title: Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression.
abstract: Primary mediastinal large B cell lymphoma (PMBCL) is an aggressive non-Hodgkin's lymphoma, predominantly affecting young patients. We analyzed 45 primary PMBCL tumor biopsies and 3 PMBCL-derived cell lines for the presence of genetic alterations involving the major histocompatibility complex (MHC) class II transactivator CIITA and found frequent aberrations consisting of structural genomic rearrangements, missense, nonsense, and frame-shift mutations (53% of primary tumor biopsies and all cell lines). We also detected intron 1 mutations in 47% of the cases, and detailed sequence analysis strongly suggests AID-mediated aberrant somatic hypermutation as the mutational mechanism. Furthermore, we demonstrate that genomic lesions in CIITA result in decreased protein expression and reduction of MHC class II surface expression, creating an immune privilege phenotype in PMBCL. In summary, we establish CIITA alterations as a common mechanism of immune escape through reduction of MHC class II expression in PMBCL, with potential implications for future treatments targeting microenvironment-related biology.
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Anja
authors.initials: A
authors.lastname: Mottok
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Bruce
authors.initials: B
authors.lastname: Woolcock
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Bioinformatics Training Program, University of British Columbia, Vancouver, BC V5Z 4S6, Canada.
authors.forename: Fong Chun
authors.initials: FC
authors.lastname: Chan
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: King Mong
authors.initials: KM
authors.lastname: Tong
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Bioinformatics Training Program, University of British Columbia, Vancouver, BC V5Z 4S6, Canada.
authors.forename: Lauren
authors.initials: L
authors.lastname: Chong
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Pedro
authors.initials: P
authors.lastname: Farinha
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Adèle
authors.initials: A
authors.lastname: Telenius
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chavez
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Suvan
authors.initials: S
authors.lastname: Ramchandani
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Drake
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Merrill
authors.initials: M
authors.lastname: Boyle
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Susana
authors.initials: S
authors.lastname: Ben-Neriah
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: Department of Pathology, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rimsza
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Centre for Lymphoid Cancer, Department of Lymphoid Cancer Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada. Electronic address: csteidl@bccancer.bc.ca.
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
mesh_terms: D002460:Cell Line; D004252:DNA Mutational Analysis; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007438:Introns; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008479:Mediastinal Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D017354:Point Mutation; D017384:Sequence Deletion; D015534:Trans-Activators / Q000235:genetics*; D019139:Tumor Escape
chemical_list: D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators