Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response.
Lee Shawn H R et al. Nature medicine 2023 1
Analyzing samples from 805 children with newly diagnosed ALL from three consecutive clinical trials, we determined the ex vivo sensitivity of primary leukemia cells to 18 therapeutic agents across 23 molecular subtypes defined by leukemia genomics. There was wide variability in drug response, with favorable ALL subtypes exhibiting the greatest sensitivity to L-asparaginase and glucocorticoids. Leukemia sensitivity to these two agents was highly associated with MRD although with distinct patterns and only in B cell ALL.
Association of Inherited Genetic Factors With Drug-Induced Hepatic Damage Among Children With Acute Lymphoblastic Leukemia.
Yang Wenjian et al. JAMA network open 2022 12 (12) e2248803
In this genetic association study of 3557 children, adolescents, and young adults receiving ALL therapy, variants in UGT1A1 and PNPLA3 were associated with hyperbilirubinemia and elevated alanine aminotransferase and aspartate aminotransferase levels, respectively. A polygenic risk score–based analysis demonstrated that the UGT1A1 variant was the primary driver of elevated bilirubin levels, while other genetic variants contributed to aminotransferase levels even after adjusting for PNPLA3.
Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features.
Robbe Pauline et al. Nature genetics 2022 11
We report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom’s 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy.
The genomic landscape of pediatric acute lymphoblastic leukemia
SW Brady et al, Nature Genetics, September 1, 2022
Using whole-genome, exome and transcriptome sequencing of 2,754?childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376?putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70?putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions.