Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma
NATURE COMMUNICATIONS
Authors: Arthur, Sarah E.; Jiang, Aixiang; Grande, Bruno M.; Alcaide, Miguel; Cojocaru, Razvan; Rushton, Christopher K.; Mottok, Anja; Hilton, Laura K.; Lat, Prince Kumar; Zhao, Eric Y.; Culibrk, Luka; Ennishi, Daisuke; Jessa, Selin; Chong, Lauren; Thomas, Nicole; Pararajalingam, Prasath; Meissner, Barbara; Boyle, Merrill; Davidson, Jordan; Bushell, Kevin R.; Lai, Daniel; Farinha, Pedro; Slack, Graham W.; Morin, Gregg B.; Shah, Sohrab; Sen, Dipankar; Jones, Steven J. M.; Mungall, Andrew J.; Gascoyne, Randy D.; Audas, Timothy E.; Unrau, Peter; Marra, Marco A.; Connors, Joseph M.; Steidl, Christian; Scott, David W.; Morin, Ryan D.
Abstract
Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3' UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-kappa B pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fc gamma receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.
Evaluation of High-Throughput Genomic Assays for the Fc Gamma Receptor Locus
PLOS ONE
Authors: Hargreaves, Chantal E.; Iriyama, Chisako; Rose-Zerilli, Matthew J. J.; Nagelkerke, Sietse Q.; Hussain, Khiyam; Ganderton, Rosalind; Lee, Charlotte; Machado, Lee R.; Hollox, Edward J.; Parker, Helen; Latham, Kate V.; Kuijpers, Taco W.; Potter, Kathleen N.; Coupland, Sarah E.; Davies, Andrew; Stackpole, Michael; Oates, Melanie; Pettitt, Andrew R.; Glennie, Martin J.; Cragg, Mark S.; Strefford, Jonathan C.
Abstract
Cancer immunotherapy has been revolutionised by the use monoclonal antibodies (mAb) that function through their interaction with Fc gamma receptors (Fc gamma Rs). The low-affinity Fc gamma R genes are highly homologous, map to a complex locus at 1p23 and harbour single nucleotide polymorphisms (SNPs) and copy number variation (CNV) that can impact on receptor function and response to therapeutic mAbs. This complexity can hinder accurate characterisation of the locus. We therefore evaluated and optimised a suite of assays for the genomic analysis of the Fc gamma R locus amenable to peripheral blood mononuclear cells and formalin-fixed paraffin-embedded (FFPE) material that can be employed in a high-throughput manner. Assessment of TaqMan genotyping for FCGR2A-131H/R, FCGR3A-158F/V and FCGR2B-232I/T SNPs demonstrated the need for additional methods to discriminate genotypes for the FCGR3A-158F/V and FCGR2B-232I/T SNPs due to sequence homology and CNV in the region. A multiplex ligation-dependent probe amplification assay provided high quality SNP and CNV data in PBMC cases, but there was greater data variability in FFPE material in a manner that was predicted by the BIOMED-2 multiplex PCR protocol. In conclusion, we have evaluated a suite of assays for the genomic analysis of the Fc gamma R locus that are scalable for application in large clinical trials of mAb therapy. These assays will ultimately help establish the importance of Fc gamma R genetics in predicting response to antibody therapeutics.
COA
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