Comprehensive genomic profiling of orbital and ocular adnexal lymphomas identifies frequent alterations in MYD88 and chromatin modifiers: new routes to targeted therapies

• Published in: Modern pathology 2016-07, Vol.29 (7), p.685-697
• Main Authors: Cani, Andi K, Soliman, Moaaz, Hovelson, Daniel H, Liu, Chia-Jen, McDaniel, Andrew S, Haller, Michaela J, Bratley, Jarred V, Rahrig, Samantha E, Li, Qiang, Briceño, César A, Tomlins, Scott A, Rao, Rajesh C
• Format: Article
• Language: English
• Subjects: 692/308/2056; 692/308/2778; Aged; Aged, 80 and over; Biomarkers, Tumor - genetics; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p18 - genetics; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein - genetics; Epigenetics; Eye Neoplasms - genetics; Eye Neoplasms - pathology; Female; Gene Expression Profiling; Genomics; Histone-Lysine N-Methyltransferase - genetics; Humans; Laboratory Medicine; Lymphoma; Lymphoma - genetics; Lymphoma - pathology; Male; Medical schools; Medicine; Medicine & Public Health; Middle Aged; Mutation; Nuclear Proteins - genetics; Ophthalmology; original-article; Pathology; Proto-Oncogene Proteins p21(ras) - genetics; PTEN Phosphohydrolase - genetics; Radiation therapy; Transcription Factors - genetics; Tumors
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.2016.79

Non-Hodgkin lymphoma of the orbit and ocular adnexa is the most common primary orbital malignancy. Treatments for low- (extra-nodal marginal zone and follicular lymphomas) and high-grade (diffuse large B-cell lymphoma) are associated with local and vision-threatening toxicities. High-grade lymphomas relapse frequently and exhibit poor survival rates. Despite advances in genomic profiling and precision medicine, orbital and ocular adnexal lymphomas remain poorly characterized molecularly. We performed targeted next-generation sequencing (NGS) profiling of 38 formalin-fixed, paraffin-embedded orbital and ocular adnexal lymphomas obtained from a single-center using a panel targeting near-term, clinically relevant genes. Potentially actionable mutations and copy number alterations were prioritized based on gain- and loss-of-function analyses, and catalogued, approved, and investigational therapies. Of 36 informative samples, including marginal zone lymphomas ( n =20), follicular lymphomas ( n =9), and diffuse large B-cell lymphomas ( n =7), 53% harbored a prioritized alteration (median=1, range 0–5/sample). MYD88 was the most frequently altered gene in our cohort, with potentially clinically relevant hotspot gain-of-function mutations identified in 71% of diffuse large B-cell lymphomas and 25% of marginal zone lymphomas. Prioritized alterations in epigenetic modulators were common and included gain-of-function EZH2 and loss-of-function ARID1A mutations (14% of diffuse large B-cell lymphomas and 22% of follicular lymphomas contained alterations in each of these two genes). Single prioritized alterations were also identified in the histone methyltransferases KMT2B (follicular lymphoma) and KMT3B (diffuse large B-cell lymphoma). Loss-of-function mutations and copy number alterations in the tumor suppressors TP53 (diffuse large B-cell and follicular lymphoma), CDKN2A (diffuse large B-cell and marginal zone lymphoma), PTEN (diffuse large B-cell lymphoma), ATM (diffuse large B-cell lymphoma), and NF1 (diffuse large B-cell lymphoma), and gain-of-function mutations in the oncogenes HRAS (follicular lymphoma) and NRAS (diffuse large B-cell lymphoma) were also observed. Together, our study demonstrates that NGS can be used to profile routine formalin-fixed, paraffin-embedded orbital and ocular adnexal lymphomas for identification of somatic-driving alterations and nomination of potential therapeutic strategies.