Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma.
Vasiliki LeventakiTimothy I ShawStanley B PoundsXueyuan CaoJing MaGustavo PalaciosJohn MasonSherrie PerkinsGang WuYiping FanJian WangXin ZhouAlyssa ObermayerMarsha KinneyJacqueline KravekaThomas GrossJohn SandlundJinghui ZhangCharles G MullighanMegan LimPublished in: Research square (2024)
Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL(ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA-sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by diferential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK- high group, which had more frequent copy number changes, and was enriched with pathways associated with cell growth, proliferation, metabolic pathways, and. Taken together, these findings suggest that there is molecular heterogeneity within pediatric ALK+ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers.
Keyphrases
- single cell
- advanced non small cell lung cancer
- copy number
- dna methylation
- gene expression
- genome wide
- dna damage
- mitochondrial dna
- diffuse large b cell lymphoma
- epidermal growth factor receptor
- poor prognosis
- transcription factor
- stem cells
- single molecule
- toll like receptor
- inflammatory response
- young adults
- binding protein
- long non coding rna
- dendritic cells