Organizing knowledge to enable personalization of medicine in cancer

Interpretation of the clinical significance of genomic alterations remains the most severe bottleneck preventing the realization of personalized medicine in cancer. We propose a knowledge commons to facilitate collaborative contributions and open discussion of clinical decision-making based on genomic events in cancer

Genome remodelling in a basal-like breast cancer metastasis and xenograft

Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour

10 steps to integrate CIViCdb with other public data in Wikidata

<div>Precision medicine has shifted our understanding of the etiology and treatment of cancer from a focus on anatomical to molecular features. The genetic fingerprint of a patient can be deterministic in both the onset and treatment of the disease. However the etiological network of a specific disease consists of very diverse factors from genetic to environmental. With such diverse knowledge comes a diverse data infrastructure. Data is scattered across data silos and different data formats/structures. This poses a serious bottleneck when interpreting data in a clinical and/or research setting. </div><div>CIViC (http://www.civicdb.org) is an open-access, community-based, highly-curated cancer variant database. It is a platform where data on cancer genomic alterations from different data sources are curated and interpreted for clinical application. These interpretations with their evidence are captured and stored as structured data in the public domain. In order to reach an even broader audience an effort was made to include CIViC's data into Wikidata. Wikidata contains and feeds structured data into Wikipedia and to other Wikimedia projects. It has all the traits of Wikipedia (open-access, editable, community-driven) and is accessible to both humans and machines. Although Wikidata has a Wikipedia narrative, its application is not limited to it. The open APIs allow broader application. </div><div>Adding public domain datasets to Wikidata benefits audiences in both directions. In this case, Wikidata gains additional content from a highly-curated resource, while CIViC gains exposure to a wider audience, the ability to link to other data types and domains (e.g. drugs) and the benefits of Wikidata’s being a hub on the Semantic Web, allowing complex queries to be performed. We report the process involved in linking CIViC to Wikidata. This led to eight new Wikidata relations and a model to capture provenance. The resulting statements are built upon common standards coming from ontologies and other resources. The success of the data integration is proof that different data models can work together without any loss of information and we invite other resources to follow.</div

Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome

<p>Abstract</p> <p>Background</p> <p>A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL) on viral fitness in the context of the cognate transmitted/founder (T/F) genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS) method.</p> <p>Results</p> <p>The T/F and mutant viruses were competed in CD4⁺ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K) in Env and a reversion mutation in the Tat/Rev overlapping region.</p> <p>Conclusions</p> <p>These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness.</p