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than those who did not have a CD mutation ( p < 0.001 ). However , only 12.6 percent ( n = 177 / 1,403 ) of patients had mutations in the 18 known CD genes . “ Targeting known pre-leukemic driver mutations may address only a fraction of the at-risk individuals ,” the authors wrote , noting that a deeper understanding of the nature and risk factors of CH is necessary .
Of the 246 patients with CD mutations , 177 ( 72 %) were also WGS outliers and that proportion increased significantly with age ( p < 0.001 ), the authors wrote .
WGS outliers had significantly higher rates of all-cause mortality ( hazard ratio [ HR ] = 1.18 ; p = 2.7x10 -4 ), and participants with CD mutations were also at increased risk , regardless of WGS outlier status ( HR = 1.30 ; p = 0.0042 ). To place these results in context , the authors determined that the effect of CH on mortality rate is similar to the effect of having ever smoked ( HR = 1.19 ; p < 0.001 ).
CH , per outlier status , was also associated with a “ substantially increased risk ” of developing a hematologic malignancy 6 months after sampling ( HR = 2.43 ; p = 9.0x10 -5 ), and the risk increased with the number of mosaic somatic mutations , to an HR of 42.2 ( p = 1.3x10 -9 ) in those with > 250 mutations .
Compared with a control cohort of 1,482 phenotypes from the deCODE database , the authors found significant associations between WGS outlier status and smoking , treatment for addiction , psychiatric disease , smoking-related diseases , and chronic pulmonary disease ( p < 0.001 for all ).
Shorter telomeres and loss of the Y chromosome also showed significant associations with CH ( p = 1.0x10 -3 and p = 5.02x10 -110 , respectively ), suggesting that “ telomerase activity might have a role in CH ,” the researchers wrote . On multivariate regression analysis , both telomere length ( p = 0.008 ) and rs34002450 genotype ( p = 0.003 ) were significantly independent predictors of WGS outlier status .
“ The ability to identify CH cases presents opportunities for monitoring and intervention . … Clearly a deeper understanding of the nature and associated risks of CH would be valuable ,” the authors concluded .
“ Because so many of our cases have no detectable driver
mutation , we speculated whether clonal hematopoiesis might in some cases arise spontaneously through neutral drift in the hematopoietic stem cell population ,” Dr . Stefánsson said . “ We used modelling to show that this is plausible , particularly if the active stem cell population is small or has poor fitness .”
The study findings are potentially limited because the detection methods used to identify CD mutations may not have had high enough sensitivity levels . In addition , the WGS outlier method the researchers used was “ likely to under-report CH ” in younger individuals because they had not accumulated enough mosaic somatic mutations to qualify as outliers . ●
Drs . Zink , Stacey , and Norddahl are employees of deCODE Genetics , a subsidiary of Amgen .
REFERENCE
Zink F , Stacey SN , Norddahl GL , et al . Clonal hematopoiesis , with and without candidate driver mutations , is common in the elderly . Blood . 2017 May 8 . [ Epub ahead of print ]
Focus on BTK : Know what ’ s outside the lines
• Bruton tyrosine kinase ( BTK ) plays a critical role in the B-cell receptor signaling pathway , which is responsible for normal B-cell development , function , and survival 1 , 2
• BTK has been implicated in the pathogenesis of B-cell malignancies , and has emerged as a therapeutic target 1
• BTK is a member of a family of kinases that share a similar protein structure 3-5
To learn more about the role of BTK in B-cell malignancies , visit FocusOnBTK . com
References : 1 . Rickert RC . New insights into pre-BCR and BCR signalling with relevance to B cell malignancies . Nat Rev Immunol . 2013 ; 13 ( 8 ): 578-591 . 2 . Hendriks RW , Yuvaraj S , Kil LP . Targeting Bruton ’ s tyrosine kinase in B cell malignancies . Nat Rev Cancer . 2014 ; 14 ( 4 ): 219-232 . 3 . Berglöf A , Hamasy A , Meinke S , et al . Targets for ibrutinib beyond B cell malignancies . Scand J Immunol . 2015 ; 82 ( 3 ): 208-217 . 4 . Takesono A , Finkelstein LD , Schwartzberg PL . Beyond calcium : new signaling pathways for Tec family kinases . J Cell Sci . 2002 ; 115 ( Pt 15 ): 3039-3048 . 5 . Mano H . Tec family of protein-tyrosine kinases : an overview of their structure and function . Cytokine Growth Factor Rev . 1999 ; 10 ( 3-4 ): 267-280 .
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