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Whole exome sequencing of relapsed/refractory patients expands the repertoire of somatic mutations in diffuse large B ‐cell lymphoma
Author(s) -
Mareschal Sylvain,
Dubois Sydney,
Viailly PierreJulien,
Bertrand Philippe,
Bohers Elodie,
Maingonnat Catherine,
Jaïs JeanPhilippe,
Tesson Bruno,
Ruminy Philippe,
Peyrouze Pauline,
CopieBergman Christiane,
Fest Thierry,
Jo Molina Thierry,
Haioun Corinne,
Salles Gilles,
Tilly Hervé,
Lecroq Thierry,
Leroy Karen,
Jardin Fabrice
Publication year - 2016
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22328
Subject(s) - diffuse large b cell lymphoma , exome sequencing , biology , cdkn2a , cancer research , exome , lymphoma , gene , germinal center , mutation , genetics , b cell , immunology , antibody
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 the 30% of patients who will relapse or resist current immunochemotherapies. To address this issue, we performed whole‐exome sequencing of normal/tumoral DNA pairs in 14 relapsed/refractory (R/R) patients subclassified by full‐transcriptome arrays (six activated B‐cell like, three germinal center B‐cell like, and five primary mediastinal B‐cell lymphomas), from the LNH‐03 LYSA clinical trial program. Aside from well‐known DLBCL features, gene and pathway level recurrence analyses proposed several interesting leads including TBL1XR1 and activating mutations in IRF4 or in the insulin regulation pathway. Sequencing‐based copy number analysis defined 23 short recurrently altered regions involving genes such as REL , CDKN2A , HYAL2 , and TP53 . Moreover, it highlighted mutations in genes such as GNA13 , CARD11, MFHAS1 , and PCLO as associated with secondary variant allele amplification events. The five primary mediastinal B‐cell lymphomas (PMBL), while unexpected in a R/R cohort, showed a significantly higher mutation rate ( P = 0.003) and provided many insights on this classical Hodgkin lymphoma related subtype. Novel genes such as XPO1 , MFHAS1 , and ITPKB were found particularly mutated, along with various cytokine‐based signaling pathways. Among these analyses, somatic events in the NF‐κB pathway were found preponderant in the three DLBCL subtypes, confirming its major implication in DLBCL aggressiveness and pinpointing several new candidate genes. © 2015 Wiley Periodicals, Inc.