Genetic and epigenetic heterogeneity and the impact on cancer relapse

Abstract

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with an exceedingly poor prognosis, showing a 5-year overall survival rate of 40–45% in the young and a 5-year survival rate of below 10% in the elderly (>60y). Though a high percentage of patients enter complete remission following chemotherapeutic intervention, the majority of patients relapse within three years. Such stark prognostic outcomes highlight the need for additional clinical research, basic discovery, and molecular delineation of the etiologies and mechanisms behind responses to therapy that lead to relapse. Here we summarize recent discoveries in tumor heterogeneity at the genetic and epigenetic levels, and their independent molecular trajectories and dynamics in response to therapy. These new discoveries may have significant implications for understanding, monitoring, and treating leukemia and other cancers.

Hypoxia‐inducible transgelin 2 selects epithelial‐to‐mesenchymal transition and γ‐radiation‐resistant subtypes by focal adhesion kinase‐associated insulin‐like growth factor 1 receptor activation in non‐small‐cell lung cancer cells

“…Therefore, intrinsic to the CSC hypothesis is the heterogeneity of tumor cells. There is a growing body of evidence that patient tumors contain various heterogeneous cell populations . Such heterogeneity would be beneficial to survival under harsh conditions such as extreme hypoxia (<1%).…”

“…There is a growing body of evidence that patient tumors contain various heterogeneous cell populations. 61,62 Such heterogeneity would be beneficial to survival under harsh conditions such as extreme hypoxia (<1%). If cancer cells are all essentially identical with only natural variability among them, such a harsh condition may kill most of a cell population.…”

Practical Considerations for Treatment of Relapsed/Refractory FLT3-ITD Acute Myeloid Leukaemia with Quizartinib: Illustrative Case Reports

“…The genomic architecture of AML evolves through the course of the disease, as chemotherapy and disease progression affect blast characteristics [16][17][18][19]. Relapse is often caused by the emergence of chemo-resistant clones after treatment [20]. However, because mutations like FLT3 are now targets for novel chemotherapeutic agents, it is worthwhile retesting a patient's molecular biology at relapse to identify the emergence of novel mutations that may be sensitive to targeted therapies.…”

Patient-tailored design of AML cell subpopulation-selective drug combinations

“…Even though genomic analyses have led to improvements in understanding of the molecular landscape of AML, patient-specific therapeutic responses are often associated with unique clusters of non-recurrent and co-occurring mutations, making even the large-scale genomic profiling resources under-powered for identifying patientcustomized combinatorial mechanisms. Furthermore, many of the most frequent AML mutations generate broad changes in the epigenome, RNA splicing and translation 15,16 , suggesting that precision medicine approaches based solely on mutation signature may fail to predict clinically useful combinations 2 . An additional clinical challenge comes from intolerable, drug-induced toxicities, especially in older AML patients 11,17,18 .…”