Genetic Heterogeneity and Enrichment of Variants in DNA-Repair Genes in Ameloblastoma.

OBJECTIVE: Ameloblastomas are a group of common odontogenic tumors that 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 (dWES).

METHODS: Archived formalin-fixed paraffin-embedded (FFPE) 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 FFPE block. The exomes were enriched using the IDT Exome Research Panel (IDT, Coralville, IA) and paired-end sequencing was completed on an Illumina NovaSeq 6000 with an average output of 20GB of data resulting in a mean coverage of 400X. Variant analysis was completed using custom developed software: RUNES and VIKING.

RESULTS: Our analyses focused on examining somatic variants (gnomAD minor allele frequency ≤1%) in genes found on an FDA-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.

CONCLUSIONS: The 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.