Genomic Characterization of Lymphomas in Patients With Inborn Errors of Immunity Publisher Pubmed



Ye X^{1, 2} ; Maglione PJ³ ; Wehr C^{4, 5} ; Li X^{6, 7} ; Wang Y¹ ; Abolhassani H^{1, 8} ; Deripapa E⁹ ; Liu D^{6, 7} ; Borte S¹⁰ ; Du L¹ ; Wan H¹ ; Plotner A¹¹ ; Giannoula Y¹ ; Ko HB¹² Show All Authors Show Affiliations
Source: Blood Advances Published:2022

Abstract

Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is complex and remains elusive. Here, we perform an in-depth analysis of lymphoma genomes derived from 23 IEI patients. We identified and validated disease-causing or -associated germline mutations in 14 of 23 patients involving ATM, BACH2, BLM, CD70, G6PD, NBN, PIK3CD, PTEN, and TNFRSF13B. Furthermore, we profiled somatic mutations in the lymphoma genome and identified 8 genes that were mutated at a significantly higher level in IEI-associated diffuse large B-cell lymphomas (DLBCLs) than in non-IEI DLBCLs, such as BRCA2, NCOR1, KLF2, FAS, CCND3, and BRWD3. The latter, BRWD3, is furthermore preferentially mutated in tumors of a subgroup of activated phosphoinositide 3-kinase d syndrome patients. We also identified 5 genomic mutational signatures, including 2 DNA repair deficiency-related signatures, in IEI-associated lymphomas and a strikingly high number of inter- and intrachromosomal structural variants in the tumor genome of a Bloom syndrome patient. In summary, our comprehensive genomic characterization of lymphomas derived from patients with rare genetic disorders expands our understanding of lymphomagenesis and provides new insights for targeted therapy. © 2022 by The American Society of Hematology.