An estimated 15% or more of the cancer burden worldwide is attributable to known infectious agents. We screened colorectal carcinoma and matched normal tissue specimens using RNA-seq followed by host sequence subtraction and found marked over-representation of Fusobacterium nucleatum sequences in tumors relative to control specimens. F. nucleatum is an invasive anaerobe that has been linked previously to periodontitis and appendicitis, but not to cancer. Fusobacteria are rare constituents of the fecal microbiota, but have been cultured previously from biopsies of inflamed gut mucosa. We obtained a Fusobacterium isolate from a frozen tumor specimen; this showed highest sequence similarity to a known gut mucosa isolate and was confirmed to be invasive. We verified overabundance of Fusobacterium sequences in tumor versus matched normal control tissue by quantitative PCR analysis from a total of 99 subjects ( p = 2.5 3 10 -6), and we observed a positive association with lymph node metastasis.[Supplemental material is available for this article.] There are variations on the method, but the basic approach involves shotgun sequencing bulk DNA or RNA isolated from disease tissue, computational subtraction of all sequence reads recognized as human, and comparison of the residual reads to databases of known microbial sequences in order to identify microbial species present in the initial specimen. The method is complementary to traditional culture and histolology-based protocols, and new massively parallel sequencing technologies impart high sensitivity. At present the power of the method remains restricted by the content of microbial sequence databases, but with our increasing reach into microbial sequence space, the comprehensiveness of these data resources continues to improve. In oncology, the identification of a novel polyomavirus in Merkel Cell carcinoma (Feng et al. 2008) is a recent demonstration of the utility of a metagenomics approach.Colorectal carcinoma (CRC) is the fourth leading cause of cancer deaths, responsible for approximately 610,000 deaths per year worldwide (World Health Organization 2011). It is also one of the first and best genetically characterized cancers, and specific somatic mutations in oncogenes and tumor suppressor genes have been found that are associated with progression from adenomatous lesions (polyps) to invasive carcinoma (Vogelstein et al. 1988). The root cause of CRC is unclear, but inflammation is a well-recognized risk factor (Wu et al. 2009;McLean et al. 2011). Given the link between H. pylori-mediated inflammation and gastric cancer (Marshall and Warren 1984), we asked if inflammatory microorganisms are associated with other gastrointestinal (GI) cancers. We began to address this question by undertaking a metagenomic survey of colorectal carcinoma. ResultsTotal RNA was isolated from frozen sections of 11 matched pairs of colorectal carcinoma and adjacent normal tissue specimens. RNA was purified by host ribosomal sequence depletion, rather than poly(A) selection, in order to re...

BackgroundTumor-infiltrating T cells are associated with survival in epithelial ovarian cancer (EOC), but their functional status is poorly understood, especially relative to the different risk categories and histological subtypes of EOC.Methodology/Principal FindingsTissue microarrays containing high-grade serous, endometrioid, mucinous and clear cell tumors were analyzed immunohistochemically for the presence of lymphocytes, dendritic cells, neutrophils, macrophages, MHC class I and II, and various markers of activation and inflammation. In high-grade serous tumors from optimally debulked patients, positive associations were seen between intraepithelial cells expressing CD3, CD4, CD8, CD45RO, CD25, TIA-1, Granzyme B, FoxP3, CD20, and CD68, as well as expression of MHC class I and II by tumor cells. Disease-specific survival was positively associated with the markers CD8, CD3, FoxP3, TIA-1, CD20, MHC class I and class II. In other histological subtypes, immune infiltrates were less prevalent, and the only markers associated with survival were MHC class II (positive association in endometrioid cases) and myeloperoxidase (negative association in clear cell cases).Conclusions/SignificanceHost immune responses to EOC vary widely according to histological subtype and the extent of residual disease. TIA-1, FoxP3 and CD20 emerge as new positive prognostic factors in high-grade serous EOC from optimally debulked patients.

Each year funding agencies and academic institutions spend millions of dollars and euros on biobanking. All funding providers assume that after initial investments biobanks should be able to operate sustainably. However the topic of sustainability is challenging for the discipline of biobanking for several major reasons: the diversity in the biobanking landscape, the different purposes of biobanks, the fact that biobanks are dissimilar to other research infrastructures and the absence of universally understood or applicable value metrics for funders and other stakeholders. In this article our aim is to delineate a framework to allow more effective discussion and action around approaches for improving biobank sustainability. The term sustainability is often used to mean fiscally self-sustaining, but this restricted definition is not sufficient for biobanking. Instead we propose that biobank sustainability should be considered within a framework of three dimensions - financial, operational, and social. In each dimension, areas of focus or elements are identified that may allow different types of biobanks to distinguish and evaluate the relevance, likelihood, and impact of each element, as well as the risks to the biobank of failure to address them. Examples of practical solutions, tools and strategies to address biobank sustainability are also discussed.

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Human research biobanks have rapidly expanded in the past 20 years, in terms of both their complexity and utility. To date there exists no agreement upon classification schema for these biobanks. This is an important issue to address for several reasons: to ensure that the diversity of biobanks is appreciated, to assist researchers in understanding what type of biobank they need access to, and to help institutions/funding bodies appreciate the varying level of support required for different types of biobanks. To capture the degree of complexity, specialization, and diversity that exists among human research biobanks, we propose here a new classification schema achieved using a conceptual classification approach. This schema is based on 4 functional biobank "elements" (donor/participant, design, biospecimens, and brand), which we feel are most important to the major stakeholder groups (public/participants, members of the biobank community, health care professionals/researcher users, sponsors/funders, and oversight bodies), and multiple intrinsic features or "subelements" (eg, the element "biospecimens" could be further classified based on preservation method into fixed, frozen, fresh, live, and desiccated). We further propose that the subelements relating to design (scale, accrual, data format, and data content) and brand (user, leadership, and sponsor) should be specifically recognized by individual biobanks and included in their communications to the broad stakeholder audience.