Abstract
More than 2% of people exhibit blood-specific mutations in the absence of hematologic disease.
Major finding: More than 2% of people exhibit blood-specific mutations in the absence of hematologic disease.
Approach: Sequencing analysis revealed recurrent mutations in genes associated with hematologic malignancies.
Impact: This analysis identifies mutations that may drive disease initiation and clonal expansion of HSPCs.
Human hematopoietic stem/progenitor cells (HSPC) possess self-renewal properties that allow them to divide for many years in order to regenerate blood cells. Over time, dividing HSPCs acquire mutations that may confer a growth advantage, which when combined with subsequent mutations can lead to hematopoietic malignancies. Previous work suggests that the frequency of these genetic events increases with age and that they can be detected in the absence of overt hematologic disease, prompting Xie, Lu, Wang, and colleagues to characterize the specific set of genes that are mutated in HSPCs and that may promote clonal outgrowth of premalignant cells. Analysis of blood normal control sequence data from 2,728 patients with various types of cancer from The Cancer Genome Atlas identified 77 blood-specific somatic mutations in 31 genes that were absent or present at very low levels in matched tumor samples. Importantly, 83% of all events occurred in 19 genes that have been previously linked to hematopoietic malignancies, including DNMT3A, TET2, JAK2, ASXL1, TP53, SF3B1, BCORL1, ASXL2, and SH2B3, and were present in only a fraction of blood cells. The overall frequency of blood-specific mutations increased with age and was independent of cancer type. Further analysis revealed the presence of additional recurrent mutations with low-level variant allele fractions, suggestive of early clonal expansion, and revealed that more than 2% of individuals harbor blood-specific cancer-associated mutations in the absence of hematologic malignancy. Comparison of these mutations with sequencing data from separate cohorts of patients with hematologic disease revealed both shared and disease-specific mutations, which may represent early initiating events and cooperating events that promote disease progression, respectively. Together, these results highlight age-related mutations that are likely to play a role in driving hematopoietic malignancies and suggest that the presence of blood-specific variants complicates the use of blood as a normal genome reference in sequencing studies.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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