Importance of studying cancer
Cancer is a vastly complex disease exhibiting a plethora of genomic alterations and resulting regulatory failures at the root of its progression. Following the milestone of the Human Genome Project (HGP) era, researchers are now focusing on integrating the rich genome-wide association studies (GWAS), single-nucleotide polymorphism (SNP) data, and identified gene signatures within the in vitro, in vivo and clinical frameworks to further our understanding of the molecular mechanisms of carcinogenesis. More recently, the study of epigenetic changes that occur during carcinogenesis is rapidly deve¬loping into an important research field. For example, epigenetic silencing that occurs through the CpG island methylator …show more content…
Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those present in the initial tumor. To explore this hypothesis, our group sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients [REF]. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF. This suggests that recurrent tumors could be derived from cells that separated at the very early stage of primary tumor evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis (Cancer Genome Atlas Research Network, 2008, Johnson et al., 2014, Louis, 2006). It was earlier reported that adjuvant treatment with alkylating chemotherapeutics such as TMZ can induce hypermutation that emerges in recurrent tumors (Hunter et al., 2006), and we recently linked treatment-associated driver mutations in these two pathways to malignant progression of grade II glioma to GBM (Johnson et al., 2014). It remains unknown, however, how …show more content…
Powerful in vitro and in vivo models have shown that epigenetic heterogeneity can drive variable responses to therapy and differences in tumor-propagating potential. Gupta et al. (2011) show that upon separation of a breast cancer cell line into its basal, luminal, and stem-like cell populations, each of the purified cell types expands into a heterogeneous culture that fully recapitulates the initial cell type heterogeneity through cell state interconversions. Kreso et al. (2013) further show that after isolating individual cells from the same genetic background and transplanting them into mice, the separate transplants display differences in growth dynamics and treatment-response. Similarly, Sharma et al. (2010) find that while the majority of cells in a single cell derived non-small cell lung cancer subline are drug-sensitive, a small subpopulation of cells are drug-tolerant. Following removal of drug, these drug-tolerant persister cells expand and reacquire drug-sensitivity. Persister cells display an altered chromatin landscape, suggesting that epigenetic therapies could block persister cells. Indeed, treatment of cell lines with HDAC inhibitors or knockdown of the histone demethylase KDM5A reduces the emergence of persister
Cancer is a vastly complex disease exhibiting a plethora of genomic alterations and resulting regulatory failures at the root of its progression. Following the milestone of the Human Genome Project (HGP) era, researchers are now focusing on integrating the rich genome-wide association studies (GWAS), single-nucleotide polymorphism (SNP) data, and identified gene signatures within the in vitro, in vivo and clinical frameworks to further our understanding of the molecular mechanisms of carcinogenesis. More recently, the study of epigenetic changes that occur during carcinogenesis is rapidly deve¬loping into an important research field. For example, epigenetic silencing that occurs through the CpG island methylator …show more content…
Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those present in the initial tumor. To explore this hypothesis, our group sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients [REF]. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF. This suggests that recurrent tumors could be derived from cells that separated at the very early stage of primary tumor evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis (Cancer Genome Atlas Research Network, 2008, Johnson et al., 2014, Louis, 2006). It was earlier reported that adjuvant treatment with alkylating chemotherapeutics such as TMZ can induce hypermutation that emerges in recurrent tumors (Hunter et al., 2006), and we recently linked treatment-associated driver mutations in these two pathways to malignant progression of grade II glioma to GBM (Johnson et al., 2014). It remains unknown, however, how …show more content…
Powerful in vitro and in vivo models have shown that epigenetic heterogeneity can drive variable responses to therapy and differences in tumor-propagating potential. Gupta et al. (2011) show that upon separation of a breast cancer cell line into its basal, luminal, and stem-like cell populations, each of the purified cell types expands into a heterogeneous culture that fully recapitulates the initial cell type heterogeneity through cell state interconversions. Kreso et al. (2013) further show that after isolating individual cells from the same genetic background and transplanting them into mice, the separate transplants display differences in growth dynamics and treatment-response. Similarly, Sharma et al. (2010) find that while the majority of cells in a single cell derived non-small cell lung cancer subline are drug-sensitive, a small subpopulation of cells are drug-tolerant. Following removal of drug, these drug-tolerant persister cells expand and reacquire drug-sensitivity. Persister cells display an altered chromatin landscape, suggesting that epigenetic therapies could block persister cells. Indeed, treatment of cell lines with HDAC inhibitors or knockdown of the histone demethylase KDM5A reduces the emergence of persister