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Age-related mutations associated with clonal hematopoietic expansion and malignancies

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.

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Figure 1: Blood-specific mutations identified in 58 out of 2,728 TCGA cases from 11 cancer types.
Figure 2: Blood-specific mutations and their association with age.
Figure 3: Low-VAF blood-specific hotspot mutations identified in the TCGA and WHISP cohorts.
Figure 4: Comparison of mutation frequencies in blood samples from 58 TCGA cases with mutations in cancer-associated genes in 151 MPN, 150 MDS, 160 CLL and 200 AML cases.
Figure 5: Clonal expansion model.

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Acknowledgements

This work was supported by US National Cancer Institute grants R01CA180006 to L.D. and PO1CA101937 to T.J.L. and US National Human Genome Research Institute grants U54HG003079 to R.K.W. and U01HG006517 to L.D. M.J.W. is supported by a Leukemia and Lymphoma Society Scholar Award (1230-14), and J.S.W. is supported by R00HL103975. We thank M. Wyczalkowski for suggestions on figures and C. Kandoth on somatic mutation analysis. We also acknowledge The Cancer Genome Atlas as the source of primary data.

Author information

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Authors

Contributions

L.D. designed and supervised research. M.X., C.L., J.W., M.D.M., M.C.W., H.K.S., V.Y., C.A.M., J.S.W., D.C.L., M.J.W., T.J.L., F.C. K.J.J. and L.D. analyzed the data. T.J.L., J.S.W., D.C.L., M.J.W. and J.F.D. provided disease-specific analysis. M.C.W. performed statistical analysis. E.R.M. and R.K.W. directed sequencing experiments. M.X., M.D.M., C.L., M.C.W. and J.F.M. prepared figures and tables. L.D. and F.C. wrote the manuscript. L.D., T.J.L., B.A.O. and M.C.W. revised the manuscript.

Corresponding author

Correspondence to Li Ding.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2 (PDF 538 kb)

Supplementary Table 1

Sample IDs for the 2,728 TCGA cases included in this study. (XLSX 90 kb)

Supplementary Table 2

Samples included in the study and their clinical characteristics. (XLSX 12 kb)

Supplementary Table 3

The distribution of germline variants across 2,728 TCGA samples. TCGA ovarian counts were collected from the previous report (XLSX 10 kb)

Supplementary Table 4

Somatic mutations in 2,241 TCGA tumor samples included in the study. Somatic mutation data are unavailable for a subset of samples. (XLSX 23405 kb)

Supplementary Table 5

Somatic mutations in 3,355 TCGA tumor samples from 12 cancer types used for identifying recurrent mutations. (XLSX 24682 kb)

Supplementary Table 6

Recurrent somatic mutations from 12 TCGA cancer types used for hotspot analysis. (XLSX 859 kb)

Supplementary Table 7

556 cancer-associated genes used in this study. (XLSX 15 kb)

Supplementary Table 8

77 blood-specific events detected in 2,728 cases using our standard discovery pipeline. (XLSX 53 kb)

Supplementary Table 9

Low-level blood-specific events detected in DNMT3A, JAK2, SF3B1, GNAS and IDH2 in TCGA samples. (XLSX 9 kb)

Supplementary Table 10

Deep-sequencing based validation of low-level blood-specific events detected in DNMT3A, JAK2 and SF3B1 in TCGA samples. (XLSX 13 kb)

Supplementary Table 11

Truncation and hotspot variants in four prominent genes (DNMT3A, TET2, JAK2 and ASXL1) involved in HSPC clonal expansion in 6,503 ESP samples. (XLSX 13 kb)

Supplementary Table 12

Rare truncation variants and known hotspot variants detected in DNMT3A, TET2, ASXL1, GNAS, JAK2, SF3B1, IDH1 and IDH2 in 557 WHISP samples. (XLSX 10 kb)

Supplementary Table 13

Exome capture sequencing coverage for 11 TCGA cancer types analyzed. (XLSX 9 kb)

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Xie, M., Lu, C., Wang, J. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 20, 1472–1478 (2014). https://doi.org/10.1038/nm.3733

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