We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

The somatic genomic landscape of glioblastoma

Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

SF-010-4 Distant metastasis occurs late during the genetic evolution of pancreatic cancer

The development of tumor-specific T cell tolerance is largely responsible for tumor escape. Accumulation of myeloid-derived suppressor cells (MDSCs) in animal tumor models as well as in cancer patients is involved in tumor-associated T cell tolerance. In recent years, it has become increasingly evident that MDSCs bring about antigen-specific T cell tolerance by various mechanisms, which is the focus of this chapter.

https://cancerimmunolres.aacrjournals.org/content/canimm/5/1/3.full.pdf

Myeloid-Derived Suppressor Cells

Our understanding of the role of myeloid-derived suppressor cells (MDSCs) in cancer is becoming increasingly complex. In addition to their eponymous role in suppressing immune responses, they directly support tumor growth, differentiation, and metastasis in a number of ways that are only now beginning to be appreciated. It is because of this increasingly complex role that these cells may become an important factor in the treatment of human cancer. In this Review, we discuss the most pertinent and controversial issues of MDSC biology and their role in promoting cancer progression and highlight how these cells may be used in the clinic, both as prognostic factors and as therapeutic targets.

/pdf/myeloid-derived-suppressor-cells-in-the-tumor-ckkc229rq6.pdf

Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

Single-cell expression profiles of melanoma Tumors harbor multiple cell types that are thought to play a role in the development of resistance to drug treatments. Tirosh et al. used single-cell sequencing to investigate the distribution of these differing genetic profiles within melanomas. Many cells harbored heterogeneous genetic programs that reflected two different states of genetic expression, one of which was linked to resistance development. Following drug treatment, the resistance-linked expression state was found at a much higher level. Furthermore, the environment of the melanoma cells affected their gene expression programs. Science, this issue p. 189 Melanoma cells show transcriptional heterogeneity. To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.

Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

Esophageal cancer is among the most common tumors in the world and is associated with poor outcomes, with a 5-year survival rate of about 10–20%. Two main histological subtypes are observed: esophageal squamous cell carcinoma (ESCC), more frequent among Asian populations, and esophageal adenocarcinoma (EAC), the predominant type in Western populations. The development of molecular analysis techniques has led to the definition of the molecular alterations observed in ESCC, consistently differing from those observed in EAC. The genetic alterations observed are complex and heterogeneous and involve gene mutations, gene deletions and gene amplifications. However, despite the consistent progress in the definition of the molecular basis of ESCC, precision oncology for these patients is still virtually absent. The recent identification of molecular subtypes of ESCC with clinical relevance may foster the development of new therapeutic strategies. It is estimated that about 40% of the genetic alterations observed in ESCC are actionable. Furthermore, the recent introduction of solid tumor immunotherapy with immune checkpoint inhibitors (ICIs) showed that a minority of ESCC patients are responsive, and the administration of ICIs, in combination with standard chemotherapy, significantly improves overall survival over chemotherapy in ESCC patients with advanced disease.

/pdf/the-molecular-characterization-of-genetic-abnormalities-in-164eh51o.pdf

The Molecular Characterization of Genetic Abnormalities in Esophageal Squamous Cell Carcinoma May Foster the Development of Targeted Therapies

TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct and heterogeneous group of myeloid malignancies associated with poor outcomes. Studies carried out in the last years have in part elucidated the complex role played by TP53 mutations in the pathogenesis of these myeloid disorders and in the mechanisms of drug resistance. A consistent number of studies has shown that some molecular parameters, such as the presence of a single or multiple TP53 mutations, the presence of concomitant TP53 deletions, the association with co-occurring mutations, the clonal size of TP53 mutations, the involvement of a single (monoallelic) or of both TP53 alleles (biallelic) and the cytogenetic architecture of concomitant chromosome abnormalities are major determinants of outcomes of patients. The limited response of these patients to standard treatments, including induction chemotherapy, hypomethylating agents and venetoclax-based therapies and the discovery of an immune dysregulation have induced a shift to new emerging therapies, some of which being associated with promising efficacy. The main aim of these novel immune and nonimmune strategies consists in improving survival and in increasing the number of TP53-mutated MDS/AML patients in remission amenable to allogeneic stem cell transplantation.

TP53-Mutated Myelodysplasia and Acute Myeloid Leukemia

MCL1 regulates AML cells metabolism via direct interaction with HK2. Metabolic signature at onset predicts overall survival in AMLs' patients.

ABSTRACT Introduction Cholangiocarcinomas (CCAs) are a heterogenous group of epithelial malignancies originating at any level of the biliary tree and are subdivided according to their location into intrahepatic (iCCA) and extrahepatic (eCCA). Areas covered This review provides an updated analysis of studies of genetic characterization of CCA at the level of gene mutation profiling, copy number alterations and gene expression, with definition of molecular subgroups and identification of some molecular biomarkers and therapeutic targets. Expert opinion With the development of genetic sequencing, several driver mutations have been identified and targeted as novel therapeutic approaches, including FGFR2, IDH1, BRAF, NTRK, HER2, ROS, and RET. Furthermore, identification of the cellular and molecular structure of the tumor microenvironment has contributed to the development of novel therapies, such as tumor immunotherapy. Combination therapies of chemotherapy plus targeted molecules or immunotherapy are under evaluation and offer the unique opportunity to improve the outcomes of CCA patients with advanced disease.

Germana Castelli

Papers

The Molecular Characterization of Genetic Abnormalities in Esophageal Squamous Cell Carcinoma May Foster the Development of Targeted Therapies

TP53-Mutated Myelodysplasia and Acute Myeloid Leukemia

MCL1 regulates AML cells metabolism via direct interaction with HK2. Metabolic signature at onset predicts overall survival in AMLs' patients.

The clinical value of identifying genetic abnormalities that can be targeted in cholangiocarcinomas

megakaryocytic precursors through Flt1 receptor Autocrine-paracrine VEGF loops potentiate the maturation of