The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia. (2nd June 2021)

• Record Type: Journal Article
• 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.; van Delft, Frederik W.
• Is Part Of: Cancer medicine. Volume 10:Number 14(2021)
• Page Start: 4864
• Page End: 4873
• Publication Date: 2021-06-02
• Subjects: clonal selection -- genomics -- relapse -- T‐ALL -- teenagers and young adults; 616.994005
• DOI: 10.1002/cam4.4024
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: 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. Abstract : 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.