Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.clonality | exome sequencing | mutation | ERBB | BRCA2 G astric cancer (GC) is the fourth most common cancer and the second leading cause of cancer death worldwide, accounting for 8% of all newly diagnosed cancers and 10% of cancer mortality(1). Environmental risk factors for GC include a high-salt diet, smoking, and infectious agents (1), including the bacterium Helicobacter pylori (2), and Epstein Barr Virus (3). Consistent with its complicated etiology (e.g., diet) and anatomical environment, GC is clinically and pathologically highly heterogeneous (4), with a large variation in 5-y survival rates in different countries, and even different cities in the same country (5, 6). This clinical heterogeneity is mirrored by concomitant heterogeneous molecular signatures in GC mRNA, protein, and miRNA expression profiles (7,8). Standard treatment strategies have largely ignored the heterogeneity and individuality of different subtypes of GC. The current approach entails surgical removal of the tumor followed by adjuvant fluoropyrimidine, taxane, and platinum-based chemotherapy doublets or triplets, especially for advanced GC, and this is exacerbated by the lack of reliable markers to predict response. Recently, the US Food and Drug Administratio...
Glioblastoma (GBM) is a deadly disease with few effective therapies. Although much has been learned about the molecular characteristics of the disease, this knowledge has not been translated into clinical improvements for patients. At the same time, many new therapies are being developed. Many of these therapies have potential biomarkers to identify responders. The result is an enormous amount of testable clinical questions that must be answered efficiently. The GBM Adaptive Global Innovative Learning Environment (GBM AGILE) is a novel, multi-arm, platform trial designed to address these challenges. It is the result of the collective work of over 130 oncologists, statisticians, pathologists, neurosurgeons, imagers, and translational and basic scientists from around the world. GBM AGILE is composed of two stages.The first stage is a Bayesian adaptively randomized screening stage to identify effective therapies based on impact on overall survival compared with a common control. This stage also finds the population in which the therapy shows the most promise based on clinical indication and biomarker status. Highly effective therapies transition in an inferentially seamless manner in the identified population to a second confirmatory stage. The second stage uses fixed randomization to confirm the findings from the first stage to support registration. Therapeutic arms with biomarkers may be added to the trial over time, while others complete testing. The design of GBM AGILE enables rapid clinical testing of new therapies and biomarkers to speed highly effective therapies to clinical practice.
The authors hope that this schema will give physicians an evidence-based and rational framework to make the best referral decisions to better guide and serve this patient population.
The Szent-Györgyi Prize for Progress in Cancer Research is a prestigious scientific award established by the National Foundation for Cancer Research (NFCR)—a leading cancer research charitable organization in the United States that is committed to supporting innovative cancer research on the global scale that aims to cure cancer. Each year, the Szent-Györgyi Prize honors an outstanding researcher whose original discoveries have expanded our understanding of cancer and resulted in notable advances in cancer prevention, diagnosis, or treatment. The prize also promotes public awareness of the importance of basic cancer research and encourages the sustained investment needed to accelerate the translation of these research discoveries into new cancer treatments. This report highlights the history and mission of the Szent-Györgyi Prize, its role in promoting discovery-oriented cancer research, and the pioneering work led by the 2014 prize winner, Dr. James Allison. Dr. Allison's work in the area of cancer immunotherapy led to the successful development of immune checkpoint therapy, and the first drug approved by the United States Food and Drug Administration for the treatment of metastatic melanoma.
The Szent-Györgyi Prize for Progress in Cancer Research is a prestigious scientific award established by the National Foundation for Cancer Research (NFCR)—a leading cancer research charitable organization in the United States that is committed to supporting scientific research and public education relating to the prevention, early diagnosis, better treatments, and ultimately, a cure for cancer. Each year, the Szent-Györgyi Prize honors an outstanding researcher, nominated by colleagues or peers, who has contributed outstanding, significant research to the fight against cancer, and whose accomplishments have helped improve treatment options for cancer patients. The Prize also promotes public awareness of the importance of basic cancer research and encourages the sustained investment needed to accelerate the translation of these research discoveries into new cancer treatments. This report highlights the pioneering work led by the 2015 Prize winner, Dr. Frederick Alt. Dr. Alt’s work in the area of cancer genetics over four decades has helped to shape the very roots of modern cancer research. His work continues to profoundly impact the approaches that doctors around the globe use to diagnose and treat cancer. In particular, his seminal discoveries of gene amplification and his pioneering work on molecular mechanisms of DNA damage repair have helped to usher in the era of genetically targeted therapy and personalized medicine.
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