microarrays and gene fusion-targeted assays, to characterize the mutational landscape of 73 Mexican children with preB-ALL, exploring the profile of clinically significant variants. We classified the variants following the AMP-ASCO-CAP 2017 and ACMG-CG 2019 guidelines recommendations. The mutational landscape includes a broad molecular spectrum of variants affecting cell cycle regulation, B-cell development, kinase signaling, and epigenetic regulation genes. Tier 1 diagnostic variants allowed the identification of pre-B ALL genetic subtypes, diminishing the preB-ALL NOS group from 63% to 37%. Furthermore, 37% of cases presented Tier 1 variants conferring intermediate to adverse prognoses (primarily involving CRLF2 gene fusions, as well as PAX5, IKZF1, and TP53 inactivating mutations). Notably, these patients exhibited high-risk clinical features and a lower event free survival rate than patients without these variants (60% versus 41.2%; p = 0.046; 95% CI). Between 19% and 42% of patients had Tier 2 variants targetable with JAK-STAT or RAS-MAPK signaling inhibitors. These patients showed a lower overall survival rate than patients without these variants (64% versus 90%; p = 0.048; 95% CI). Tier 1 potential germline variants in cancer predisposition genes (mainly BRCA1/2 and CHEK2) were observed in 10% of patients, some of whom had a family history of cancer. This highlights the importance of genetic counseling for patients and their families. Finally, 33% of patients had Tier 3 variants that were predicted to be deleterious and potentially upgraded to pathogenic with plausible clinical relevance. In conclusion, the mutational landscape analysis revealed variants useful for oncologic management and genetic counseling of Mexican children with preB-ALL.