Celiac disease: how complicated can it get?

In the small intestine of celiac disease patients, dietary wheat gluten and similar proteins in barley and rye trigger an inflammatory response. While strict adherence to a gluten-free diet induces full recovery in most patients, a small percentage of patients fail to recover. In a subset of these refractory celiac disease patients, an (aberrant) oligoclonal intraepithelial lymphocyte population develops into overt lymphoma. Celiac disease is strongly associated with HLA-DQ2 and/or HLA-DQ8, as both genotypes predispose for disease development. This association can be explained by the fact that gluten peptides can be presented in HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Gluten-specific CD4+ T cells in the lamina propria respond to these peptides, and this likely enhances cytotoxicity of intraepithelial lymphocytes against the intestinal epithelium. We propose a threshold model for the development of celiac disease, in which the efficiency of gluten presentation to CD4+ T cells determines the likelihood of developing celiac disease and its complications. Key factors that influence the efficiency of gluten presentation include: (1) the level of gluten intake, (2) the enzyme tissue transglutaminase 2 which modifies gluten into high affinity binding peptides for HLA-DQ2 and HLA-DQ8, (3) the HLA-DQ type, as HLA-DQ2 binds a wider range of gluten peptides than HLA-DQ8, (4) the gene dose of HLA-DQ2 and HLA-DQ8, and finally,(5) additional genetic polymorphisms that may influence T cell reactivity. This threshold model might also help to understand the development of refractory celiac disease and lymphoma

Pan-cancer deconvolution of tumour composition using DNA methylation

The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: ‘immune hot’ and ‘immune cold’, which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to cytotoxic T-lymphocyte infiltration, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations, potentially explaining the heterogeneity of immunotherapy response and prognosis seen within this group. Finally, we define a catalogue of mediators of active antitumour immunity, deriving candidate biomarkers and potential targets for precision immunotherapy

Genome-wide identification of novel regions of DNA copy number alterations in natural killer cell lymphoma by array comparative genomic hybridization

Introduction: Natural killer (NK) cell lymphoma encompasses a related spectrum of diseases and is among the most aggressive of all lymphoid malignancies. The nasal type is characterized by necrotic lesions in the nasal cavity, nasopharynx, or palate, whereas patients suffering from the aggressive type might die within a short time from disseminated disease or multi-organ failure. It is a relatively rare disease and is generally more common in Asians than in other races. Since it has not been well characterized until recently, the identification of genetic alterations would provide important insights into the genomic mechanism of lymphomagenesis. Hypotheses: NK cell lymphoma pathogenesis occurs via multiple genomic alterations and the critical alterations will be present in multiple NK cell lines. Objective: Alignment of high resolution genomic profiles from multiple NK cell lines will reveal minimal regions of alteration important in the pathogenesis of NK-cell lymphoma. Experimental Approach: To determine segmental DNA copy number changes across an entire genome, whole genome tiling path array is employed to evaluate segmental DNA gains and losses which may contain oncogenes and tumor suppressors. Currently, the whole genome has been arrayed as 26,819 bacterial artificial chromosome (BAC) derived amplified fragment pools spotted in duplicate (53,638 elements) resulting in tiling resolution with complete coverage of the sequenced human genome. Results: Whole genome array CGH was used to generate high resolution segmental copy number profiles of seven NK cell lymphoma cell lines (HANK1, KHYG-1, NK-92, NK-YS, SNK1, SNK6, and KAI3). Alignment of these profiles with the human genome map has resulted in fine-mapping the regional losses of 6q. Numerous novel regions, including gain of 5p15.33, and loss of 4q21.23-q32.1, 9p21.1-p22.3, and 12q24.32-q24.33 were also identified in at least five (>70%) of these cell lines. Conclusions: The generation of the high resolution segmental copy number profiles by array CGH allows the identification of genomic alterations of NK-cell lymphomas as well as the candidate genes involved in the pathogenesis of NK-cell lymphoma. Novel candidate oncogenes and tumor suppressor genes identified in this study will provide further insights into the genetic basis of lymphomagenesis. Acknowledgements: This work was supported by funds from Genome Canada/British Columbia. WCC is supported by the Director’s Challenge grant (U01-CA 84967). We would like to thank Spencer Watson for BAC array production and Magan Trottier for technical assistance

Genomic Analyses Reveal Global Functional Alterations That Promote Tumor Growth and Novel Tumor Suppressor Genes in Natural Killer-Cell Malignancies

50th Annual Meeting of the American-Society-of-Hematology, San Francisco, CA, 06-09 December 2008. In Blood, v. 112 n. 11, p. 129