The Genetic Landscape of Ocular Adnexa MALT Lymphoma Reveals Frequent Aberrations in NFAT and MEF2B Signaling Pathways

Author:

Magistri Marco1,Happ Lanie E.2,Ramdial Jeremy1ORCID,Lu XiaoQing1,Stathias Vasileios34,Kunkalla Kranthi5,Agarwal Nitin5,Jiang Xiaoyu1ORCID,Schürer Stephan C.34ORCID,Dubovy Sander R.6,Chapman Jennifer R.5,Vega Francisco5ORCID,Dave Sandeep2,Lossos Izidore S.13ORCID

Affiliation:

1. Division of Hematology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.

2. Center for Genomic and Computational Biology and Department of Medicine, Duke University, Durham, North Carolina.

3. Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida.

4. Center for Computational Science, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.

5. Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Miami, Miami, Florida.

6. Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.

Abstract

A comprehensive constellation of somatic nonsilent mutations and copy-number (CN) variations in ocular adnexa marginal zone lymphoma (OAMZL) is unknown. By utilizing whole-exome sequencing in 69 tumors, we define the genetic landscape of OAMZL. Mutations and CN changes in CABIN1 (30%), RHOA (26%), TBL1XR1 (22%), and CREBBP (17%) and inactivation of TNFAIP3 (26%) were among the most common aberrations. Candidate cancer driver genes cluster in the B-cell receptor (BCR), NF-κB, NOTCH, and NFAT signaling pathways. One of the most commonly altered genes is CABIN1, a calcineurin inhibitor acting as a negative regulator of the NFAT and MEF2B transcriptional activity. CABIN1 deletions enhance BCR-stimulated NFAT and MEF2B transcriptional activity, while CABIN1 mutations enhance only MEF2B transcriptional activity by impairing binding of mSin3a to CABIN1. Our data provide an unbiased identification of genetically altered genes that may play a role in the molecular pathogenesis of OAMZL and serve as therapeutic targets. Significance: We report systematic application of whole-exome sequencing and CN variations in OAMZL, revealing common alterations in regulation of NFAT signaling pathway that may facilitate identification of new therapies.

Funder

HHS | NIH | National Cancer Institute

Anthony Rizzo Families Foundation

Jaime Erin Follicular Lymphoma Research Consortium

Publisher

American Association for Cancer Research (AACR)

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