Precision cancer medicine depends on defining distinct tumour subgroups using biomarkers that may occur at very modest frequencies. One such subgroup comprises patients with exceptionally mutated ...(ultramutated) cancers caused by mutations that impair DNA polymerase epsilon (POLE) proofreading.
We examined the association of POLE proofreading domain mutation with clinicopathological variables and immune response in colorectal cancers from clinical trials (VICTOR, QUASAR2, and PETACC-3) and colorectal cancer cohorts (Leiden University Medical Centre 1 and 2, Oslo 1 and 2, Bern, AMC-AJCC-II, and Epicolon-1). We subsequently investigated its association with prognosis in stage II/III colorectal cancer by Cox regression of pooled individual patient data from more than 4500 cases from these studies.
Pathogenic somatic POLE mutations were detected in 66 (1·0%) of 6517 colorectal cancers, and were mutually exclusive with mismatch repair deficiency (MMR-D) in the 6277 cases for whom both markers were determined (none of 66 vs 833 13·4% of 6211; p<0·0001). Compared with cases with wild-type POLE, cases with POLE mutations were younger at diagnosis (median 54·5 years vs 67·2 years; p<0·0001), were more frequently male (50 75·8% of 66 vs 3577 55·5% of 6445; p=0·0010), more frequently had right-sided tumour location (44 68·8% of 64 vs 2463 39·8% of 6193; p<0·0001), and were diagnosed at an earlier disease stage (p=0·006, χ
test for trend). Compared with mismatch repair proficient (MMR-P) POLE wild-type tumours, POLE-mutant colorectal cancers displayed increased CD8+ lymphocyte infiltration and expression of cytotoxic T-cell markers and effector cytokines, similar in extent to that observed in immunogenic MMR-D cancers. Both POLE mutation and MMR-D were associated with significantly reduced risk of recurrence compared with MMR-P colorectal cancers in multivariable analysis (HR 0·34 95% CI 0·11-0·76; p=0·0060 and 0·72 0·60-0·87; p=0·00035), although the difference between the groups was not significant.
POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. This association underscores the importance of rare biomarkers in precision cancer medicine, but also raises important questions about how to identify and implement them in practice.
Cancer Research UK, Academy of Medical Sciences, Health Foundation, EU, ERC, NIHR, Wellcome Trust, Dutch Cancer Society, Dutch Digestive Foundation.
How Political Parties Respond focuses specifically on the question of interest aggregation. Do parties today perform that function? If so, how? If not, in what different ways do they seek to show ...themselves responsive to the electorate? This fascinating book studies these questions with reference to Great Britain, France, Germany, Italy, Spain, Denmark, Norway, Sweden, and Canada. A chapter on Russia demonstrates how newly powerful private interest groups and modern techniques of persuasion can work together to prevent effective party response to popular interests in systems where the authoritarian tradition remains strong.
Kay Lawson is Professor Emerita, San Francisco State University, and General Editor of the International Political Science Review. Her research and publications have focussed on the comparative study of political parties, including Political Parties and Democracy in the United States, The Comparative Study of Political Parties, Political Parties and Linkage (co-edited), When Parties Fail (co-edited), How Political Parties Work (editor), and Cleavages, Parties and Voters (co-edited). She is also the author of The Human Polity , now in its fifth edition. She is the 2003 recipient of the Eldersveld Award (for a lifetime of outstanding scholarly and professional contributions to the study of parties and political organizations). Thomas Poguntke is Professor of Political Science at SPIRE, Keele University, UK and Fellow at the Mannheim Centre for European Social Research. He is author of Parteiorganisation im Wandel: Gesellschaftliche Verankerung und organisatorische Anpassung im Europäischen Vergleich (Westdeutscher Verlag 2000), Alternative Politics: The German Green Party , (Edinburgh University Press 1993) and co-editor of several volumes politics and parties in western democracies. His main research interests are political parties and the comparative analysis of democratic regimes.
