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Nat Med. 2014 Dec;20(12):1472-8. doi: 10.1038/nm.3733. Epub 2014 Oct 19.

Age-related mutations associated with clonal hematopoietic expansion and malignancies.

Author information

1
1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
2
The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
3
Brown School Master of Public Health Program, Washington University in St. Louis, St. Louis, Missouri, USA.
4
1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA. [3] Department of Mathematics, Washington University in St. Louis, St. Louis, Missouri, USA.
5
1] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
6
1] The Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [3] Department of Genetics, Washington University in St. Louis, St. Louis, Missouri, USA. [4] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.

Abstract

Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.

PMID:
25326804
PMCID:
PMC4313872
DOI:
10.1038/nm.3733
[Indexed for MEDLINE]
Free PMC Article
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