TBL1XR1 Mutations in Primary Marginal Zone Lymphomas of Ocular Adnexa are Associated with Unique Morphometric Phenotypes

ABSTRACT

Purpose

Extranodal marginal zone B-cell lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT) that affects the ocular adnexa, also known as ocular adnexal MALT lymphomas (OAML), are low-grade lymphomas that mostly affect elderly individuals. This study was conducted to explore the genetic and microbial drivers of OMAL, and unique morphometric phenotypes associated with these mutations and infections.

Materials and Methods

In this study, we performed targeted deep sequencing of 8 OAML cases to identify its potential genetic and microbial drivers. We additionally performed computational digital image analysis of cases to determine if morphologic features corresponded to genetic mutations and disease biology.

Results

We identified TBL1XR1 as recurrently mutated in OAML (4/8), and mutations in several other oncogenes, tumor suppressors, transcription regulators, and chromatin remodeling genes. Morphologically, OAML cases with mutations in TBL1XR1 showed lymphoma cells with significantly lower circularity and solidity by computational digital image analysis (p-value <0.0001). Additionally, cases of OAML with mutations in TBL1XR1 showed equivalent or increased vascular density compared to cases without mutations in TBL1XR1. Finally, we did not find any infectious microbial organisms associated with OAML.

Conclusions

Our study showed recurrent mutations in TBL1XR1 are associated with unique morphometric phenotypes in OMAL cases. Additionally, mutations in genes associated with the methylation status of histone 3, nuclear factor (NF)-κB pathway, and NOTCH pathway were enriched in OMAL cases. Our findings have biologic and clinical implications as mutations in TBL1XR1 and other genes have the potential to be used as markers for the diagnosis of OAML, and also demonstrate a specific biologic phenotypic manifestation of TBL1XR1 mutations.

KEYWORDS:

• Extranodal Marginal Zone Lymphoma
• ocular adnexa
• OAML
• mutation analysis

Authorship

DJ wrote the manuscript, analyzed data, and performed experiments. KS, AB, and PS edited the manuscript, analyzed data, and performed experiments. EDP designed research and edited the manuscript. RSO conceived of and designed the study, wrote the manuscript, and analyzed data.

Supplementary Material

Supplemental data for this article can be accessed here.

Statement of Ethics

This study was approved by Stanford University’s Institutional Review Board.

Additional information

Funding

This work was funded through grant funding from Agilent Technologies.