Landscape of TET2 Mutations: From Hematological Malignancies to Solid Tumors

The ten-eleven translocation (TET) enzyme family is a key regulator of DNA methylation, responsible for the conversion of 5-methylcytosine to 5-hydroxymethylcytosine to promote locus-specific demethylation. Thus, it is not surprising that loss or attenuation of TET enzymes is implicated in genomic hypermethylation and transcriptional reprogramming that drives cancer development. Somatic mutations in TET2 are observed in the bone marrow of 5%-10% of healthy adults over 65 years of age, imparting a hematopoietic stem cell advantage and subsequent clonal hematopoiesis of indeterminate potential (CHIP), a condition which is associated with increased risk of myeloid malignancy. Somatic TET2 mutations are frequently reported in myeloid disorders, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Evidence suggests that TET2 mutations also affect prognosis in myeloid leukemia and other hematopoietic malignancies. However, there is a paucity of collated data on the frequency of TET2 mutations in solid human cancers.

We review the published literature on TET2 mutation in human solid cancers and explore their frequency and impact on patient outcomes.

Somatic TET2 mutations are reported in numerous solid human cancers, including those arising in the skin, lung and prostate. Many of the somatic TET2 mutations reported in solid cancers are recurrent, suggesting functionality. There is also evidence to suggest that somatic TET2 mutations affect prognosis in solid human cancers.