The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia

• Published in: Cancer medicine (Malden, MA) Vol. 10; no. 14; pp. 4864 - 4873
• Main Authors: Mansur, Marcela B., Furness, Caroline L., Nakjang, Sirintra, Enshaei, Amir, Alpar, Donat, Colman, Sue M., Minto, Lynne, Irving, Julie, Poole, Beth V., Noronha, Elda P., Savola, Suvi, Iqbal, Sameena, Gribben, John, Pombo‐de‐Oliveira, Maria S., Ford, Tony M., Greaves, Mel F., Delft, Frederik W.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.07.2021; John Wiley and Sons Inc; Wiley
• Subjects: 1-Phosphatidylinositol 3-kinase; Acute lymphoblastic leukemia; Adolescent; Adult; Age Factors; Age groups; AKT protein; Cancer Biology; Chemotherapy; Chromosomes; Chromosomes, Human, Pair 7; Clonal Evolution; clonal selection; DNA methylation; Drug metabolism; Drug resistance; Gene Expression Profiling; Genes; Genetic analysis; Genomic analysis; genomics; Humans; Isochromosomes; Kinases; Leukemia; Lymphatic leukemia; Medical research; Mutation; Notch1 protein; Original Research; p53 Protein; Pathogenesis; Patients; Pediatrics; Point mutation; Polymorphism, Single Nucleotide; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Recurrence; relapse; Retrospective Studies; Sequence analysis; Single-nucleotide polymorphism; teenagers and young adults; TOR protein; T‐ALL; Whole Exome Sequencing; Young Adult; Young adults; United Kingdom > UK; genomics; relapse; teenagers and young adults; T-ALL; clonal selection
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.4024

Background Treatment on risk adapted intensive pediatric protocols has improved outcome for teenagers and young adults (TYA) with T‐cell acute lymphoblastic leukemia (T‐ALL). Understanding the biology of disease in this age group and the genetic basis of relapse is a key goal as patients with relapsed/refractory disease have poor outcomes with conventional chemotherapy and novel molecular targets are required. This study examines the question of whether TYA T‐ALL has a specific biological‐molecular profile distinct from pediatric or adult T‐ALL. Methods Genomic characterization was undertaken of a retrospective discovery cohort of 80 patients aged 15–26 years with primary or relapsed T‐ALL, using a combination of Genome‐Wide Human SNP Array 6.0, targeted gene mutation and promoter methylation analyses. Findings were confirmed by MLPA, real‐time quantitative PCR, and FISH. Whole Exome Sequencing was performed in 4 patients with matched presentation and relapse to model clonal evolution. A prevalence analysis was performed on a final data set of 1,792 individual cases to identify genetic lesions with age specific frequency patterns, including 972 pediatric (1–14 years), 439 TYA (15–24 years) and 381 adult (≥25 years) cases. These cases were extracted from 19 publications with comparable genomic data identified through a PubMed search. Results Genomic characterization of this large cohort of TYA T‐ALL patients identified recurrent isochromosome 7q i(7q) in our discovery cohort (n = 3). Prevalence analysis did not identify any age specific genetic abnormalities. Genomic analysis of 6 pairs of matched presentation – relapsed T‐ALL established that all relapses were clonally related to the initial leukemia. Whole exome sequencing analysis revealed recurrent, targetable, mutations disrupting NOTCH, PI3K/AKT/mTOR, FLT3, NRAS as well as drug metabolism pathways. Conclusions All genetic aberrations in TYA T‐ALL occurred with an incidence similar or intermediate to that reported in the pediatric and adult literature, demonstrating that overall TYA T‐ALL exhibits a transitional genomic profile. Analysis of matched presentation – relapse supported the hypothesis that relapse is driven by the Darwinian evolution of sub‐clones associated with drug resistance (NT5C2 and TP53 mutations) and re‐iterative mutation of known key T‐ALL drivers, including NOTCH1. The DNA molecular profile of teenagers and young adults (TYA) T‐cell acute lymphoblastic leukemia was compared with pediatric and adult data and revealed recurrent isochromosome 7q. All genetic aberrations in TYA T‐ALL occurred with an incidence similar or intermediate to that reported in the pediatric and adult literature, demonstrating that overall TYA T‐ALL exhibits a transitional genomic profile. Relapse is driven by the Darwinian evolution of sub‐clones present at initial diagnosis associated with drug resistance (NT5C2 and TP53 mutations) and re‐iterative mutation of known key T‐ALL drivers, including NOTCH1.