Genetic Heterogeneity in Follicular and Plexiform Ameloblastomas

Objectives: 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 identify somatic variants associated with follicular and plexiform ameloblastomas using deep whole-exome sequencing (dWES).
Methods: This study was approved by the University of Missouri Kansas City (UMKC) (#17-042) and the University of Iowa (#201910778) Institutional Review Board. Archived formalin-fixed paraffin-embedded (FFPE) tissue blocks of follicular (n=4) and plexiform (n=6) ameloblastomas were retrieved from the UMKC Department of Oral Pathology, Medicine, and Radiology. A sample of tumour tissue was dissected from the FFPE block and used for genomic DNA isolation via the Covaris® LE220 protocol. Samples were prepared for dWES using the IDT Exome Research Panel (IDT, Coraville, IA). Sequencing (paired end, 150 nucleotide reads) was completed on an Illumina NovaSeq 6000 with an average of 20GB of data resulting in a mean coverage of 400X. Gapped alignment to reference sequences (GRCh37.p5) was performed with Dragen (Illumina) and variant calling with Mutect (Broad Institute). Variant analysis was completed using custom-developed software: RUNES and VIKING.
Results: Our analyses focused on examining somatic variants (gnomAD minor allele frequency <0.1%) in genes found on an FDA-approved clinical cancer sequencing panel (Foundation One). In follicular tumours, variants (>20% of the reads) were identified in BRAF, KMT2D, and ABL1 genes. In plexiform tumours, variants (>20% of the reads) were identified in ALK, BRAF, KRAS, KMT2D, SMO, KMT2A, and BRCA2 genes.
Conclusions: Follicular and plexiform ameloblastomas present with genetic heterogeneity, which may contribute to the aggressive nature and recurrence risk of these tumors. Additional studies are needed to identify differentiating genetic markers between follicular and plexiform ameloblastomas.