Summary The Collaborative Cross (CC) is a panel of reproducible recombinant inbred mouse strains with high levels of standing genetic variation, thereby affording unprecedented opportunity to perform experiments in a small animal model containing controlled genetic diversity while allowing for genetic replicates. Here, we advance the utility of this unique mouse resource for immunology research, as it allows for both examination and genetic dissection of mechanisms behind adaptive immune states in mice with distinct and defined genetic makeups. This approach is founded on quantitative trait locus mapping: identifying genetically variant genome regions associated with phenotypic variance in traits-of-interest. Furthermore, the CC can be utilized for mouse model development; distinct strains have unique immunophenotypes and immune properties, making them suitable for research on particular diseases and infections. Here, we describe variation in cellular immune phenotypes across F1 crosses of CC strains, and reveal quantitative trait loci responsible for several immune phenotypes.

Infection with West Nile virus (WNV) leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013)F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans.

BackgroundHead and neck cancer is morbid with a poor prognosis that has not significantly improved in the past several decades. The purpose of this study was to identify biological pathways underlying progressive head and neck cancer to inform prognostic and adjuvant strategies. We identified 235 head and neck cancer patients in The Cancer Genome Atlas (TCGA) with sufficient clinical annotation regarding therapeutic treatment and disease progression to identify progressors and non-progressors. We compared primary tumor gene expression and mutational status between these two groups.Results105 genes were differentially expressed between progressors and nonprogressors (FDR < 0.05). Pathway analyses revealed deregulation (FDR < 0.05) of multiple pathways related to integrin signaling as well as IL-10 signaling. A number of genes were uniquely mutated in the progressor cohort including increased frequency of truncating mutations in CTCF (P = 0.007). An 11-gene signature derived from a combination of unique mutations and differential expression was identified (PAGE4, SMTNL1, VTN, CA5A, C1orf43, KRTAP19-1, LEP, HRH4, PAGE5, SEZ6L, CREB3). This signature was associated with decreased overall survival (Logrank Test; P = 0.03443). Cox modeling of both key clinical features and the signature was significant (P = 0.032) with the greatest prognostic improvement seen in the model based on nodal extracapsular spread and alcohol use alone (P = 0.004).ConclusionsMolecular analyses of head and neck cancer tumors that progressed despite treatment, identified IL-10 and integrin pathways to be strongly associated with cancer progression. In addition, we identified an 11-gene signature with implications for patient prognostication. Mutational analysis highlighted a potential role for CTCF, a crucial regulator of long-range chromatin interactions, in head and neck cancer progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2359-6) contains supplementary material, which is available to authorized users.

The oligoadenylate-synthetase (Oas) gene locus provides innate immune resistance to virus infection. In mouse models, variation in the Oas1b gene influences host susceptibility to flavivirus infection. However, the impact of Oas variation on overall innate immune programming and global gene expression among tissues and in different genetic backgrounds has not been defined. We examined how Oas1b acts in spleen and brain tissue to limit West Nile virus (WNV) susceptibility and disease across a range of genetic backgrounds. The laboratory founder strains of the mouse Collaborative Cross (CC) (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, and NZO/HlLtJ) all encode a truncated, defective Oas1b, whereas the three wild-derived inbred founder strains (CAST/EiJ, PWK/PhJ, and WSB/EiJ) encode a full-length OAS1B protein. We assessed disease profiles and transcriptional signatures of F1 hybrids derived from these founder strains. F1 hybrids included wild-type Oas1b (F/F), homozygous null Oas1b (N/N), and heterozygous offspring of both parental combinations (F/N and N/F). These mice were challenged with WNV, and brain and spleen samples were harvested for global gene expression analysis. We found that the Oas1b haplotype played a role in WNV susceptibility and disease metrics, but the presence of a functional Oas1b allele in heterozygous offspring did not absolutely predict protection against disease. Our results indicate that Oas1b status as wild-type or truncated, and overall Oas1b gene dosage, link with novel innate immune gene signatures that impact specific biological pathways for the control of flavivirus infection and immunity through both Oas1b-dependent and independent processes.

A core tenet of precision oncology is the rational choice of drugs to interact with patient-specific biological targets of interest, but it is currently difficult for researchers to obtain consistent and well-supported target information for pharmaceutical drugs. We review current drug target interaction resources and critically assess how supporting evidence is handled. We introduce the concept of a unified Cancer Targetome to aggregate drug target interactions within an evidence-based framework. We discuss current unmet needs and the implications for evidence based-clinical omics. The focus of this review is precision oncology but the discussion is highly relevant to targeted therapies of any area.