Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis

Abstract

Aging is characterized by clonal expansion of myeloid-biased hematopoietic stem cells and by increased risk of myeloid malignancies. Exome sequencing of three elderly females with clonal hematopoiesis, demonstrated by X-inactivation analysis, identified somatic TET2 mutations. Recurrence testing identified TET2 mutations in 10 out of 182 individuals with X-inactivation skewing. TET2 mutations were specific to individuals with clonal hematopoiesis without hematological malignancies and were associated with alterations in DNA methylation.

Figure 1. Somatic TET2 mutations are present in normal elderly individuals with myeloid skewing and associated with epigenetic alterations

Exome sequencing identifies somatic TET2 mutation in myeloid cells of an elderly normal subject with non-random X-inactivation (A). LC/MS analysis reveals a decrease in 5-hmC with age and increased 5-mC in PMNs of elderly individuals with TET2 mutations (asterisk indicates p<0.05; arrowheads indicate comparator) (B). This is associated with site-specific hypermethylation and transcriptional silencing (C) in normal individuals with TET2 mutations as revealed by MassArray Epityper and qRT-PCR analysis in the PMNs of 6 TET2 wildtype and 6 mutant individuals. Error bars represent standard deviation relative to mean in panels B and C.