When parties fail Lawson, Kay; Merkl, Peter H
2014., 20140701, 2014, 2014-07-14
eBook
Throughout history parties have faltered and new groups have emerged, but rarely has this process been so accelerated, so widespread, and so conducive to dramatic political change as in our present ...era. When Parties Fail explores alternative organizations in depth and comparatively. Among the organizations discussed are environmentalist groups, such as the West German and Swedish Greens, the Italian Radicals, and local protest groups in Japan, Switzerland, and the United States. Also considered are new groups seeking attention in unresponsive party systems, such as the Danish Gilstrup party, the British SDP, and American PACs; community parties and movements in Israel, India, Britain, and the American South; and antiauthoritarian movements in Poland (Solidarity), Taiwan, and Ghana. The case of France provides an example of major party survival. Three broadly comparative chapters consider the reasons for major party persistence in some nations and the causes and impact of their decline in others.
The contributors to the book are David Apter, Myron J. Aronoff, Liang-shing Fan, Frank B. Feigert, Zvi Gitelman, Ronald J. Herring, Jon Kraus, Kay Lawson, Tom Mackie, Peter H. Merkl, Raffaela Y. Nanetti, Angelo Panebianco, Mogens N. Pedersen, Geoffrey Pridham, Peter Pulzer, Richard Rose, Donald Schoonmaker, Frank Sorauf, Robert C. A. Sorensen, Evert Vedung, Hanes Walton, Jr., and Frank L. Wilson.
Originally published in 1988.
ThePrinceton Legacy Libraryuses the latest print-on-demand technology to again make available previously out-of-print books from the distinguished backlist of Princeton University Press. These paperback editions preserve the original texts of these important books while presenting them in durable paperback editions. The goal of the Princeton Legacy Library is to vastly increase access to the rich scholarly heritage found in the thousands of books published by Princeton University Press since its founding in 1905.
Repeat expansion disorders affect about 1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, ...resulting in underdiagnosis of people who have atypical clinical presentations, especially in paediatric patients without a previous positive family history. Whole genome sequencing is increasingly used as a first-line test for other rare genetic disorders, and we aimed to assess its performance in the diagnosis of patients with neurological repeat expansion disorders.
We retrospectively assessed the diagnostic accuracy of whole genome sequencing to detect the most common repeat expansion loci associated with neurological outcomes (AR, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, C9orf72, CACNA1A, DMPK, FMR1, FXN, HTT, and TBP) using samples obtained within the National Health Service in England from patients who were suspected of having neurological disorders; previous PCR test results were used as the reference standard. The clinical accuracy of whole genome sequencing to detect repeat expansions was prospectively examined in previously genetically tested and undiagnosed patients recruited in 2013–17 to the 100 000 Genomes Project in the UK, who were suspected of having a genetic neurological disorder (familial or early-onset forms of ataxia, neuropathy, spastic paraplegia, dementia, motor neuron disease, parkinsonian movement disorders, intellectual disability, or neuromuscular disorders). If a repeat expansion call was made using whole genome sequencing, PCR was used to confirm the result.
The diagnostic accuracy of whole genome sequencing to detect repeat expansions was evaluated against 793 PCR tests previously performed within the NHS from 404 patients. Whole genome sequencing correctly classified 215 of 221 expanded alleles and 1316 of 1321 non-expanded alleles, showing 97·3% sensitivity (95% CI 94·2–99·0) and 99·6% specificity (99·1–99·9) across the 13 disease-associated loci when compared with PCR test results. In samples from 11 631 patients in the 100 000 Genomes Project, whole genome sequencing identified 81 repeat expansions, which were also tested by PCR: 68 were confirmed as repeat expansions in the full pathogenic range, 11 were non-pathogenic intermediate expansions or premutations, and two were non-expanded repeats (16% false discovery rate).
In our study, whole genome sequencing for the detection of repeat expansions showed high sensitivity and specificity, and it led to identification of neurological repeat expansion disorders in previously undiagnosed patients. These findings support implementation of whole genome sequencing in clinical laboratories for diagnosis of patients who have a neurological presentation consistent with a repeat expansion disorder.
Medical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, and Illumina.
Intratumoural T-cell infiltrate intensity cortes wrelaith clinical outcome in stage II/III colorectal cancer (CRC). We aimed to determine whether this association varies across this heterogeneous ...group.
We performed a pooled analysis of 1804 CRCs from the QUASAR2 and VICTOR trials. Intratumoural CD8
and CD3
densities were quantified by immunohistochemistry in tissue microarray (TMA) cores, and their association with clinical outcome analysed by Cox regression. We validated our results using publicly available gene expression data in a pooled analysis of 1375 CRCs from seven independent series.
In QUASAR2, intratumoural CD8
was a stronger predictor of CRC recurrence than CD3
and showed similar discriminative ability to both markers in combination. Pooled multivariable analysis of both trials showed increasing CD8
density was associated with reduced recurrence risk independent of confounders including DNA mismatch repair deficiency, POLE mutation and chromosomal instability (multivariable hazard ratio HR for each two-fold increase = 0.92, 95%CI = 0.87-0.97, P = 3.6 × 10
). This association was not uniform across risk strata defined by tumour and nodal stage: absent in low-risk (pT3,N0) cases (HR = 1.03, 95%CI = 0.87-1.21, P = 0.75), modest in intermediate-risk (pT4,N0 or pT1-3,N1-2) cases (HR = 0.92, 95%CI = 0.86-1.0, P = 0.046) and strong in high-risk (pT4,N1-2) cases (HR = 0.87, 95%CI = 0.79-0.97, P = 9.4 × 10
); P
= 0.090. Analysis of tumour CD8A expression in the independent validation cohort revealed similar variation in prognostic value across risk strata (P
= 0.048).
The prognostic value of intratumoural CD8
cell infiltration in stage II/III CRC varies across tumour and nodal risk strata.
We present clinicopathologic data on 10 pulmonary myxoid sarcomas, which are defined by distinctive histomorphologic features and characterized by a recurrent fusion gene, that appear to represent a ...distinct tumor entity at this site. The patients 7 female, 3 male; aged 27 to 67 y (mean, 45 y) presented with local or systemic symptoms (n=5), symptoms from cerebral metastasis (1), or incidentally (2). Follow-up of 6 patients showed that 1 with brain metastasis died shortly after primary tumor resection, 1 developed a renal metastasis but is alive and well, and 4 are disease free after 1 to 15 years. All tumors involved pulmonary parenchyma, with a predominant endobronchial component in 8 and ranged from 1.5 to 4 cm. Microscopically, they were lobulated and composed of cords of polygonal, spindle, or stellate cells within myxoid stroma, morphologically reminiscent of extraskeletal myxoid chondrosarcoma. Four cases showed no or minimal atypia, 6 showed focal pleomorphism, and 5 had necrosis. Mitotic indices varied, with most tumors not exceeding 5/10 high-power fields. Tumors were immunoreactive for only vimentin and weakly focal for epithelial membrane antigen. Of 9 tumors, 7 were shown to harbor a specific EWSR1-CREB1 fusion by reverse transcription-polymerase chain reaction and direct sequencing, with 7 of 10 showing EWSR1 rearrangement by fluorescence in situ hybridization. This gene fusion has been described previously in 2 histologically and behaviorally different sarcomas: clear cell sarcoma-like tumors of the gastrointestinal tract and angiomatoid fibrous histiocytomas; however, this is a novel finding in tumors with the morphology we describe and that occur in the pulmonary region.
T-cell non-Hodgkin's lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell ...non-Hodgkin's lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin's T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma.
Abstract
Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders ...characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100 000 Genomes Project.
This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights and strategies that raise the diagnostic yield.
To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene’s structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from up to 2182 individuals presenting with ataxia and 6658 non-neurological probands recruited in the 100 000 Genomes Project.
Using this approach, we demonstrated a high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100 000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs within known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100 000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia.
Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known ataxia-associated genes, in effect treating these regions as candidate pathogenic loci.
Using a systems biology approach without a priori assumptions, Chen et al. show that genes associated with adult- and child-onset ataxia have many common characteristics, including a relatively high density of short tandem repeats. Removing the age-of-onset partition, and screening for repeat expansions, could improve the diagnostic rate for hereditary ataxia.
PDF
