The value of high‐throughput germline genetic testing is increasingly recognized in clinical cancer care. Disease‐associated germline variants in cancer patients are important for risk management and ...surveillance, surgical decisions and can also have major implications for treatment strategies since many are in DNA repair genes. With the increasing availability of high‐throughput DNA sequencing in cancer clinics and research, there is thus a need to provide clinically oriented sequencing reports for germline variants and their potential therapeutic relevance on a per‐patient basis. To meet this need, we have developed the Cancer Predisposition Sequencing Reporter (CPSR), an open‐source computational workflow that generates a structured report of germline variants identified in known cancer predisposition genes, highlighting markers of therapeutic, prognostic and diagnostic relevance. A fully automated variant classification procedure based on more than 30 refined American College of Medical Genetics and Genomics (ACMG) criteria represents an integral part of the workflow. Importantly, the set of cancer predisposition genes profiled in the report can be flexibly chosen from more than 40 virtual gene panels established by scientific experts, enabling customization of the report for different screening purposes and clinical contexts. The report can be configured to also list actionable secondary variant findings, as recommended by ACMG. CPSR demonstrates comparable sensitivity and specificity for the detection of pathogenic variants when compared to other algorithms in the field. Technically, the tool is implemented in Python/R, and is freely available through Docker technology. Source code, documentation, example reports and installation instructions are accessible via the project GitHub page: https://github.com/sigven/cpsr.
What's new?
The Cancer Predisposition Sequencing Reporter is a unique bioinformatics tool for identifying genetic variants that may be therapeutically relevant. Many cancers arise from rare germline mutations in cancer predisposition genes. Knowing what variants a patient is carrying can help clinicians make decisions about risk‐reduction interventions and surveillance, but interpretation of the variant profile can be challenging. This tool generates a report of variants in known cancer predisposition genes, highlighting those with therapeutic, prognostic, and diagnostic relevance.
Abstract
Cancer drug sensitivity screens combined with multi-omics characterisation of the cancer cells have become an important tool to determine the optimal treatment for each patient. We propose a ...multivariate Bayesian structured variable selection model for sparse identification of multi-omics features associated with multiple correlated drug responses. Our model uses known structure between drugs and their targeted genes via a Markov random field (MRF) prior in sparse seemingly unrelated regression. The use of MRF prior can improve the model performance compared to other common priors. The proposed model is applied to the Genomics of Drug Sensitivity in Cancer data.
Abstract
Precision cancer medicine is a multidisciplinary team effort that requires involvement and commitment of many stakeholders including the society at large. Building on the success of ...significant advances in precision therapy for oncological patients over the last two decades, future developments will be significantly shaped by improvements in scalable molecular diagnostics in which increasingly complex multilayered datasets require transformation into clinically useful information guiding patient management at fast turnaround times. Adaptive profiling strategies involving tissue‐ and liquid‐based testing that account for the immense plasticity of cancer during the patient's journey and also include early detection approaches are already finding their way into clinical routine and will become paramount. A second major driver is the development of smart clinical trials and trial concepts which, complemented by real‐world evidence, rapidly broaden the spectrum of therapeutic options. Tight coordination with regulatory agencies and health technology assessment bodies is crucial in this context. Multicentric networks operating nationally and internationally are key in implementing precision oncology in clinical practice and support developing and improving the ecosystem and framework needed to turn invocation into benefits for patients. The review provides an overview of the diagnostic tools, innovative clinical studies, and collaborative efforts needed to realize precision cancer medicine.
Cancer is generally caused by the molecular alterations which lead to specific mutations. Advances in molecular biology have provided an impetus to the study of cancers with valuable prognostic and ...predictive significance. Over the hindsight various attempts have been undertaken by scientists worldwide, in the management of cancer; where, we have witnessed a number of molecular markers which allow the early detection of cancers and lead to a decrease in its mortality rate. Recent advances in oncology have led to the discovery of cancer markers that has allowed early detection and targeted therapy of tumors. In this context, current review provides a detail outlook on various molecular markers for diagnosis, prognosis and management of therapeutic response in cancer patients.
Cancer Treatment in the Genomic Era Doherty, Gary J; Petruzzelli, Michele; Beddowes, Emma ...
