Date of Award

Winter 12-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Cancers, including hematologic malignancies, arise as a result of the stepwise accumulation of mutations. Some early mutations that potentially initiate clonal expansion might exist in patients many years before they develop obvious disease symptoms. Therefore, identifying and characterizing these early mutations are critical to understanding the genetic basis of tumorigenesis. Here, we analyzed blood-derived DNA sequencing data from 2,728 individuals without apparent hematologic malignancies and identified 77 blood-specific mutations in 31 cancer-associated genes. Importantly, 83% of all mutations occurred in 19 genes that have been previously linked to hematological malignancies, such as DNMT3A, TET2, JAK2, and ASXL1. By investigating these mutations in different hematologic diseases, we identified several recurrently mutated genes that may be disease initiators. To obtain more comprehensive profiling of genes and variants associated with clonal hematopoietic expansion, we processed an additional 3,221 normal blood samples from The Cancer Genome Atlas (TCGA) and developed a statistical approach to systematically identify blood-specific mutations in all human genes. 26 genes were significantly mutated in human blood samples, including PPM1D. Functional validation showed that PPM1D mutations suppressed the phosphorylation of TP53 at Ser15, suggesting that the blood-specific mutants in PPM1D retain its phosphatase activity in regulating TP53. We also characterized rare copy number variations (CNVs) in blood samples and discovered about half of the individuals examined carried rare somatic CNVs in their blood. Some of these CNVs were associated with genes involved in hematological malignancies, such as JAK2, ASXL1, and FLT3. In summary, we systematically identified early genomic alterations in normal blood cells by utilizing the large-scale sequencing data and further determined the functional impact of the mutations in the recurrently mutated gene. Our comprehensive analysis of blood-specific genomic alterations will shed light on understanding the complex mechanisms of hematologic malignancies and also facilitate the development of more efficient strategies for early detection, prevention, and treatment of hematologic cancer.


English (en)

Chair and Committee

Li Ding

Committee Members

Barak A. Cohen, Todd E. Druley, John R. Edwards, Daniel C. Link


Permanent URL: https://doi.org/10.7936/K7D798V9