Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia.

[waldenström macroglobulinemia]

Whole genome sequencing has revealed activating somatic mutations in MYD 88 (L 265 P ) and CXCR 4 in Waldenström macroglobulinemia (WM ). CXCR 4 somatic mutations in WM are the first ever reported in human cancer and are similar to nonsense (NS ) and frameshift (FS ) germline mutations found in warts , hypogammaglobulinemia , infections and myelokathexis (WHIM ) syndrome . We genotyped lymphoplasmacytic cells from 175 WM patients and observed significantly higher bone marrow (BM ) disease involvement , serum immunoglobulin-M levels , and symptomatic disease requiring therapy , including hyperviscosity syndrome in those patients with MYD 88 (L 265 P )CXCR 4 (WHIM /NS ) mutations (P < .03 ). Patients with MYD 88 (L 265 P )CXCR 4 (WHIM /FS ) or MYD 88 (L 265 P )CXCR 4 (WILDTYPE (WT )) had intermediate BM and serum immunoglobulin-M levels ; those with MYD 88 (WT )CXCR 4 (WT ) showed lowest BM disease burden . Fewer patients with MYD 88 (L 265 P ) and CXCR 4 (WHIM /FS or NS ) vs MYD 88 (L 265 P )CXCR 4 (WT ) presented with adenopathy (P < .01 ), further delineating differences in disease tropism based on CXCR 4 status . Neither MYD 88 nor CXCR 4 mutations correlated with SDF-1 a (RS 1 801157 ) polymorphisms in 54 patients who were genotyped for these variants . Unexpectedly , risk of death was not impacted by CXCR 4 mutation status , but by MYD 88 (WT ) status (hazard ratio 10 .54 ; 95 % confidence interval 2 .4 -46 .2 , P = .0018 ). Somatic mutations in MYD 88 and CXCR 4 are important determinants of clinical presentation and impact overall survival in WM . Targeted therapies directed against MYD 88 and /or CXCR 4 signaling may provide a personalized treatment approach to WM .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated