Cancer genomics articles within Nature Reviews Clinical Oncology

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  • Review Article |

    FGFR inhibitors are now approved for use in patients with advanced-stage urothelial carcinoma, cholangiocarcinoma and myeloid or lymphoid neoplasms that harbour certain FGFR alterations. Nonetheless, challenges such as tolerability and acquired resistance limit the clinical potential of these agents. In this Review, the authors summarize the available clinical data on FGFR inhibitors, describe promising novel agents and highlight future research directions that might optimize the efficacy of FGFR-targeted therapies.

    • Masuko Katoh
    • , Yohann Loriot
    •  & Masaru Katoh

  • Review Article |

    Lung cancer is a disease typically associated with tobacco smoking; however, lung cancer in individuals who have never smoked (LCINS) is estimated to be the fifth most common cause of cancer-related deaths globally. Moreover, smoking rates are declining around the world and therefore LCINS is likely to increase as a proportion of all lung cancers over time. Thus, understanding the aetiology and features of LCINS is increasingly important. Herein, the authors review the emerging data on the epidemiology, clinical characteristics and molecular features of LCINS as well as the genetic and environmental risk factors for this disease. They also summarize the unique diagnostic and management paradigms of LCINS.

    • Jaclyn LoPiccolo
    • , Alexander Gusev
    •  & Pasi A. Jänne

  • Review Article |

    Identifying patients who are likely to benefit from immune-checkpoint inhibitors remains one of the major challenges in immunotherapy. Cancer immunogenomics is an emerging field that bridges genomics and immunology. The authors of this Review provide an overview of the computational approaches currently available to analyse bulk tissue and single-cell sequencing data from cancer, stromal and immune cells.

    • Venkateswar Addala
    • , Felicity Newell
    •  & Nicola Waddell

  • Review Article |

    Immune-checkpoint inhibitors (ICI) constitute a paradigm shift in the treatment of non-small-cell lung cancer (NSCLC); however, identifying the minority of patients who derive long-term benefit remains problematic, particularly among those with targetable oncogenic drivers who have typically been under-represented in or excluded from clinical trials of ICIs. This Review summarizes the associations of common oncogenic drivers of NSCLC with sensitivity or resistance to ICIs as well as the underlying effects on the immune tumour microenvironment. Potential vulnerabilities that could potentially be exploited to overcome primary resistance to ICIs conferred by certain oncogenic drivers are also highlighted.

    • Itziar Otano
    • , Alvaro C. Ucero
    •  & Luis Paz-Ares

  • News & Views |

    New genetic analyses demonstrate that the presence of low-frequency subclonal populations, including high-risk subclones, at diagnosis in multiple myeloma can contribute to disease relapse and poor clinical outcomes. Thus, sensitive detection approaches are required to detect these subclones at diagnosis together with innovative treatment strategies to eradicate low-frequency, high-risk subclones and prevent them from becoming dominant.

    • Eileen M. Boyle
    •  & Faith E. Davies

  • Review Article |

    Neuroendocrine neoplasms (NENs), which can develop in almost any organ and range from indolent neuroendocrine tumours (NETs) to rapidly progressive and fatal neuroendocrine carcinomas (NECs), have historically been approached in a siloed manner according to their specific tissue of origin. However, NETs and NECs across different sites of origin often share genomic and phenotypic characteristics. In this Review, the authors discuss both the clinical and biological commonalities as well as key organ-specific differences of NENs, with a focus on those of the gastrointestinal system and lung. Moreover, they advocate for a cross-cutting, tissue-agnostic approach to drug development for these rare tumours that might enable advances in one disease entity to accelerate research in others, ultimately improving patient care.

    • Kenta Kawasaki
    • , Natasha Rekhtman
    •  & Charles M. Rudin

  • Review Article |

    The RAS oncogenes are among the most common drivers of tumour development and progression but have historically been considered undruggable. The development of direct KRAS inhibitors has changed this paradigm, although currently clinical use of these novel therapeutics is limited to a select subset of patients, and intrinsic or acquired resistance presents an inevitable challenge to cure. Herein, the authors provide an overview of the RAS pathway in cancer and review the ongoing efforts to develop effective therapeutic strategies for RAS-mutant cancers. They also discuss the current understanding of mechanisms of resistance to direct KRAS inhibitors and strategies by which they might be overcome.

    • Salman R. Punekar
    • , Vamsidhar Velcheti
    •  & Kwok-Kin Wong

  • Review Article |

    Advances in circulating tumour DNA (ctDNA) detection and analysis are beginning to be implemented in clinical practice. Nonetheless, much of this development has thus far focused on plasma ctDNA. Theoretically, all bodily fluids, including urine, cerebrospinal fluid, saliva, pleural fluid and others, can also contain measurable ctDNA and can provide several advantages over the reliance on plasma ctDNA. In this Review, Tivey et al. describe the potential roles of ctDNA obtained from non-plasma sources in optimizing the outcomes of patients with cancer.

    • Ann Tivey
    • , Matt Church
    •  & Natalie Cook

  • Review Article |

    Multiple myeloma and its precursor stages, monoclonal gammopathy of undetermined significance and smouldering multiple myeloma, have a considerable degree of genetic heterogeneity. The authors of this Review discuss how single-cell studies in these individuals are enabling the mutational and phenotypic characterization of cells within the bone marrow tumour, immune microenvironment and peripheral blood to eventually guide early diagnosis, risk stratification and treatment strategies.

    • Ankit K. Dutta
    • , Jean-Baptiste Alberge
    •  & Irene M. Ghobrial

  • Review Article |

    Circular RNAs (circRNAs) are a novel class of primarily non-coding RNAs with increasingly recognized roles in cancer development and progression through diverse mechanisms of action. Herein, the authors review the current understanding of circRNA biogenesis, regulation, physiological functions and pathophysiological roles in cancer. They also discuss the clinical potential of circRNAs as biomarkers, therapeutic agents and drug targets in oncology as well as research controversies, technical issues and biological knowledge gaps that need to be addressed before this promise can be realized.

    • Lasse S. Kristensen
    • , Theresa Jakobsen
    •  & Jørgen Kjems

  • Review Article |

    EGFR exon 19 deletions and exon 21 mutations, and HER2 amplification and/or overexpression, are predictive of response to matched molecularly targeted therapies that have greatly improved patient outcomes. However, insertion mutations in exon 20 of either EGFR or HER2 generally do not confer sensitivity to these therapies. In this Review, the authors discuss the prevalence of EGFR and HER2 exon 20 insertions across cancers, their biology and detection, and associated responses to current molecularly targeted therapies and immunotherapies. In addition, they focus on new therapeutic strategies that are being developed to target tumours driven by these non-classic EGFR and HER2 alterations.

    • Alex Friedlaender
    • , Vivek Subbiah
    •  & Alfredo Addeo

  • Review Article |

    Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)-associated malignancy endemic to southern China, southeast Asia and north Africa. The authors of this Review present a comprehensive overview of advances from the past three decades on the pathogenic role of EBV, and the genomic, epigenomic and immune landscape of NPC, which have led to the development of new biomarkers, therapeutic targets and improved treatment approaches for patients with NPC.

    • Kenneth C. W. Wong
    • , Edwin P. Hui
    •  & Anthony T. C. Chan

  • News & Views |

    Whole-genome sequencing of samples from patients with myeloid malignancies can enable more accurate risk stratification than is possible with conventional cytogenetics. Research by Duncavage et al. demonstrates that such an approach can now be delivered within several days using a highly streamlined and automated workflow.

    • Karilyn T. M. Larkin
    •  & John C. Byrd

  • Perspective |

    The availability of ever more sensitive cell sorting and sequencing technologies has enabled the interrogation of tumour cell biology at the highest possible level of resolution — analysis of a single cell. In this Perspective, the authors describe the application of such approaches to the analysis of single tumour-associated immune cells and their potential for improving the outcomes in patients receiving anti-cancer immunotherapies.

    • Satyen H. Gohil
    • , J. Bryan Iorgulescu
    •  & Kenneth J. Livak

  • News & Views |

    Noninvasive liquid biopsy assays integrating tumour and immune biomarkers are a promising tool to enhance clinical decision-making in immuno-oncology. Here, we discuss how circulating tumour DNA dynamics, in conjunction with pre-treatment tumour and immune features, can predict clinical response to immune-checkpoint inhibitors alongside the challenges in making their use a clinical reality.

    • Joseph C. Murray
    •  & Valsamo Anagnostou

  • Review Article |

    Technological advances have enabled the analysis of whole genomes, leading to the identification of causal factors that present new opportunities to prevent cancer. The authors of this Review discuss relevant findings in cancer genetics and genomics from the perspective of global cancer prevention and present a conceptual framework for the translation of such findings into clinical practice and evidence-based policies.

    • Ophira Ginsburg
    • , Patricia Ashton-Prolla
    •  & Paul Brennan

  • Perspective |

    Genotyping is recommended for all patients with metastatic non-squamous non-small-cell lung cancers (NSCLC), both to enable patients to receive targeted therapies and to avoid therapies they are unlikely to benefit from. However, obtaining tumour biopsy material for genotyping is often challenging and is unfeasible in some patients, indicating the need to incorporate liquid biopsy approaches. In this Perspective, the authors provide guidance on how analysis of ctDNA from liquid biopsy samples in patients with metastatic NSCLC prior to first-line therapy has the potential to extend the benefits of genotyping to virtually all patients.

    • Charu Aggarwal
    • , Christian D. Rolfo
    •  & David R. Gandara

  • Review Article |

    ROS1 fusions can be identified across a range of malignancies and confer a high level of sensitivity to ROS1 tyrosine kinase inhibitors. Herein, the authors discuss the non-malignant and malignant biology of ROS1, the diagnostic approaches to identifying ROS1 fusions and the current therapeutic concepts relating to ROS1 fusion-positive cancers, including the resistance mechanisms that have emerged with current ROS1 inhibitors.

    • Alexander Drilon
    • , Chelsea Jenkins
    •  & Monika A. Davare

  • Consensus Statement
    | Open Access

    The analysis of ctDNA obtained from low-volume blood samples has the potential to transform the management of patients with colorectal cancer. Nevertheless, research priorities and minimum standards for sample collection and analysis in this area are currently missing. In this Position Paper, the NCI Colon and Rectal–Anal Task Forces provide a set of recommendations designed to address these challenges and accelerate the implementation of ctDNA in the management of patients with colorectal cancer.

    • Arvind Dasari
    • , Van K. Morris
    •  & Scott Kopetz

  • News & Views |

    Bacteria within tumours affect progression and response to therapy; in addition, bacterial DNA can be detected in cell-free plasma. Herein, we discuss evidence showing that intratumoural bacteria are characteristic for each tumour type, and that detection of cell-free bacterial DNA in blood could provide an accurate and non-invasive test for cancer diagnosis.

    • Amiran Dzutsev
    •  & Giorgio Trinchieri

  • News & Views |

    Liu et al. report data from the largest sequencing analysis of tumour material from patients with metastatic melanoma receiving immune-checkpoint inhibitors. These data confirm the correlations between baseline immune infiltrate and treatment response, but also demonstrate inconsistent associations of tumour mutational burden, specific gene mutations and previously described gene expression patterns with clinical outcomes.

    • Jason J. Luke
    •  & Paolo A. Ascierto

  • News & Views |

    The identification of biomarkers and the development of genomics-based assays predictive of outcomes following radiotherapy, in an effort to help guide the treatment of patients with cancer, is an area of increasing research interest. Here, we discuss the validity of one such classifier, ARTIC, in the context of complementary genomic approaches designed to predict both tumour response and the susceptibility of nonmalignant tissues to toxicities resulting from radiotherapy.

    • David Azria
    •  & Barry S. Rosenstein

  • Perspective |

    A systems biology-based approach incorporating multiscale, longitudinal measurements (from single-cell analyses to whole-body monitoring) would help to decipher the complexity of cancer and would facilitate the development of personalized therapies. The authors of this Perspective discuss how systems biology-based approaches can provide data for early detection of disease transitions, prediction of therapeutic responses and clinical outcomes, and for the design of personalized treatments.

    • James T. Yurkovich
    • , Qiang Tian
    •  & Leroy Hood

  • News & Views |

    BRCA1/2 mutations and poly (ADP-ribose) polymerase (PARP) inhibitors are paradigmatic of synthetic lethal therapy. However, the activity of PARP inhibitors seems to vary considerably across BRCA1/2-mutant cancers and new insights into the tumour-lineage dependency of this synthetic lethal relationship might explain why BRCA1/2 mutations are not tumour-agnostic biomarkers of a response to PARP inhibitors.

    • Nicola J. Curtin
    • , Yvette Drew
    •  & Sweta Sharma-Saha

  • Perspective |

    Precision medicine approaches to the treatment of cancer are largely reliant on genomic analysis alone. In this Perspective the authors provide a rationale for the incorporation of analysis of the proteome, which is a rich source of biological heterogeneity, into the treatment and management of patients with cancer.

    • Bing Zhang
    • , Jeffrey R. Whiteaker
    •  & Amanda G. Paulovich

  • Review Article |

    Developments in genomic sequencing technologies have enabled increasing amounts of information on the genomes of individual cancers to be revealed. At the same time, increasing numbers of therapies targeting specific genomic alterations are being made available, necessitating the use of genomics to diagnose and treat patients with cancer. In this Review, the authors describe the emerging clinical relevance of genomics in oncology, in addition to the many challenges that currently preclude routine clinical use.

    • Michael F. Berger
    •  & Elaine R. Mardis

  • News & Views |

    The biological complexity of triple-negative breast cancers (TNBCs) and the lack of highly recurrent targetable genetic alterations pose major challenges for the implementation of targeted therapies for this disease. A recent multiomic in silico study has identified genetic drivers of five different TNBC molecular subtypes, providing new opportunities for precision medicine approaches.

    • Fresia Pareja
    •  & Jorge S. Reis-Filho

  • News & Views |

    Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease for which treatment has, historically, lagged behind that of other solid tumour types. A more detailed understanding of the biology of individual tumours, and the identification of molecular features providing prognostic and predictive information is key to the application of personalized care for patients with MIBC. The publication of a study of 412 samples now provides such data.

    • Carolyn D. Hurst
    •  & Margaret A. Knowles

  • Opinion |

    Precision cancer medicine has the potential to dramatically improve the outcomes of patients with cancer; however, despite the precise nature of the therapies involved, generating reliable evidence of efficacy is often challenging. In this Perspective, the authors describe the challenges and potential solutions that might address the need for evidence in precision cancer medicine.

    • Jeffrey A. Moscow
    • , Tito Fojo
    •  & Richard L. Schilsky

  • Review Article |

    Radiomics is the high-throughput mining of quantitative image features from standard-of-care medical imaging to enable data to be extracted and applied within clinical-decision support systems. The process of radiomics is described and its pitfalls, challenges, opportunities, and capacity to improve clinical decision making. The radiomics field requires standardized evaluation of scientific findings and their clinical relevance. This review provides guidance for investigations to meet this urgent need in the field of radiomics.

    • Philippe Lambin
    • , Ralph T.H. Leijenaar
    •  & Sean Walsh

  • News & Views |

    The Cancer Genome Atlas Research Network recently published the most comprehensive, multi-omic molecular characterization of cervical cancers performed to date. The data reveal novel disease subtypes, and provide new insights into the aetiology and pathogenesis of cervical cancer. Importantly, the information obtained has potentially major clinical implications.

    • Chris J. L. M. Meijer
    •  & Renske D. M. Steenbergen

  • News & Views |

    Fraser and colleagues describe the whole-genome sequencing (WGS) profiles of over 200 localized intermediate-risk prostate cancers. WGS has been widely used in research but not, thus far, in clinical settings. Herein, we consider the possible use of WGS in the field of precision oncology.

    • Marcin Imielinski
    •  & Mark A. Rubin

  • Review Article |

    In 2016, a revised WHO classification of glioma was published, in which molecular data and traditional histological information are incorporated into integrated diagnoses. Herein, the authors highlight the developments in our understanding of the molecular genetics of gliomas that underlie this classification, and review the current landscape of molecular biomarkers used in the classification of disease subtypes. In addition, they discuss how these advances can promote the development of novel pathogenesis-based therapeutic approaches, paving the way to precision medicine.

    • Guido Reifenberger
    • , Hans-Georg Wirsching
    •  & Michael Weller

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