Whole exome sequencing of relapsed/refractory patients expands the repertoire of somatic mutations in diffuse large B‐cell lymphoma

• DOI: 10.1002/gcc.22328
• Publication Date: 2015-11-26T07:57:57Z
• Authors: Sylvain Mareschal; Sydney Dubois; Pierre‐Julien Via...; Philippe Bertrand; Elodie Bohers; Catherine Maingonnat; Jean‐Philippe Jaïs; Bruno Tesson; Philippe Ruminy; Pauline Peyrouze; Christiane Copie‐...; Thierry Fest; Thierry Jo Molina; Corinne Haioun; Gilles Salles; Hervé Tilly; Thierry Lecroq; Karen Leroy; Fabrice Jardin
• Keywords: Exome

Despite the many efforts already spent to enumerate somatic mutations in diffuse large B‐cell lymphoma (DLBCL), previous whole‐genome and whole‐exome studies conducted on patients of mixed outcomes failed at characterizing 30% who will relapse or resist current immunochemotherapies. To address this issue, we performed sequencing normal/tumoral DNA pairs 14 relapsed/refractory (R/R) subclassified by full‐transcriptome arrays (six activated like, three germinal center five primary mediastinal lymphomas), from LNH‐03 LYSA clinical trial program. Aside well‐known DLBCL features, gene pathway level recurrence analyses proposed several interesting leads including TBL1XR1 activating IRF4 insulin regulation pathway. Sequencing‐based copy number analysis defined 23 short recurrently altered regions involving genes such as REL , CDKN2A HYAL2 TP53 . Moreover, it highlighted GNA13 CARD11, MFHAS1 PCLO associated with secondary variant allele amplification events. The lymphomas (PMBL), while unexpected a R/R cohort, showed significantly higher mutation rate ( P = 0.003) provided insights classical Hodgkin related subtype. Novel XPO1 ITPKB were found particularly mutated, along various cytokine‐based signaling pathways. Among these analyses, events NF‐κB preponderant subtypes, confirming its major implication aggressiveness pinpointing new candidate genes. © 2015 Wiley Periodicals, Inc.