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Characterization of genomic alterations in CIITA and their functional and clinical implications in malignant lymphomas Mottok, Anja

Abstract

Emerging evidence that the interplay between tumour cells and reactive immune cells has profound impact on tumour development, evolution and progression inspired the field of cancer research for the last decade. It has become apparent that the evolutionary pressure exerted by the immune system leads to the evolution of various mechanisms by which tumour cells escape immune surveillance. These often include somatically acquired genetic alterations, resulting in disturbed expression of surface molecules or an altered chemokine/cytokine milieu. B cells play an important role in the adaptive immune response and are potent antigen-presenting cells with high expression of major histocompatibility complexes (MHC) I and II. Multiple studies have reported on defective antigen presentation pathways in malignant lymphomas, however, many of the underlying genetic alterations are largely unexplored. Herein, we applied next generation sequencing techniques and fluorescence in situ hybridization to explore the landscape of genetic alterations in CIITA, the master transcriptional regulator of MHC class II, in various B cell lymphomas and to determine the spectrum of rearrangement partner genes. The functional impact of these mutations on MHC class II expression and the composition of the tumour microenvironment were subsequently evaluated in cell line model systems, and by immunohistochemistry performed on primary lymphoma specimens. Finally, we integrated our findings with patient outcomes to ascertain the clinical impact. We discovered that genomic rearrangements and coding sequence mutations in CIITA are frequent across B cell lymphoma subtypes and can result in diminished MHC class II expression, coinciding with a lower abundance of CD4- and CD8-positive T cells in the tumour microenvironment. We identified that at least some of the genetic alterations are likely a byproduct of AID-mediated somatic hypermutation, as evidenced by the co-occurrence of mutations in the non-coding region of CIITA intron 1. In addition, we described novel translocations involving a broad spectrum of rearrangement partner genes and intra-chromosomal structural variants. In summary, we established CIITA genetic alterations as a frequent immune escape strategy exploited by a variety of malignant B cell lymphomas. These mutations resulted in reduced MHC class II expression and altered microenvironment composition.

Item Metadata

Title
Characterization of genomic alterations in CIITA and their functional and clinical implications in malignant lymphomas
Creator
Mottok, Anja
Publisher
University of British Columbia
Date Issued
2017
Description
Emerging evidence that the interplay between tumour cells and reactive immune cells has profound impact on tumour development, evolution and progression inspired the field of cancer research for the last decade. It has become apparent that the evolutionary pressure exerted by the immune system leads to the evolution of various mechanisms by which tumour cells escape immune surveillance. These often include somatically acquired genetic alterations, resulting in disturbed expression of surface molecules or an altered chemokine/cytokine milieu. B cells play an important role in the adaptive immune response and are potent antigen-presenting cells with high expression of major histocompatibility complexes (MHC) I and II. Multiple studies have reported on defective antigen presentation pathways in malignant lymphomas, however, many of the underlying genetic alterations are largely unexplored. Herein, we applied next generation sequencing techniques and fluorescence in situ hybridization to explore the landscape of genetic alterations in CIITA, the master transcriptional regulator of MHC class II, in various B cell lymphomas and to determine the spectrum of rearrangement partner genes. The functional impact of these mutations on MHC class II expression and the composition of the tumour microenvironment were subsequently evaluated in cell line model systems, and by immunohistochemistry performed on primary lymphoma specimens. Finally, we integrated our findings with patient outcomes to ascertain the clinical impact. We discovered that genomic rearrangements and coding sequence mutations in CIITA are frequent across B cell lymphoma subtypes and can result in diminished MHC class II expression, coinciding with a lower abundance of CD4- and CD8-positive T cells in the tumour microenvironment. We identified that at least some of the genetic alterations are likely a byproduct of AID-mediated somatic hypermutation, as evidenced by the co-occurrence of mutations in the non-coding region of CIITA intron 1. In addition, we described novel translocations involving a broad spectrum of rearrangement partner genes and intra-chromosomal structural variants. In summary, we established CIITA genetic alterations as a frequent immune escape strategy exploited by a variety of malignant B cell lymphomas. These mutations resulted in reduced MHC class II expression and altered microenvironment composition.
Genre
Thesis/Dissertation
Type
Text
Language
eng
Date Available
2017-06-13
Provider
Vancouver : University of British Columbia Library
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
DOI
10.14288/1.0348247
URI
http://hdl.handle.net/2429/61943
Degree
Doctor of Philosophy - PhD
Program
Pathology and Laboratory Medicine
Affiliation
Medicine, Faculty of; Pathology and Laboratory Medicine, Department of
Degree Grantor
University of British Columbia
Graduation Date
2017-09
Campus
UBCV
Scholarly Level
Graduate
Rights URI
http://creativecommons.org/licenses/by-nc-nd/4.0/
Aggregated Source Repository
DSpace

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Attribution-NonCommercial-NoDerivatives 4.0 International