Comprehensive Genomic Analysis of Cemento-Ossifying Fibroma

Abstract

Cemento-ossifying fibroma (COF) of the jaws is currently classified as a benign mesenchymal odontogenic tumor and only targeted approaches have been used to assess its genetic alterations. A minimal proportion of COFs harbor CDC73 somatic mutations, and copy number alterations (CNAs) involving chromosomes 7 and 12 have recently been reported in a small proportion of cases. However, the genetic background of COFs remains obscure. We used a combination of whole-exome sequencing (WES) and RNA sequencing (RNAseq) to assess somatic mutations, fusion transcripts, and CNAs in a cohort of 12 freshly collected COFs. No recurrent fusions have been identified among the 5 cases successfully analyzed by RNAseq, with in-frame fusions being detected in two cases (MARS1::GOLT1B and PARG::BMS1 in one case, and NCLN::FZR1 and NFIC::SAMD1 in the other) and no candidate fusions identified for the remaining three cases. No recurrent pathogenic mutations were detected in the 11 cases that had undergone WES. A KRAS p.L19F missense variant was detected in one case and two CDC73 deletions were detected in another. The other variants were of uncertain significance and included variants in PC, ACTB, DOK6, HACE1, COL1A2, and previously unreported variants in PTPN14, ATP5F1C, APOBEC1, HDAC5, ATF7IP, PARP2, and ACTR3B. The affected genes do not clearly converge on any signaling pathway. CNAs were detected in 5/11 (45%) cases, with copy gains involving chromosome 12 occurring in 3/11(27%). In conclusion, no recurrent fusions or pathogenic variants have been detected in the present COF cohort, with copy gains involving chromosome 12 occurring in 27% of cases.