Age-related mutations associated with clonal hematopoietic expansion and malignancies

Mingchao Xie, Charles Lu, Jiayin Wang, Michael D. McLellan, Kimberly J. Johnson, Michael C. Wendl, Joshua F. McMichael, Heather K. Schmidt, Venkata Yellapantula, Christopher A. Miller, Bradley A. Ozenberger, John S. Welch, Daniel C. Link, Matthew J. Walter, Elaine R. Mardis, John F. Dipersio, Feng Chen, Richard K. Wilson, Timothy J. Ley, Li Ding

Research output: Contribution to journalArticlepeer-review

1149 Scopus citations


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.

Original languageEnglish
Pages (from-to)1472-1478
Number of pages7
JournalNature medicine
Issue number12
StatePublished - Dec 1 2014


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