Abstract
Hematopoietic malignancies, including multiple myeloma, are associated with characteristic mutations and genetic instabilities that drive malignant transformation. On the other hand, tumor formation is also associated with drastic epigenetic aberrations, which can impact the genetic sequence. Therefore, the question arises if malignant transformation is primarily caused by genetic or epigenetic events. The tight connection of these processes becomes obvious by the fact that in several malignancies, as well as in age-related clonal hematopoiesis, mutations are particularly observed in epigenetic writers such as DNMT3A and TET2. On the other hand, specific epigenetic aberrations, so-called “epimutations,” can mimic genomic mutations. In contrast to the genetic sequence, which remains relatively stable throughout life, the epigenome notoriously undergoes drastic changes in normal hematopoietic development and aging. It is conceivable that such epigenetic reorganization, e.g., in 3D chromatin conformation, paves the way for secondary chromosomal instabilities, which then result in tumor-specific genomic changes that further trigger disease progression. This scenario might explain the occurrence of tumor-specific mutations particularly in the elderly. Taken together, the causality dilemma is difficult to solve because genetic and epigenetic aberrations are interlinked during disease development. A better understanding of how the chromatin structure or 3D nuclear organization can evoke specific mutations might provide new perspectives for prevention, early diagnostics, and targeted therapy.
Highlights
The tight connection of these processes becomes obvious by the fact that in several malignancies, as well as in age-related clonal hematopoiesis, mutations are observed in epigenetic writers such as DNMT3A and ten-eleven translocation 2 (TET2)
Breast cancer 1 (BRCA1) mutations often occur after tumor protein 53 (TP53) mutations (Martins et al, 2012), because an initial breast cancer 1 (BRCA1) mutation leads to a cell cycle arrest, which is not in favor of tumor progression (Ashworth et al, 2011)
The clinical image of myeloproliferative neoplasms was demonstrated to be dependent on the mutation order of ten-eleven translocation 2 (TET2) versus janus kinase 2 (JAK2): A JAK2 initial mutation increased the likelihood of presenting with polycythemia vera, with an increased risk of thrombosis and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro (Ortmann et al, 2015)
Summary
Tumor formation is associated with drastic epigenetic aberrations, which can impact the genetic sequence. Specific epigenetic aberrations, so-called “epimutations,” can mimic genomic mutations. In contrast to the genetic sequence, which remains relatively stable throughout life, the epigenome notoriously undergoes drastic changes in normal hematopoietic development and aging. It is conceivable that such epigenetic reorganization, e.g., in 3D chromatin conformation, paves the way for secondary chromosomal instabilities, which result in tumor-specific genomic changes that further trigger disease progression. This scenario might explain the occurrence of tumor-specific mutations in the elderly.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
