Genomic Landscape of CXCR4 Mutations in Waldenström Macroglobulinemia.
OBJECTIVE
Whole-genome sequencing has revealed MYD88 L265P and CXCR4 mutations (CXCR4(mut)) as the most prevalent somatic mutations in Waldenström macroglobulinemia. CXCR4 mutation has proved to be of critical importance in Waldenström macroglobulinemia, in part due to its role as a mechanism of resistance to several agents. We have therefore sought to unravel the different aspects of CXCR4 mutations in Waldenström macroglobulinemia.


METHODS
We have scanned the two coding exons of CXCR4 in Waldenström macroglobulinemia using deep next-generation sequencing and Sanger sequencing in 98 patients with Waldenström macroglobulinemia and correlated with SNP array landscape and mutational spectrum of eight candidate genes involved in TLR, RAS, and BCR pathway in an integrative study.


RESULTS
We found all mutations to be heterozygous, somatic, and located in the C-terminal domain of CXCR4 in 25% of the Waldenström macroglobulinemia. CXCR4 mutations led to a truncated receptor protein associated with a higher expression of CXCR4. CXCR4 mutations pertain to the same clone as to MYD88 L265P mutations but were mutually exclusive to CD79A/CD79B mutations (BCR pathway). We identified a genomic signature in CXCR4(mut) Waldenström macroglobulinemia traducing a more complex genome. CXCR4 mutations were also associated with gain of chromosome 4, gain of Xq, and deletion 6q.


CONCLUSIONS
Our study panned out new CXCR4 mutations in Waldenström macroglobulinemia and identified a specific signature associated to CXCR4(mut), characterized with complex genomic aberrations among MYD88L265P Waldenström macroglobulinemia. Our results suggest the existence of various genomic subgroups in Waldenström macroglobulinemia.
Service d'Hématologie-Immunologie-Cytogénétique, Centre Hospitalier de Valenciennes, France. Laboratoire d'Hématologie, Centre de Biologie et Pathologie, CHRU de Lille, France. INSERM UMR 1172, IRCL, Lille, France.
Stéphanie
S
Poulain
Laboratoire d'Hématologie, Centre de Biologie et Pathologie, CHRU de Lille, France. INSERM UMR 1172, IRCL, Lille, France.
Christophe
C
Roumier
Laboratoire d'Hématologie, Centre de Biologie et Pathologie, CHRU de Lille, France.
Aurélie
A
Venet-Caillault
IFR114, Plateforme de Génomique, Lille, France.
Martin
M
Figeac
INSERM UMR 1172, IRCL, Lille, France. Service des Maladies du Sang, Hôpital Huriez, CHRU, Lille, France.
Charles
C
Herbaux
Université de Lille, UDSL, EA2694 Biostatistics/Inria Lille Nord Europe, MODAL, Lille, France.
Guillemette
G
Marot
Laboratoire d'Hématologie, Centre de Biologie et Pathologie, CHRU de Lille, France.
Emmanuelle
E
Doye
INSERM UMR 1172, IRCL, Lille, France.
Elisabeth
E
Bertrand
Laboratoire d'Hématologie, Centre de Biologie et Pathologie, CHRU de Lille, France.
Sandrine
S
Geffroy
IFR114, Plateforme de Génomique, Lille, France.
Frédéric
F
Lepretre
Laboratoire d'Hématologie, Centre de Biologie et Pathologie, CHRU de Lille, France. INSERM UMR 1172, IRCL, Lille, France.
Olivier
O
Nibourel
Service d'Hématologie-Immunologie-Cytogénétique, Centre Hospitalier de Valenciennes, France.
Audrey
A
Decambron
INSERM UMR 1172, IRCL, Lille, France. Service des Maladies du Sang, Hôpital Huriez, CHRU, Lille, France.
Eileen Mary
EM
Boyle
Laboratoire d'Hématologie, Centre de Biologie et Pathologie, CHRU de Lille, France.
Aline
A
Renneville
Service d'Hématologie-Immunologie-Cytogénétique, Centre Hospitalier de Valenciennes, France.
Sabine
S
Tricot
Service d'Hématologie-Immunologie-Cytogénétique, Centre Hospitalier de Valenciennes, France.
Agnès
A
Daudignon
INSERM UMR 1172, IRCL, Lille, France. IFR114, Plateforme de Génomique, Lille, France.
Bruno
B
Quesnel
Service d'Hématologie-Immunologie-Cytogénétique, Centre Hospitalier de Valenciennes, France.
Patrick
P
Duthilleul
Laboratoire d'Hématologie, Centre de Biologie et Pathologie, CHRU de Lille, France. INSERM UMR 1172, IRCL, Lille, France.
Claude
C
Preudhomme
INSERM UMR 1172, IRCL, Lille, France. Service des Maladies du Sang, Hôpital Huriez, CHRU, Lille, France. xavier.leleu@chru-lille.fr.
Xavier
X
Leleu
D000483:Alleles; D019943:Amino Acid Substitution; D015415:Biomarkers; D016000:Cluster Analysis; D020732:Cytogenetic Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study / Q000379:methods; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics* / Q000378:metabolism / Q000401:mortality
D015415:Biomarkers; C527276:CXCR4 protein, human; D019718:Receptors, CXCR4