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Genes Chromosomes Cancer. 2016 Mar;55(3):251-67. doi: 10.1002/gcc.22328. Epub 2015 Nov 26.

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

Author information

1
INSERM U918, Centre Henri Becquerel, Rouen, France.
2
LITIS, INSA EA 4108, Saint-Etienne-du-Rouvray, France.
3
AP-HP Hôpital Necker, INSERM UMRS 872, Paris, France.
4
Institut Carnot CALYM, Pierre-Bénite, France.
5
Plate-Forme De Génomique Fonctionnelle Et Structurale, Université De Lille 2, Lille, France.
6
AP-HP Hôpital Henri Mondor, INSERM U955, IMRB, Créteil, France.
7
INSERM U917, CHU Pontchaillou, Rennes, France.
8
AP-HP Hôpital Necker, EA 7324, Paris, France.
9
AP-HP Hôpital Henri Mondor, Unité Hémopathies Lymphoïdes, Créteil, France.
10
CNRS UMR 5239, Hospices Civils De Lyon, Lyon, France.

Abstract

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.

PMID:
26608593
DOI:
10.1002/gcc.22328
[Indexed for MEDLINE]

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