Comprehensive Genomic Profiling of Orbital and Ocular Adnexal Lymphomas Identifies Frequent Alterations in MYD88 and Chromatin Modifiers: New Routes to Targeted Therapies

Abstract

Purpose : Non-Hodgkin lymphomas of the eye and surrounding tissues (orbital and ocular adnexal lymphomas, OOALs) are the most common primary orbital malignancy, are increasing in incidence in some populations, and often have high relapse rates and toxicity from localized treatment. Despite recent advances in genomic profiling and precision medicine of cancer in general, orbital tumors remain poorly characterized molecularly.

Methods : We performed targeted next generation sequencing (NGS) profiling of 38 OOAL formalin-fixed paraffin-embedded (FFPE) specimens obtained from a single academic ophthalmology clinic using a panel targeting near-term clinically relevant genes. This panel used is part of the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH) , a clinical trial that has enrolled adults 18 years of age and older with advanced solid tumors and lymphomas that are no longer responding (or never responded) to standard therapy and have begun to grow.

Results : Potentially actionable mutations and copy number alterations (CNAs) were prioritized based on gain- and loss-of function (GoF and LoF, respectively) analyses and catalogued approved and investigational therapies. Of 36 informative samples, 53% harbored a prioritized alteration (median of 1, range 0-5 per sample). MYD88 was the most frequently altered gene in our cohort, with potentially clinically relevant hot-spot GoF mutations identified in 28% of OOALs. Prioritized alterations in epigenetic modulators were common and included GoF EZH2 mutations (of clinical importance) and LoF ARID1A mutations (both in 8% of OOALs). Single prioritized alterations were also identified in the histone methyltransferases KMT2B and KMT3B. Lastly, LoF mutations and CNAs in the tumor suppressors TP53, CDKN2A, PTEN, ATM and NF1, as well as GoF mutations in the oncogenes HRAS and NRAS were also observed.

Conclusions : Taken together, our study demonstrates that NGS can be used to profile routine OOAL FFPE tissue for identification of somatic driving alterations and nomination of potential therapeutic strategies.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.