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Department of Oncology researchers Dr Andrew Blackford and Dr Simon Lord have been appointed as Fellows of Oriel College.
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Bernard Galewski, bernardiwo.com
COGENT (COlorectal cancer GENeTics) revisited.
Many colorectal cancers (CRCs) develop in genetically susceptible individuals most of whom are not carriers of germ line mismatch repair or APC gene mutations and much of the heritable risk of CRC appears to be attributable to the co-inheritance of multiple low-risk variants. The accumulated experience to date in identifying this class of susceptibility allele has highlighted the need to conduct statistically and methodologically rigorous studies and the need for the multi-centre collaboration. This has been the motivation for establishing the COGENT (COlorectal cancer GENeTics) consortium which now includes over 20 research groups in Europe, Australia, the Americas, China and Japan actively working on CRC genetics. Here, we review the rationale for identifying low-penetrance variants for CRC and the current and future challenges for COGENT.
The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.
BACKGROUND: A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. METHODS: Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. FINDINGS: In 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25,458 coronary heart disease cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10(-5)). INTERPRETATION: On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses. FUNDING: UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.
The co-evolution of multiple female mating preferences and preferred male characters: The "gene-for-gene" hypothesis of sexual selection
The males of some animals possess a number of characters that may have evolved because they are preferred by females in mating. Some of these characters are exaggerations of corresponding female traits and may be under polygenic control. Other characters appear to show discrete or discontinuous variation between males and females; these traits often make the male phenotype more elaborate and may be controlled by single loci. We propose the "gene-for-gene" hypothesis of sexual selection to account for the evolution of multiple male ornaments that differ discontinuously from their female counterparts: each male trait, controlled by a single locus, has a corresponding female preference, also controlled by a single locus. Each character and its preference might have evolved sequentially; alternatively, more than one such combination might have evolved more or less at the same time. To analyse the latter possibility, we have constructed a "gene-for-gene" model of the simultaneous co-evolution of two preferred characters and their preferences. Simulations show that large genetic interactions can arise between different combinations of character and preference, usually if one character is deleterious and the other is advantageous. "Gene-for-gene" models may hereby promote the co-evolution of deleterious male ornaments and their preferences. The simultaneous co-evolution of preferences and male traits is therefore a serious and important alternative to sequential evolution. The "gene-for-gene" hypothesis may explain the evolution of some of the male ornaments of animals like peacocks, ruffs, domestic fowls and pheasants. It might also apply to characters thought to be the preserve of polygenic models. © 1989 Academic Press Limited.
Molecular pathology of solid tumours: some practical suggestions for translating research into clinical practice.
"Molecular pathology" can be broadly defined as the use of genetic data, in addition to the standard pathological parameters, to optimise diagnosis and to indicate treatment and prognosis. The benefit to be gained from the exploitation of molecular techniques to provide additional information to aid patient management is potentially vast. Currently, molecular pathology is rarely used in clinical practice, although it is anticipated that it will eventually become a part of routine practice. However, incorporating molecular techniques into routine practice will not be straightforward because there are several issues to be resolved. Following on from a symposium held at the Royal College of Pathologists to discuss some of these issues, the establishment of a committee of molecular pathology is proposed to plan and coordinate the introduction of molecular pathology into routine clinical practice.
PHLDA1 expression marks the putative epithelial stem cells and contributes to intestinal tumorigenesis
Studies employing mouse models have identified crypt base and position +4 cells as strong candidates for intestinal epithelial stem cells. Equivalent cell populations are thought to exist in the human intestine; however robust and specific protein markers are lacking. Here, we show that in the human small and large intestine, PHLDA1 is expressed in discrete crypt base and some position +4 cells. In small adenomas, PHLDA1 was expressed in a subset of undifferentiated and predominantly Ki-67-negative neoplastic cells, suggesting that a basic hierarchy of differentiation is retained in early tumorigenesis. In large adenomas, carcinomas, and metastases PHLDA1 expression became widespread, with increased expression and nuclear localization at invasive margins. siRNA-mediated suppression of PHLDA1 in colon cancer cells inhibited migration and anchorage-independent growth in vitro and tumor growth in vivo. The integrins ITGA2 and ITGA6 were downregulated in response to PHLDA1 suppression, and accordingly cell adhesion to laminin and collagen was significantly reduced. We conclude that PHLDA1 is a putative epithelial stem cell marker in the human small and large intestine and contributes to migration and proliferation in colon cancer cells. ©2011 AACR.
Genetics of inflammatory bowel disease and associated cancers
The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, result from an altered host response to intestinal flora, and genome-wide searches have identified a number of disease susceptibility alleles, such as NOD2/CARD15. IBD confers a high risk of development of a number of malignancies, especially colorectal cancer, and this risk is related to chronic inflammation. Genomic instability in the form of gross chromosomal changes is common, with microsatellite instability occurring in a small subset of colitis-associated lesions. The carcinogenesis pathway in colitis-associated cancers is less clearly understood than its sporadic counterpart. Mutations in the APC gene appear to be less frequent and occur later, whereas inflammation-induced p53 mutations are found early in nondysplastic tissue. Selection and clonal expansion of inflammation-induced mutations is likely to account for the high mutational load seen in carcinoma tissue. Development of an effective biomarker to predict development of malignancy in colitis has so far been unsuccessful. Copyright © 2006 by Current Science Inc.
Evidence for a colorectal cancer susceptibility locus on chromosome 3q21-q24 from a high-density SNP genome-wide linkage scan.
To identify a novel susceptibility gene for colorectal cancer (CRC), we conducted a genome-wide linkage analysis of 69 pedigrees segregating colorectal neoplasia in which involvement of known loci had been excluded, using a high-density single nucleotide polymorphism (SNP) array containing 10,204 markers. Multipoint linkage analyses were undertaken using both non-parametric (model-free) and parametric (model-based) methods. After the removal of SNPs in strong linkage disequilibrium, we obtained a maximum non-parametric linkage statistic of 3.40 (P=0.0003) at chromosomal region 3q21-q24. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=3.10, genome-wide P=0.038) with 62% of families linked to the locus. We provide evidence for a novel CRC susceptibility gene. Further studies are needed to confirm this localization and to evaluate the contribution of this locus to disease incidence.
Chromosomal instability confers intrinsic multidrug resistance.
Aneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote chromosomal instability (CIN) that may contribute to the acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models. Identification of distinct therapeutic agents that target tumor karyotypic complexity has important clinical implications. To identify distinct therapeutic approaches to specifically limit the growth of CIN tumors, we focused on a panel of colorectal cancer (CRC) cell lines, previously classified as either chromosomally unstable (CIN(+)) or diploid/near-diploid (CIN(-)), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle, and transmembrane receptor signaling pathways. CIN(+) cell lines displayed significant intrinsic multidrug resistance compared with CIN(-) cancer cell lines, and this seemed to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multidrug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing chromosomal heterogeneity and isogenic cell line models of CIN(+) displayed multidrug resistance relative to their CIN(-) parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN(+) predicted worse progression-free or disease-free survival relative to patients with CIN(-) disease. Our results suggest that stratifying tumor responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity.
Cancer genetics
This chapter outlines the contribution of inherited genetic variation to cancer susceptibility and of acquired somatic mutations to cancer growth. The chapter deals with all forms of cancer susceptibility from rare, high-penetrance Mendelian syndromes to common alleles with small effects with importance for population risk. The section on somatic cancer genetics deals with underlying processes, such as genomic instability, and the types of functional change that result in the growth of both benign and malignant tumors. Genetic and epigenetic changes in cancers, from chromosomal scale to small mutations, are discussed. Overall, rather than performing an exhaustive survey in this large field, the chapter outlines the principles of cancer genetics using examples from both common and rare tumor types.
Low-penetrance susceptibility variants in familial colorectal cancer.
