Comprehensive Genomic Profiling of Aggressive Central Giant Cell Lesions

Background: Previously reported comprehensive genomic profiling (CGP) of a patient’s aggressive central giant cell lesion of the jaws (CGCL) demonstrated clinically relevant somatic mutations in KRAS and HRAS genes and novel targeted medical therapy options.¹  These mutations are known oncogenic drivers in other malignancies and possibly contributed to the aggressive behavior of the CGCL. Further information on etiology, prognostication, surgical, and medical therapies for CGCL, particularly aggressive variants, is highly sought.

Purpose:  This pilot study aims to describe somatic mutations present in aggressive CGCL lesions to characterize further utility of CGP in the evaluation of aggressive CGCL patients. 

Methods: Under IRB approval, electronic medical records were searched for patients with histologically confirmed CGCL who underwent biopsy at Mayo Clinic from 2000 through 2014.  Clinical characteristics were recorded from the medical record to stratify each lesion as aggressive or non-aggressive, according to previously published criteria.² Hybridization captured, adaptor ligation-based libraries for 315 cancer-related genes plus introns commonly rearranged in cancer (FoundationOne^TM) from ≥ 50ng of DNA extracted from 8 formalin-fixed paraffin embedded archival aggressive CGCL specimens were sequenced to high, uniform coverage. All classes of genomic alterations were assessed including base substitutions, small insertions and deletions, rearrangements, and copy number alterations.

Results: 3 of 8 aggressive CGCL specimens demonstrated clinically relevant genomic alterations, including base substitutions predicted to be activating in BRAF, GNAS, and KRAS.  In one sample a focal high level amplification of MITF gene mutations was detected. In a fourth sample, a rearrangement of unknown significance in the PDGFRB gene was identified.

Conclusions: This pilot study demonstrates a high rate of clinically relevant genomic alterations in aggressive CGCL that can be identified by CGP; 25% of aggressive CGCL in this study  had somatic mutations predicted to activate the MAP kinase signaling pathway, suggesting its role as a driver of the aggressive behavior of these lesions.  A previously reported patient response to trametinib in the setting of MAPK activating mutations¹ suggests that identification of mutations by CGP may identify novel and effective targeted therapy treatment options in aggressive CGCL. Based on this small pilot study, genomic profiling of a larger cohort of aggressive CGCL to validate these observations, potentially to identify and correlate additional mutations with biologic behavior and therapeutic responses, appears warranted. 

References

1.  Bezak BJ, Elvin J, Markovic S, Viozzi CF. Comprehensive Genomic Profiling of Aggressive Central Giant Cell Lesion Identifies Targeted Therapy Treatment Option With Subsequent Response. J Oral Maxillofac Surg; 73:e42-e3.

2.   Chuong R, Kaban LB, Kozakewich H, Perez-Atayde A. Central giant cell lesions of the jaws: a clinicopathologic study. J Oral Maxillofac Surg 1986; 44:708-13.