Cancer Genome Landscapes Vogelstein, Bert; Papadopoulos, Nickolas; Velculescu, Victor E. ...
Science,
03/2013, Volume:
339, Issue:
6127
Journal Article
Peer reviewed
Open access
Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of ..."mountains" (genes altered in a high percentage of tumors) and a much larger number of "hills" (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or "drive" tumorigenesis. A typical tumor contains two to eight of these "driver gene" mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The ability to study nonhematologic cancers through noninvasive sampling of blood is one of the most exciting and rapidly advancing fields in cancer diagnostics. This has been driven both by major ...technologic advances, including the isolation of intact cancer cells and the analysis of cancer cell-derived DNA from blood samples, and by the increasing application of molecularly driven therapeutics, which rely on such accurate and timely measurements of critical biomarkers. Moreover, the dramatic efficacy of these potent cancer therapies drives the selection for additional genetic changes as tumors acquire drug resistance, necessitating repeated sampling of cancer cells to adjust therapy in response to tumor evolution. Together, these advanced noninvasive diagnostic capabilities and their applications in guiding precision cancer therapies are poised to change the ways in which we select and monitor cancer treatments.
Recent advances in technologies to analyze circulating tumor cells and circulating tumor DNA are setting the stage for real-time, noninvasive monitoring of cancer and providing novel insights into cancer evolution, invasion, and metastasis.
The article discusses some of the new therapies that have been developed for cancer. The key role being plated by the liquid biopsy as a form of treatment for cancer is highlighted. Some of the ...advantages and disadvantages of this form of treatment are included.
Combining DNA-demethylating agents (DNA methyltransferase inhibitors DNMTis) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and ...isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.
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•Azacitidine depletes MYC and sensitizes NSCLC to HDACi•Combination epigenetic treatment induces a potent anti-tumor response in vivo•Epigenetic treatment potentiates anti-tumor responses by modulating T cell phenotypes•MYC status determines tumor immunophenotype
Myc depletion through combined epigenetic therapy reverses immune evasion and enables effective treatment of lung cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but ...evolutionary evidence for this hypothesis has been limited. Here, we perform whole-exome sequence and copy number analyses of laser capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients. The majority of tumor-specific alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1, BRCA2 or PTEN. Evolutionary analyses reveal that p53 signatures and STICs are precursors of ovarian carcinoma and identify a window of 7 years between development of a STIC and initiation of ovarian carcinoma, with metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for prevention, early detection and therapeutic intervention of this disease.
Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity ...and sensitivity to ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive to ATRi when combined with PARPi (PARPi-ATRi). Sensitivity to PARPi-ATRi in diverse PARPi and platinum-resistant models, including BRCA1/2 reversion and CCNE1-amplified models, correlate with synergistic increases in replication fork stalling, double-strand breaks, and apoptosis. Surprisingly, BRCA reversion mutations and an ability to form RAD51 foci are frequently not observed in models of acquired PARPi-resistance, suggesting the existence of alternative resistance mechanisms. However, regardless of the mechanisms of resistance, complete and durable therapeutic responses to PARPi-ATRi that significantly increase survival are observed in clinically relevant platinum and acquired PARPi-resistant patient-derived xenografts (PDXs) models. These findings indicate that PARPi-ATRi is a highly promising strategy for OVCAs that acquire resistance to PARPi and platinum.
We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin ...changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adenosquamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.
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•Chronic smoke exposure causes sequential chromatin changes leading to gene silencing•Silenced genes are normally polycomb controlled but adopt abnormal DNA methylation•Gene methylation causes sequential upregulation of key signal transduction pathways•Epigenetic alterations sensitize cells to transformation by a single oncogenic event
Vaz et al. show that long-term exposure of untransformed human bronchial epithelial cells to cigarette smoke condensate induces epigenetic changes, consistent with those commonly seen in smoking-related non-small cell lung cancer, that sensitize the cells to transformation with a single KRAS mutation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Liquid biopsies are emerging as powerful minimally invasive approaches that have the potential to solve several long-standing problems spanning the continuum of cancer care: early detection of ...cancer, minimal residual disease tracking, and refinement of the heterogeneity of clinical responses together with therapeutic response monitoring in the metastatic setting. Existing challenges driven by technical limitations and establishment of the clinical value of liquid biopsies represent fields of active research that call for convergence science approaches to bridge scientific discovery with clinical care.
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