Biology subjects

Weeder, B. R.

Publications and source records attributed to Weeder, B. R..

3 recordsLinked to original sources

bioRxiv2019

Putatively cancer-specific alternative splicing is shared across patients and present in developmental and other non-cancer cells

We compared cancer and non-cancer RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) Project, and the Sequence Read Archive (SRA). We found that: 1) averaging across cancer types, 80.6% of exon-exon junctions thought to be cancer-specific based on comparison with tissue-matched samples are in fact present in other adult non-cancer tissues throughout the body; 2) 30.8% of junctions not present in any GTEx or TCGA normal tissues are shared by multiple samples within at least one cancer type cohort, and 87.4% of these distinguish between different cancer types; and 3) many of these junctions not found in GTEx or TCGA normal tissues (15.4% on average) are also found in embryological and other developmentally associated cells. This study probes the distribution of putatively cancer-specific junctions across a broad set of publicly available non-cancer human RNA-seq datasets. Overall, we identify a subset of shared cancer-specific junctions that could represent novel sources of cancer neoantigens. We further describe a framework for characterizing possible origins of these junctions, including potential developmental and embryological sources, as well as cell type-specific markers particularly related to cell types of cancer origin. These findings refine the meaning of RNA splicing event novelty, particularly with respect to the human neoepitope repertoire. Ultimately, cancer-specific exon-exon junctions may affect the anti-cancer immune response and may have a substantial causal relationship with the biology of disease.

cancer biology↗

bioRxiv2019

Burden of tumor mutations, neoepitopes, and other variants are cautionary predictors of cancer immunotherapy response and overall survival

BackgroundTumor mutational burden (TMB, the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized. MethodsUsing a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential. ResultsWe find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes. ConclusionsWe find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma.

cancer biology↗

bioRxiv2019

Myeloid Lineage Enhancers Drive Oncogene Synergy in CEBPA/CSF3R Mutant Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. This finding of mutation-synergy is broadly applicable other mutations that activate the JAK/STAT pathway or disrupt CEBPA function (i.e. activating mutations in JAK3 and Core Binding Factor translocations). The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation, confirming predictions from clinical sequencing data. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.

cancer biology↗