Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development-providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small-0.004 AE 0.0004-and has major implications for experimental cancer research.genetics | mathematical biology

High-throughput RNA sequencing (RNA-seq) dramatically expands the potential for novel genomics discoveries, but the wide variety of platforms, protocols and performance has created the need for comprehensive reference data. Here we describe the Association of Biomolecular Resource Facilities next-generation sequencing (ABRF-NGS) study on RNA-seq. We tested replicate experiments across 15 laboratory sites using reference RNA standards to test four protocols (polyA-selected, ribo-depleted, size-selected and degraded) on five sequencing platforms (Illumina HiSeq, Life Technologies’ PGM and Proton, Pacific Biosciences RS and Roche’s 454). The results show high intra-platform and inter-platform concordance for expression measures across the deep-count platforms, but highly variable efficiency and cost for splice junction and variant detection between all platforms. These data also demonstrate that ribosomal RNA depletion can both enable effective analysis of degraded RNA samples and be readily compared to polyA-enriched fractions. This study provides a broad foundation for cross-platform standardization, evaluation and improvement of RNA-seq.

Despite collectively accounting for 25% of tumors in U.S. adults, rare cancers have significant unmet clinical needs as they are difficult to study due to low incidence and geographically dispersed patient populations. We sought to assess whether a patientpartnered research approach using online engagement can overcome these challenges and accelerate scientific discovery in rare cancers, focusing on angiosarcoma (AS), an exceedingly rare sarcoma with a dismal prognosis and an annual U.S. incidence of 300 cases. Here, we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling patients across the U.S. and Canada to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 AS patients registered for the ASCproject, comprising a significant fraction of all patients. Whole exome sequencing of 47 AS tumors revealed several recurrently mutated genes, including KDR, TP53, and PIK3CA. Activating mutations in PIK3CA were observed nearly exclusively in primary breast AS, suggesting a therapeutic rationale in these patients. AS of the head, neck, face, and scalp (HNFS) was associated with high tumor mutation burden and a dominant mutational signature of UV light exposure, suggesting that UV damage may be a causative factor in HNFS AS and that this AS subset might be amenable to immune checkpoint inhibitor therapy. Medical record review revealed two patients with HNFS AS received off-label treatment with anti-PD-1 therapy and experienced exceptional responses, highlighting immune checkpoint inhibition as a therapeutic avenue for HNFS AS. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for AS patients. Collectively, this proof of concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and enable biological and clinical discoveries.