Comprehensive genomic profiling of orbital and ocular adnexal lymphomas identifies frequent alterations in MYD88 and chromatin modifiers: new routes to targeted therapies.
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.
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Andi K
AK
Cani
Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA.
Moaaz
M
Soliman
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
Daniel H
DH
Hovelson
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Chia-Jen
CJ
Liu
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Andrew S
AS
McDaniel
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Michaela J
MJ
Haller
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Jarred V
JV
Bratley
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Samantha E
SE
Rahrig
Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA.
Qiang
Q
Li
Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA.
César A
CA
Briceño
Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.
Scott A
SA
Tomlins
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA.|Section of Ophthalmology, Surgical Service, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI, USA.
Rajesh C
0000-0002-5776-8366
RC
Rao
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics; D005134:Eye Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
C112476:ARID1A protein, human; D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; C000619080:KMT2B protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)