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An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage.sup.1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types.sup.2-6. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types. TRACERx Lung: Intratumoral transcriptional heterogeneity, which often hinders the development of clinically useful RNA-expression-biased biomarkers for cancer, can now be overcome with an approach for the identification of clonal expression biomarkers., Author(s): Dhruva Biswas [sup.1] [sup.2] [sup.3] , Nicolai J. Birkbak [sup.1] [sup.3] [sup.4] [sup.5] , Rachel Rosenthal [sup.1] [sup.2] [sup.3] , Crispin T. Hiley [sup.1] [sup.3] , Emilia L. Lim [...]

We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in [greater than] 2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML., Author(s): Hamid Bolouri (corresponding author) [1]; Jason E Farrar [2]; Timothy Triche, Jr [3]; Rhonda E Ries [4]; Emilia L Lim [5]; Todd A Alonzo [6, 7]; Yussanne Ma [5]; [...]

An amendment to this paper has been published and can be accessed via a link at the top of the paper., Author(s): Dhruva Biswas [sup.1] [sup.2] [sup.3] , Nicolai J. Birkbak [sup.1] [sup.3] [sup.4] [sup.5] , Rachel Rosenthal [sup.1] [sup.2] [sup.3] , Crispin T. Hiley [sup.1] [sup.3] , Emilia L. Lim [...]

In the version of this article originally published, the color key in Fig. 1a was wrong. In the Cytogenetics key, the box over t(8;21) originally was green. It should have been red, matching the color of the sections of the pie graphs below the key that were labeled with 15% and 19%., Author(s): Hamid Bolouri [sup.1] , Jason E Farrar [sup.2] , Timothy Triche [sup.3] [sup.17] , Rhonda E Ries [sup.4] , Emilia L Lim [sup.5] , Todd A Alonzo [sup.6] [sup.7] [...]

Author(s): Hamid Bolouri; Jason E Farrar; Timothy Triche, Jr; Rhonda E Ries; Emilia L Lim; Todd A Alonzo; Yussanne Ma; Richard Moore; Andrew J Mungall; Marco A Marra; Jinghui Zhang; [...]