Epigenetics diagnostics tests in hematology-oncology

Epigenetic aberrations play a central role in the pathophysiology of acute myeloid leukemia (AML). Recently, it has been demonstrated that DNA methylation at a single CpG site in the gene of complement component 1 subcomponent R (C1R) is indicative for overall survival in AML. Cygenia provides analysis of the DNA methylation level at C1R for physicians and scientists to gain better insight into disease development.

The genomic location with high prognostic relevance was first identified in a dataset of 194 patients from The Cancer Genome Atlas (TCGA): patients with higher methylation at this CpG site (>27% methylated DNA level) reveal significantly longer overall survival (53 months versus 11 months). This finding was also validated in an independent set of 62 DNA methylation profiles of cytogenetically normal AML patients (P= 0.009), and with a region-specific pyrosequencing assay in 84 AML samples (P= 0.012). Furthermore, DNA methylation in C1R is associated with occurrence of specific genomic mutations in AML. There is evidence that methylated DNA at C1R is an independent prognostic marker from cytogenetic and molecular risk scores. Taken together, analysis of methylated  DNA at C1R provides a simple and cost-effective biomarker for risk assessment in AML.

Acute myeloid leukemia is frequently associated with genomic mutations in the DNA-methyltransferase 3A (DNMT3A) gene, which encodes a central modifier of the DNA-methylation pattern. Newly discovered epimutations within the same gene can mimic these mutations and are indicative for survival of AML patients. Cygenia provides analysis of the DNMT3A epimutation for physicians and scientists to gain better insight into disease development. This method is based on DNA-methylation analysis at a unique genomic region – it is therefore fast and cost effective.

Aplastic anemia results in progressive bone marrow failure due to the loss of mature blood cells. The underlying cause is often unknown - chemicals, radiation, infection, autoimmune dysfunction, or heredity can be the trigger of this disease. The disease is often associated with dramatically shortened telomeres and it has recently been shown to be also associated with premature aging on epigenetic level. Aplastic anemia is still a diagnosis of exclusion since specific tests are yet elusive. It has been demonstrated that patients with aplastic anemia have often accelerated epigenetic age and aberrant DNA-methylation at the gene PRDM8.

Dyskeratosis congenita (DKC) is a rare disease that is often associated with mutations in genes required for proper telomere maintenance. Clinically, DKC usually reflects a triad of oral leukoplakia, nail dystrophy, and skin hyperpigmentation. Other typical manifestations include symptoms of bone marrow failure, and fibrosis of lung and liver. Notably, DKC is often associated with aberrant DNA-methylation in PRDM8.

Cygenia provides an Epigenetic-Aging-Signature which can support diagnosis of aplastic anemia and DKC: overestimation of age-predictions is indicative for exhaustion of the stem cell pool. Furthermore, Cygenia provides a new assay for diagnosis of both diseases, which is based on the DNA-methylation level in the gene PRDM8. These assays are developed for physicians and scientists. If the doctor in charge wants to consider these new methods to support diagnosis of individual patients, this approach may be valuable – however, it has to be noted that the validity of this new method still requires further research.