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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...

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Autores principales: Cani, Andi K., Soliman, Moaaz, Hovelson, Daniel H., Liu, Chia-Jen, McDaniel, Andrew S., Haller, Michaela J., Bratley, Jarred, Rahrig, Samantha, Li, Qiang, Briceño, César A., Tomlins, Scott A., Rao, Rajesh C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925176/
https://www.ncbi.nlm.nih.gov/pubmed/27102345
http://dx.doi.org/10.1038/modpathol.2016.79
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author Cani, Andi K.
Soliman, Moaaz
Hovelson, Daniel H.
Liu, Chia-Jen
McDaniel, Andrew S.
Haller, Michaela J.
Bratley, Jarred
Rahrig, Samantha
Li, Qiang
Briceño, César A.
Tomlins, Scott A.
Rao, Rajesh C.
author_facet Cani, Andi K.
Soliman, Moaaz
Hovelson, Daniel H.
Liu, Chia-Jen
McDaniel, Andrew S.
Haller, Michaela J.
Bratley, Jarred
Rahrig, Samantha
Li, Qiang
Briceño, César A.
Tomlins, Scott A.
Rao, Rajesh C.
author_sort Cani, Andi K.
collection PubMed
description 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 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, 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 hot-spot gain-of-function mutations identified in 71% of diffuse large B-cell 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 (all subtypes), 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 next-generation sequencing 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.
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spelling pubmed-49251762016-10-22 Comprehensive Genomic Profiling of Orbital and Ocular Adnexal Lymphomas Identifies Frequent Alterations in MYD88 and Chromatin Modifiers: New Routes to Targeted Therapies Cani, Andi K. Soliman, Moaaz Hovelson, Daniel H. Liu, Chia-Jen McDaniel, Andrew S. Haller, Michaela J. Bratley, Jarred Rahrig, Samantha Li, Qiang Briceño, César A. Tomlins, Scott A. Rao, Rajesh C. Mod Pathol Article 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 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, 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 hot-spot gain-of-function mutations identified in 71% of diffuse large B-cell 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 (all subtypes), 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 next-generation sequencing 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. 2016-04-22 2016-07 /pmc/articles/PMC4925176/ /pubmed/27102345 http://dx.doi.org/10.1038/modpathol.2016.79 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Cani, Andi K.
Soliman, Moaaz
Hovelson, Daniel H.
Liu, Chia-Jen
McDaniel, Andrew S.
Haller, Michaela J.
Bratley, Jarred
Rahrig, Samantha
Li, Qiang
Briceño, César A.
Tomlins, Scott A.
Rao, Rajesh C.
Comprehensive Genomic Profiling of Orbital and Ocular Adnexal Lymphomas Identifies Frequent Alterations in MYD88 and Chromatin Modifiers: New Routes to Targeted Therapies
title Comprehensive Genomic Profiling of Orbital and Ocular Adnexal Lymphomas Identifies Frequent Alterations in MYD88 and Chromatin Modifiers: New Routes to Targeted Therapies
title_full Comprehensive Genomic Profiling of Orbital and Ocular Adnexal Lymphomas Identifies Frequent Alterations in MYD88 and Chromatin Modifiers: New Routes to Targeted Therapies
title_fullStr Comprehensive Genomic Profiling of Orbital and Ocular Adnexal Lymphomas Identifies Frequent Alterations in MYD88 and Chromatin Modifiers: New Routes to Targeted Therapies
title_full_unstemmed Comprehensive Genomic Profiling of Orbital and Ocular Adnexal Lymphomas Identifies Frequent Alterations in MYD88 and Chromatin Modifiers: New Routes to Targeted Therapies
title_short Comprehensive Genomic Profiling of Orbital and Ocular Adnexal Lymphomas Identifies Frequent Alterations in MYD88 and Chromatin Modifiers: New Routes to Targeted Therapies
title_sort comprehensive genomic profiling of orbital and ocular adnexal lymphomas identifies frequent alterations in myd88 and chromatin modifiers: new routes to targeted therapies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925176/
https://www.ncbi.nlm.nih.gov/pubmed/27102345
http://dx.doi.org/10.1038/modpathol.2016.79
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