Primary mediastinal large B-cell lymphoma genomic profiling demonstrates thymic B-cell identity and frequent aberrant somatic hypermutation
Year: 2026
Type: article
Abstract: Primary mediastinal large B-cell lymphoma (PMBL) is a subtype of non-Hodgkin B-cell lymphoma that most frequently occurs in young adults and is thought to reflect neoplastic transformation of thymic medullary B-cells. We characterized 59 PMBL cases from the Atlas of Blood Cancer Genomes Project. The cohort was predominantly young (median age 35), female (62%), and included individuals from diverse racial backgrounds. Most individuals presented with low-stage disease, favorable ECOG performance status, and high overall survival rate at last follow-up (89%). Whole transcriptome sequencing of 49 PMBL cases revealed gene expression profiles distinct from diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), both activated B cell-like (ABC) and germinal center B cell-like (GCB) cell-of-origin subtypes. PMBLs showed significantly higher expression of thymic B cell-associated genes (p=0.032), supporting their presumed thymic origin. Whole exome and targeted sequencing confirmed recurrent mutations in JAK/STAT, NF-κB signaling, and DNA damage response pathways, with frequent aberrant somatic hypermutation (aSHM) affecting multiple genes. Recurrent copy number alterations included gains at 9p and 12, and losses at 13q. As in prior studies, CIITA rearrangements with diverse partners were recurrent. Although PMBL generally demonstrates excellent outcomes, aSHM-positive cases exhibited inferior progression-free survival (p=0.031), suggesting aSHM as a potential adverse prognostic marker. Our findings further refine the genomic landscape of PMBL and provide new insights into the biology of this neoplasm, with implications for prognostic stratification.
Source: Cancer Research Communications
Authors: Rebecca J. Leeman-Neill, Leonardo P.A. Biral, Devang Thakkar, Chee Leong. Cheng, Shin Yeu. Ong, Sarah L. Ondrejka, Eric Hsi, Jean L. Koff, David L. Jaye, Matthew S. McKinney, Chad M. McCall, Cassandra Love, Jennifer R. Shingleton, Dennis Owusu, Tushar H. Dave, Ayush Batra, Elizabeth Thacker, Clay Parker, Lanie Happ, Amy Chadburn, Mateo Mejia. Saldarriaga, Mary Ann Thompson Arildsen, Ridas Juskevicius, Shaoying Li, Amir Behdad, Carlos Galvez, Abner Louissaint, Dennis P. O'Malley, Andrew Evans, Dina Sameh. Soliman, Rashmi S. Goswami, Jiong Yan, Kikkeri N. Naresh, Sandeep S. Dave, Govind Bhagat
Institutions: Columbia University, Duke University, Singapore General Hospital, Cleveland Clinic, Mayo Clinic, Mayo Clinic in Arizona, Mayo Clinic in Florida, Emory University, Weill Cornell Medicine, Vanderbilt University Medical Center, The University of Texas MD Anderson Cancer Center, Cleveland Clinic Florida, University of Illinois Chicago, Massachusetts General Hospital, NeoGenomics (United States), University of Rochester, Hamad Medical Corporation, University of Toronto, Fred Hutch Cancer Center, Saint Louis University
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,550
OpenAlex ID: W7225779730
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