Shrink and squeeze: today\u27s teaching pressures and its effect on teaching social studies

Social studies education is one of the four core subjects taught to students in elementary schools. Teaching social studies provides students with the content knowledge and ways of thinking to allow them to be participating members in their communities. Although there are many skills students learn from social studies, due to federal legislation starting with No Child Left Behind, social studies has been put on the back burner while math and reading take the forefront. The goal of this study was to explore the perceptions and experiences of teachers regarding their social studies teaching. Semi-structured interviews were conducted with veteran teachers about their current approach to teaching social studies and changes they have made given the increasing marginalization of this subject area. Major themes related to social studies in fifth grade classes included a lack of emphasis on social studies, reduced instructional time, a changed instructional approach, gaps in student learning, a changed teaching response, and increased teacher advocacy

A morphological and molecular study of proposed early forms of the traditional serrated adenoma

AIMS: The traditional serrated adenoma (TSA) is the least common subtype of serrated colorectal polyp. Large protuberant lesions are easily recognized, however, the origins of TSAs are not known and early forms have not been described. Some large TSAs present with a flat "shoulder" component surrounding the central protuberant component. We hypothesized that small polyps with the same histology as these "shoulder" regions may represent early TSAs. METHODS AND RESULTS: We collected 70 small (< 10mm) polyps that may represent early TSAs based on typical TSA cytology covering the luminal surface. We also identified 12 large TSAs with a "shoulder" component resembling these small polyps. The study polyps patients had a mean age of 58 years, 54% were female, had a mean 4.1mm diameter and were predominantly distal (71%). Morphologically, slit-like serration was present in 81%, ectopic crypt formations in 67% and a villous component in 47%. These histological features were similar to the 12 "shoulder" lesions. Immunohistochemical stains showed absence of β-catenin nuclear expression in 96% of the small polyps, retained expression of MLH1 in 100% and Ki-67 positivity restricted to the crypt bases and ectopic crypt formations. BRAF and KRAS mutations were identified in 47% and 31% of the polyps respectively. Compared with KRAS-mutated polyps, BRAF-mutated polyps were more likely to arise in a precursor polyp (82% vs 18%, P < 0.001) and were more likely to have slit-like serrations (100% vs 73%, P = 0.003). CONCLUSIONS: These morphological, immunohistochemical and molecular findings are similar to what has been reported in large TSAs and support the hypothesis that these polyps represent early forms of TSA. This article is protected by copyright. All rights reserved

Copy number profiles of paired primary and metastatic colorectal cancers

This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Liver metastasis is the major cause of death following a diagnosis of colorectal cancer (CRC). In this study, we compared the copy number profiles of paired primary and liver metastatic CRC to better understand how the genomic structure of primary CRC differs from the metastasis. Paired primary and metastatic tumors from 16 patients and their adjacent normal tissue samples were analyzed using single nucleotide polymorphism arrays. Genome-wide chromosomal copy number alterations were assessed, with particular attention to 188 genes known to be somatically altered in CRC and 24 genes that are clinically actionable in CRC. These data were analyzed with respect to the timing of primary and metastatic tissue resection and with exposure to chemotherapy. The genomic differences between the tumor and paired metastases revealed an average copy number discordance of 22.0%. The pairs of tumor samples collected prior to treatment revealed significantly higher copy number differences compared to post-therapy liver metastases (P = 0.014). Loss of heterozygosity acquired in liver metastases was significantly higher in previously treated liver metastasis samples compared to treatment naive liver metastasis samples (P = 0.003). Amplification of the clinically actionable genes ERBB2, FGFR1, PIK3CA or CDK8 was observed in the metastatic tissue of 4 patients but not in the paired primary CRC. These examples highlight the intra-patient genomic discrepancies that can occur between metastases and the primary tumors from which they arose. We propose that precision medicine strategies may therefore identify different actionable targets in metastatic tissue, compared to primary tumors, due to substantial genomic differences

Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia

Colorectal cancer is a major cause of cancer death and approximately 20% arises within serrated polyps, which are under-recognized and poorly understood. Human serrated colorectal polyps frequently exhibit both oncogenic BRAF mutation and widespread DNA methylation changes, which are important in silencing genes restraining neoplastic progression. Here, we investigated whether in vivo induction of mutant Braf is sufficient to result in coordinated promoter methylation changes for multiple cancer-related genes. The BrafV637E mutation was induced in murine intestine on an FVB;C57BL/6J background and assessed for morphological and DNA methylation changes at multiple time points from 10 days to 14 months. Extensive intestinal hyperplasia developed by 10 days post-induction of the mutation. By 8 months, most mice had murine serrated adenomas with dysplasia and invasive cancer developed in 40% of mice by 14 months. From 5 months onwards, Braf mutant mice showed extensive, gene-specific increases in DNA methylation even in hyperplastic mucosa without lesions. This demonstrates that persistent oncogenic Braf signaling is sufficient to induce widespread DNA methylation changes. This occurs over an extended period of time, mimicking the long latency followed by rapid progression of human serrated neoplasia. This study establishes for the first time that DNA methylation arises slowly in direct response to prolonged oncogenic Braf signaling in serrated polyps; this finding has implications both for chemoprevention and for understanding the origin of DNA hypermethylation in cancer generally.Catherine E. Bond, Cheng Liu, Futoshi Kawamata, Diane M. McKeone, Winnie Fernando, Saara Jamieson, Sally-Ann Pearson, Alexandra Kane, Susan L. Woods, Tamsin R.M. Lannagan, Roshini Somashekar, Young Lee, Troy Dumenil, Gunter Hartel, Kevin J. Spring, Jennifer Borowsky, Lochlan Fennell, Mark Bettington, Jason Lee, Daniel L. Worthley, Barbara A. Leggett and Vicki L.J. Whitehal

Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome)

Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9

Risk Factors for Colorectal Cancer in Patients with Multiple Serrated Polyps: A Cross-Sectional Case Series from Genetics Clinics

Patients with multiple serrated polyps are at an increased risk for developing colorectal cancer (CRC). Recent reports have linked cigarette smoking with the subset of CRC that develops from serrated polyps. The aim of this work therefore was to investigate the association between smoking and the risk of CRC in high-risk genetics clinic patients presenting with multiple serrated polyps. Methods and Findings We identified 151 Caucasian individuals with multiple serrated polyps including at least 5 outside the rectum, and classified patients into non-smokers, current or former smokers at the time of initial diagnosis of polyposis. Cases were individuals with multiple serrated polyps who presented with CRC. Controls were individuals with multiple serrated polyps and no CRC. Multivariate logistic regression was performed to estimate associations between smoking and CRC with adjustment for age at first presentation, sex and co-existing traditional adenomas, a feature that has been consistently linked with CRC risk in patients with multiple serrated polyps. CRC was present in 56 (37%) individuals at presentation. Patients with at least one adenoma were 4 times more likely to present with CRC compared with patients without adenomas (OR = 4.09; 95%CI 1.27 to 13.14; P = 0.02). For females, the odds of CRC decreased by 90% in current smokers as compared to never smokers (OR = 0.10; 95%CI 0.02 to 0.47; P = 0.004) after adjusting for age and adenomas. For males, there was no relationship between current smoking and CRC. There was no statistical evidence of an association between former smoking and CRC for both sexes. Conclusion A decreased odds for CRC was identified in females with multiple serrated polyps who currently smoke, independent of age and the presence of a traditional adenoma. Investigations into the biological basis for these observations could lead to non-smoking-related therapies being developed to decrease the risk of CRC and colectomy in these patients.Daniel D. Buchanan, Kevin Sweet, Musa Drini, Mark A. Jenkins, Aung Ko Win, Dallas R. English, Michael D. Walsh, Mark Clendenning, Diane M. McKeone, Rhiannon J. Walters, Aedan Roberts, Sally-Ann Pearson, Erika Pavluk, John L. Hopper, Michael R. Gattas, Jack Goldblatt, Jill George, Graeme K. Suthers, Kerry D. Phillips, Sonja Woodal, Julie Arnold, Kathy Tucker, Amanda Muir, Michael Field, Sian Greening, Steven Gallinger, Renee Perrier, John A. Baron, John D. Potter, Robert Haile, Wendy Franke, Albert de la Chapelle, Finlay Macrae, Christophe Rosty, Neal I. Walker, Susan Parry and Joanne P. Youn

Methylation and expression of the tumour suppressor, PRDM5, in colorectal cancer and polyp subgroups

Background: PRDM5 is an epigenetic regulator that has been recognized as an important tumour suppressor gene. Silencing of PRDM5 by promoter hypermethylation has been demonstrated in several cancer types and PRDM5 loss results in upregulation of the Wnt pathway and increased cellular proliferation. PRDM5 has not been extensively investigated in specific subtypes of colorectal cancers. We hypothesized it would be more commonly methylated and inactivated in serrated pathway colorectal cancers that are hallmarked by a BRAF V600E mutation and a methylator phenotype, compared to traditional pathway cancers that are BRAF wild type. Methods: Cancer (214 BRAF mutant, 122 BRAF wild type) and polyp (59 serrated polyps, 40 conventional adenomas) cohorts were analysed for PRDM5 promoter methylation using MethyLight technology. PRDM5 protein expression was assessed by immunohistochemistry in cancers and polyps. Mutation of PRDM5 was analysed using cBioPortal's publicly available database. Results: BRAF mutant cancers had significantly more frequent PRDM5 promoter methylation than BRAF wild type cancers (77/214,36% vs 4/122,3%;

GNAS mutations are present in colorectal traditional serrated adenomas, serrated tubulovillous adenomas and serrated adenocarcinomas with adverse prognostic features

Activating mutations in GNAS are important in the development of a range of neoplasms, including a small proportion of conventional adenomas and colorectal carcinomas (CRCs). However, their contribution to serrated pathway neoplasia is unclear, as mutations have only been examined in small series of sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs), and not in serrated tubulovillous adenomas (sTVAs). The aim of this study was to investigate the frequency and significance of GNAS mutations in colorectal adenomas and CRCs.Using a large, well-characterized series, we identified GNAS mutations in 9.2% (18 of 196) of TSAs, 7.1% (four of 56) of sTVAs and 2.0% (nine of 459) of CRCs. Mutations were absent in SSAs (none of 43), tubular adenomas (none of 50) and conventional tubulovillous adenomas (none of 50). A BRAF or KRAS mutation was seen in 77.4% of GNAS mutant lesions, suggesting a synergistic effect with the mitogen-activated protein kinase pathway. In CRCs, GNAS mutations were associated with mucinous differentiation and serrated morphological features.GNAS mutations contribute significantly to the development of a subset of serrated adenomas and CRCs