Mutational Heterogeneity of Diffuse Large B-cell Lymphoma Highlights Importance of Personalized Medicine

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(ChemotherapyAdvisor) – Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma among adults, harbors “tremendous” gene mutation diversity, with important implications for personalized medicine, according to a study published online ahead of print in the Proceedings of the National Academy of Sciences  (PNAS). Using whole genome and exome sequencing, the authors identified 322 candidate DLBCL cancer genes found to be recurrently mutated in primary DLBCLs.

“We identified a role for a number of known and previously unknown oncogenes” in DLBCL, reported senior author Sandeep S. Dave, MD, of the Duke Institute for Genome Sciences and Policy and Duke Cancer Institute, Duke University, Durham, NC, and coauthors. “Many of these genes, including ARID1A, KIT, and IDH1, have not been previously implicated in DLBCL by any previous study.”

The study “reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients,” they reported.

The authors noted “substantial variation of mutated genes from patient to patient,” consistent with variation observed between recently published studies of DLBCL genetics.

“We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-kB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas.”

“A number of genetic mutations we identified, including those in PIK3CD, KIT, and PDGFRA, suggest therapeutic possibilities in the affected patients,” they wrote.

The authors investigated DLBCL cell line susceptibility to the PI3 kinase inhibitor BKM120 (Novartis) and found that cell lines with MTOR mutations had, on average, “a fivefold higher sensitivity” to PI3 inhibition than 18 cell lines without MTOR mutations (P=0.005).

“These results strongly suggest that the presence of mutations in MTOR is associated with sensitivity to PI3 kinase inhibition,” they wrote.

“Our data suggest that such targeted therapeutic approaches in patients will need to be combined with carefully selected assays for those genetic lesions to better understand their role in response to targeted therapies.”

Abstract 

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