This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger... Show More
This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
Alternative Stable ID
This study includes 2 datasets:
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The incidence of acute myeloid leukemia (AML) increases with age and mortalityÂ exceeds 90% when diagnosed after age 60. Only 10-15% of cases evolve from a pre-existing myeloproliferative or myelodysplastic disorder; the remaining cases arise deÂ novo without a detectable prodrome and are diagnosed upon development of boneÂ marrow failure. Analysis of diagnostic blood samples has demonstrated that deÂ novo AML is preceded by the accumulation of somatic mutations in pre-leukemicÂ hematopoietic stem and progenitor cells (preL-HSPCs) that subsequently undergoÂ clonal expansion. If individuals in this pre-leukemic phase could be identified,Â methods for determination of risk and monitoring for progression to overt AML could be developed. However recurrent AML mutations also accumulate duringÂ aging in healthy individuals who never develop AML, referred to as age relatedÂ clonal hematopoiesis (ARCH). To distinguish individuals with preL-HSPCs atÂ high risk of developing AML from those with ARCH, we undertook deep targeted sequencingÂ of genes recurrently mutated in AML in blood samplesÂ from 133 individuals in the European Prospective Investigation into Cancer andÂ Nutrition (EPIC) study taken on average 6 years before they developed AML (pre-AML group), together with 683 matched healthy individuals (Control group). Pre-AML cases displayed accelerated age-correlated accumulation of somatic mutations.The identity, number and variant allele frequency (VAF) of mutations differedÂ between the two groups, and were incorporated into a computational model of AMLÂ risk prediction that accurately distinguished pre-AML cases from controls onÂ average 7 years prior to AML development. Our findings provide proof of conceptÂ that early prediction of AML development is feasible in high-risk populations,Â paving the way for early disease detection, monitoring, and potentially prevention.
The discovery of the BRAF V600E mutation in almost all cases of hairy-cell leukemia has led to the widespread adoption of the BRAF inhibitor vemurafenib for treatment of chemotherapy-resistant cases. Impressive responses are reported; however, acquired resistance is common. Whilst diverse mechanisms of vemurafenib resistance have been elucidated in melanoma, the basis of resistance in HCL is unclear. Here we apply whole genome and deep targeted sequencing to investigate resistance mechanisms and potential therapeutic strategies in a patient with aquired resistance to vemurafenib.