Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence

作者：Giulio Genovese, Anna K. Kähler, Robert E. Handsaker, Johan Lindberg, Samuel A. Rose, Samuel F. W. Bakhoum, Kimberly Chambert, Eran Mick, Benjamin M. Neale, Menachem Fromer, Shaun Purcell, Oscar Svantesson, Mikael Landén, Martin Höglund, Sören Lehmann, Stacey B. Gabriel, Jennifer L. Moran, Eric S. Lander, Patrick F. Sullivan, Pamela B. Sklar, Henrik Grönberg, Christina M. Hultman, Steven A. McCarroll · 发表于：New England Journal of Medicine · 年份：2014 · DOI：10.1056/nejmoa1409405 · 被引用次数：3596 · 研究领域：Acute Myeloid Leukemia Research、Cancer Genomics and Diagnostics、Myeloproliferative Neoplasms: Diagnosis and Treatment

BACKGROUND: Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. METHODS: We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. RESULTS: Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. CONCLUSIONS: Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingl...