Deciphering the molecular mechanisms for how alterations in epigenetic modifiers, specifically histone and DNA methylases and demethylases, drive hematopoietic cancer could provide new avenues for developing novel targeted epigenetic therapies for treating hematological malignancies (as done in blood cancer in the past). Hence, determining the contribution of epigenetic modifiers in hematologic cancers could also have a broader impact on our understanding of the pathogenesis of solid tumors in which these factors are mutated.
Conclusion
From: Epigenetic changes in pediatric solid tumors: promising new targets
Cancer is being re-interpreted in light of recent discoveries related to the histone code and the dynamic nature of epigenetic regulation and control of gene programs during development, as well as insights gained from whole cancer genome sequencing. Somatic mutations or deregulated expression of chromatin modifying enzymes are being identified at high frequency. Nowhere is this more relevant than in pediatric embryonal solid tumors wherein a picture is emerging which shows that classic genetic alterations associated with these tumors ultimately converge on the epigenome to dysregulate developmental programs. In this review we relate how alterations in components of the transcriptional machinery and chromatin modifier genes contribute to the initiation and progression of pediatric solid tumors.
Despite intensive basic research in the field of epigenetics and chromatin biology, we have a rudimentary understanding of how epigenetic modifiers carry out their function, including the degree to which chromatin modification-dependent and -independent functions contribute to transcriptional regulation during development. Epigenetic modifiers have emerged recently as potential drivers of hematological malignancies through the sequencing of blood cancer. However, the molecular basis for hematopoietic transformation by many of these chromatin modifiers is still largely unclear. For example, the target genes whose expression is misregulated by a given mutant epigenetic modifier are unknown. Future studies need to identify the key deregulated genes and determine how their misexpression contributes to the pathogenesis of hematological malignancies.
As a result of this heterogeneity and low incidence, the ability of epidemiologists to ascribe causes to specific childhood cancers is extremely limited. Epidemiological studies have noted the effects of cancer genetics, defined family pedigrees and penetrance, and identified subsets of certain cancers and their implications for treatment and prognosis. In addition, the study of rare genetic diseases that increase the risk of malignancy in childhood has led to an understanding of important cancer genes, which has wide applicability to oncology in both children and adults.
Studies in mice that conditionally inactivate or delete these genes alone and in combination with other chromatin regulatory factors will hopefully provide a more in-depth understanding of the role of these alterations during hematopoietic transformation. Perhaps, genetic and chemical screens in different model organisms can identify regulators of oncogenesis. mutations in some of the other epigenetic modifiers may have a tissue-specific role in cancer development. The precise biochemical consequence of mutations in chromatin modifiers in the context of specific hematopoietic cancers.
Genomics landscape of pediatric cancers
Two consortium-led studies published last month in the journal Nature offer the most comprehensive surveys to-date of pediatric cancer genomes.