POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer.

PURPOSE: Recent studies have shown that 7% to 12% of endometrial cancers are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response, and clinical outcome in cancer, we investigated whether POLE-mutant endometrial cancers showed evidence of increased immunogenicity. EXPERIMENTAL DESIGN: We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA endometrial cancer series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant endometrial cancers. RESULTS: Compared with other endometrial cancers, POLE mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8(+) tumor-infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T-cell gene signature, and strong upregulation of the T-cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF, and granzyme B. This was accompanied by upregulation of T-cell exhaustion markers, consistent with chronic antigen exposure. In silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings. CONCLUSIONS: Ultramutated POLE proofreading-mutant endometrial cancers are characterized by a robust intratumoral T-cell response, which correlates with, and may be caused by an enrichment of antigenic neopeptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers.

An introduction to genes, genomes and disease.

The human and other genome projects and subsequent resequencing programmes have provided new perspectives on the nature of the gene and how genes function. Understanding the complexity of the eukaryotic nucleus and the diversity of genetic regulatory mechanisms, including the role of non-coding RNAs, translational control mechanisms and the extraordinary prevalence of splicing, will be central to understanding how genes function, as will the recognition of gene dosage issues. This introduction to the 2010 Annual Review Issue, Genes, Genomes and Disease, provides overviews of these areas and then considers their relevance to a range of human diseases, including cardiovascular and renal disease, neural tube defects and cancer. The p53 gene is considered as an example of a massively regulated gene and the genetic perturbations in cancer are considered in a historical perspective. High-throughput genomic and transcriptomic methods have led to a paradigm shift in the way cancers are perceived and have changed the way translational research is performed. The progress in our understanding of chromosomal rearrangements in cancer, once believed to be incredibly rare events in epithelial malignancies, is discussed. The identification of low-penetrance cancer susceptibility genes through genome-wide association studies and their implications are reviewed. The contribution and limitations of expression profiling are discussed. In the last series of reviews, future challenges are addressed: the promise of synthetic lethality strategies in cancer therapy, a case for 'systems' approaches to genetic networks and the potential of single molecule genetic technologies. Finally, the question 'Does massively parallel DNA resequencing signify the end of histopathology as we know it?' is posed. Readers should find that the 2010 Annual Review Issue is an invaluable resource on contemporary genetics and its applications to understanding disease.

Dercum's disease.

Dercum's disease (adiposis dolorosa, lipomatosis dolorosa morbus Dercum), is a rare disorder resulting in painful fatty deposits around the upper legs, trunk, and upper arms. The portrait painted of Dercum's disease is very complicated, with many other disorders seen associated with the disease. There are no clear pathological mechanisms known, although it is suspected that there is either a metabolic or autoimmune component involved. Here, the authors review the literature to date, including some information from their own studies. In particular, the authors will look at the different strands of evidence pointing to the pathological mechanism of the disorder.