Annual review of biochemistry,
06/2019, Letnik:
88, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The complexity of human cancer underlies its devastating clinical consequences. Drugs designed to target the genetic alterations that drive cancer have improved the outcome for many patients, but not ...the majority of them. Here, we review the genomic landscape of cancer, how genomic data can provide much more than a sum of its parts, and the approaches developed to identify and validate genomic alterations with potential therapeutic value. We highlight notable successes and pitfalls in predicting the value of potential therapeutic targets and discuss the use of multi-omic data to better understand cancer dependencies and drug sensitivity. We discuss how integrated approaches to collecting, curating, and sharing these large data sets might improve the identification and prioritization of cancer vulnerabilities as well as patient stratification within clinical trials. Finally, we outline how future approaches might improve the efficiency and speed of translating genomic data into clinically effective therapies and how the use of unbiased genome-wide information can identify novel predictive biomarkers that can be either simple or complex.
Despite poor survival for patients with relapsed or refractory neuroblastoma, only 10–16% of patients are reported to be included in early phase trials. This study aimed to explore the impact of ...molecular profiling within the prospective precision cancer medicine trial MAPPYACTS (NCT02613962) on subsequent early phase trial recruitment and treatment by matched targeted therapies in this population.
Clinical data from all French patients with relapsed/refractory neuroblastoma enrolled in MAPPYACTS were analyzed for subsequent matched/non-matched targeted treatment based on clinical tumor board (CMTB) recommendations.
From 93 patients with neuroblastoma included in French centers, 78 (84%) underwent whole exome and RNA sequencing and were discussed in the CMTB. Higher rate of successful sequencing analysis was observed in patients with relapsed disease compared to those with refractory disease (p = 0.0002). Among the 50 patients that presented with a new disease relapse/progression after the CMTB recommendations, 35 patients (70%) had at least one actionable alteration identified on the tumor at the time of relapse. Eighteen patients (36%) were included in an early phase clinical trial, 11 of these with a matched agent, 7 with a non-matched treatment; 13 patients were included in the AcSé ESMART trial. Five patients (10%) received a matched targeted therapy outside a clinical trial.
Patients with neuroblastoma in the European MAPPYACTS trial were more likely to be included in early phase trials compared to previous reports. Early deep sequencing at first treatment failure, comprehensive therapeutic discussions in molecular tumor boards and innovative trials like AcSé -ESMART improve access to innovative therapies for patients with relapsed/refractory neuroblastoma. Clinical trial registration: NCT02613962
•Early phase trial inclusion is historically low in patients with relapse neuroblastoma•Recruitment can be facilitated by deep sequencing and multidisciplinary discussions•Molecular profiling at first relapse is recommended
Background:
Cancer
poses a serious threat to one’s health, which caused significant economic burden on the family and society. Poor availability and affordability resulted in some essential medicines ...failing to meet the basic health needs of this group of patients. The objective of this study was to evaluate the availability, prices and affordability of 32 anticancer essential medicines in Hubei Province, China.
Methods:
Data on the availability and price related information of 32 essential anticancer medicines in the capital and five other cities of Hubei Province were collected. A total of 28 hospitals were sampled, which included 13 tertiary hospitals and 15 secondary hospitals. We used the standard methods developed by the World Health Organization and Health Action International to compare the differences in drug price, availability and affordability between secondary hospitals and tertiary hospitals.
Results:
Overall, the availability of medicine was higher in tertiary hospitals. The average availability of originator brand (OBs) was 13.70% (tertiary hospitals) VS 6.67% (secondary hospitals), and lowest-priced generic (LPGs) was 62.83% (tertiary hospitals) VS 42.92% (secondary hospitals). The MPR value of most sampled medicines in secondary hospitals were less than 1. In contrast, the MPR of Cytarabine (17.15), Oxaliplatin (12.73) were significantly higher than the international reference price. The top three OBs’ total expenses for 30-days treatment were Irinotecan, Oxaliplatin, Bicalutamide. Further, their affordability was relative low, as the costs for one course using these medicines were much higher than 20% of the minimum family monthly income.
Conclusion:
Though the “Zero Mark-Up” and “Centralized procurement policy of anti-tumor drugs” policies have been implemented in China, the availability issue yet to be addressed. High price and low affordability were the major barriers to the access of essential anticancer medicines. Measures should be taken to provide sufficient, available and affordable medicines to patients in need.
Malignant gliomas are highly heterogeneous brain tumors in molecular genetic background. Despite the many recent advances in the understanding of this disease, patients with adult high-grade gliomas ...retain a notoriously poor prognosis. Fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets to date. Understanding the gene fusions and how they regulate oncogenesis and malignant progression will contribute to explore new approaches for personalized treatment. By now, studies on gene fusions in gliomas remain limited. However, some current clinical trials targeting fusion genes have presented exciting preliminary findings. The aim of this review is to summarize all the reported fusion genes in high-grade gliomas so far, discuss the characterization of some of the most popular gene fusions occurring in malignant gliomas, as well as their function in tumorigenesis, and the underlying clinical implication as therapeutic targets.
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