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Age-related mutations associated with clonal hematopoietic expansion and malignancies (Nature Medicine)
2015-01-14 11:12 written by ercsb (2024-12-04 05:05 Modify)
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Nature Medicine


Received 29 May 2014
Accepted 21 September 2014
Published online 19 October 2014

 

Age-related mutations associated with clonal
hematopoietic expansion and malignancies


Mingchao Xie,1, 2, n1 Charles Lu,1, n1 Jiayin Wang,1, 2, n1 Michael D McLellan,1, Kimberly J Johnson,3, Michael C Wendl,1, 4, 5, Joshua F McMichael,1, Heather K Schmidt,1, Venkata Yellapantula,1, 2, Christopher A Miller,1, Bradley A Ozenberger,1, 2, John S Welch,2, 6, Daniel C Link,2, 6, Matthew J Walter,2, 6, Elaine R Mardis,1, 2, 4, 6, John F Dipersio,2, 6, Feng Chen,2, 6, Richard K Wilson,1, 2, 4, 6, Timothy J Ley1, 2, 4, 6, & Li Ding

 

 

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.

Background : As  hematopoietic stem/progenitor cell(HSPC)s divide, they accumulate rare random mutations. some mutations confer advantages in self-renewal, proliferation or both.  The frequency of such events appears to increase with age, with a similar trend being found for somatic structural changes in the nuclear genomes of blood cells


Question : what certain genetic mutations may confer advantages to affected HSPCs, resulting in enhanced cell renewal, clonal expansion


How to  :  by analyzing variations in 2,728 blood samples in TCGA. We observed many individuals with age-related hematopoietic clonal mosaicism and concurrent presence of over 60 mutations in 19 leukemia- and/or lymphoma-associated genes.


Concluion:
1)  Our study identified not only genes but also specific mutations, associated with the clonal expansion process. Additional statistical analysis identified low-level (2–10% variant allele fractions (VAFs)) recurrent leukemic mutations, possibly in the early stages of clonal expansion.
2)  DNMT3A, TET2, JAK2, ASXL1, SF3B1  and TP53 have distinct and overlapping roles in the development of myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL) and/or acute myelogenous leukemia (AML).
3)  Finally, these results also incidentally highlight the need for caution when using blood as a reference for a surrogate ‘germline’ genome, especially in older individuals

 

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