BACKGROUND: Genomewide association studies have identified 10 low-penetrance loci that confer modestly increased risk for colorectal cancer (CRC). Although they underlie a significant proportion of CRC in the general population, their impact on the familial risk for CRC has yet to be formally enumerated. The aim of this study was to examine the combined contribution of the 10 variants, rs6983267, rs4779584, rs4939827, rs16892766, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, on familial CRC. METHODS: The population-based series of CRC samples included in this study consisted of 97 familial cases and 691 sporadic cases. Genotypes in the 10 loci and clinical data, including family history of cancer verified from the Finnish Cancer Registry, were available. The overall number of risk alleles (0-20) was determined, and its association with familial CRC was analyzed. Excess familial risk was estimated using cancer incidence data from the first-degree relatives of the cases. RESULTS: A linear association between the number of risk alleles and familial CRC was observed (P = 0.006). With each risk-allele addition, the odds of having an affected first-degree relative increased by 1.16 (95% confidence interval, 1.04-1.30). The 10 low-penetrance loci collectively explain approximately 9% of the variance in familial risk for CRC. CONCLUSIONS: This study provides evidence to support the previous indirect estimations that these low-penetrance variants account for a relatively small proportion of the familial aggregation of CRC. IMPACT: Our results emphasize the need to characterize the remaining molecular basis of familial CRC, which should eventually yield in individualized targeting of preventive interventions.
Intestinal stem cells and the development of colorectal neoplasia
The mammalian intestinal epithelium is a rapidly renewing tissue in which tissue homeostasis is regulated by a balance between cell proliferation, differentiation, and apoptosis. Over the last three decades, investigators have described the structure and cell kinetics of the functional unit—the intestinal crypt (known as the crypt of Lieberku¨hn in the small intestine)—and evidence has accumulated to support the concept that there are principally four differentiated intestinal cell types (enterocytes, mucosecreting or goblet cells, enteroendocrine cells, and Paneth cells in the small intestine), derived from a common pluripotent progenitor cell, the intestinal stem cell, located at or just above the bottom of the intestinal crypt. The first half of this chapter will review the evidence behind these prevailing concepts. Until recently, chapters on intestinal stem cells concluded.
Mutational screen at the oeyts-jeghers (LKB1) locus in spordic colon and ovarian tumors
Objective:To screen LKB1 mutation in sporadic colon and ovarian tumors. Methods: Using PCR-SSCP analysis, 72 colon cancer, 45 ovarian cancer, 14 granulosa cell tumor were screened for LKB1 mutation. Results: no mutation was in sporadic colon and ovarian adenocarcinomas. Two mutations were detected in one of the granulosa cell tumors: a mis-sense mutation affecting the putative start codon (ATG→ACG, MIT); and a silent change in erxon 7 (CTT→CTA, leucine). Conclusion: LKB1 mutations in sporadic colon and ovarian cancers are rare event and LKB1 is not the target gene lost on chromosome 19p13.3 in ovarian cancers.
The influence of female viability differences on the evolution of mate choice
When females choose a mate, they may do so on the basis of some arbitrary character or they may prefer a trait that provides them with some direct or indirect benefit. One class of models of female choice, collectively referred to as the 'handicap principle', states that preferred ornaments act as markers of underlying heritable male fitness. 'Handicap' models have proved to be of great importance in explaining how female mating preferences can coevolve with male ornaments by an augmented form of the 'Fisherian process'. We suggest that differences in heritable female (Darwinian) fitness might affect the evolution of female mating preferences. Although little experimental evidence currently exists, it is entirely plausible that female fitness affects the expression of mating preferences. For example, fitter females might undertake more rigorous searches for rare, preferred males. In order to determine whether differences in female fitness can influence sexual selection by female choice, a model is presented in which mating preferences are more likely to be expressed by females of higher fitness. Results of the model show how specific female preferences for arbitrary, disadvantageous male characters can easily evolve, even if choice itself is costly. In many of these cases, the Fisherian process alone would not be sufficient to cause coevolution of preference and preferred character. Polymorphisms in male characters may also be maintained in the fitter female models. Some of the models show extreme and unusual fluctuations in the frequencies of male characters and female preferences before equilibrium is reached. Differences in female fitness may have important influences on sexual selection by female choice.