Genetic heterogeneity and enrichment of variants in DNA‐repair genes in ameloblastoma

Abstract

AbstractObjectiveAmeloblastomas are a group of relatively common odontogenic tumors that frequently originate from the dental epithelium. These tumors are aggressive in nature and present as slow‐growing painless cortical expansion of the jaw. Histologically, the follicular and plexiform subtypes constitute two‐thirds of solid/multicystic ameloblastomas. The objective of this study was to understand the genetic architecture of follicular and plexiform ameloblastomas using deep whole‐exome sequencing.MethodsArchived formalin‐fixed paraffin‐embedded tissue blocks of follicular (n = 4) and plexiform (n = 6) ameloblastomas were retrieved and genomic DNAs were isolated from the tumor tissue dissected from the formalin‐fixed paraffin‐embedded block. The exomes were enriched using the Integrated DNA Technologies Exome Research Panel (IDT, Coralville, IA) and paired‐end sequencing was completed on an Illumina NovaSeq 6000 with an average output of 20 GB of data resulting in a mean coverage of 400×. Variant analysis was completed using custom‐developed software: Rapid Understanding of Nucleotide variant Effect Software and variant integration and knowledge interpretation in genomes.ResultsOur analyses focused on examining somatic variants (gnomAD minor allele frequency ≤1%) in genes found on an Food and Drug Administration ‐approved clinical cancer sequencing panel (FoundationOne®CDx). In follicular tumors, variants (>20% of the reads) were identified in BRAF, KMT2D, and ABL1 genes. In plexiform tumors, variants (>20% of the reads) were identified in ALK, BRAF, KRAS, KMT2D, SMO, KMT2A, and BRCA2 genes. Enrichment analysis showed a significant role of DNA repair genes in the development of these tumors.ConclusionThe variants identified in follicular and plexiform ameloblastomas were enriched in DNA‐repair genes. The observed genetic heterogeneity in these ameloblastomas may contribute to the aggressive nature and recurrence risk of these tumors.