Association studies on 11 published colorectal cancer risk loci

Colorectal cancer (CRC) is the third most common cancer type in the Western world. Over one million patients are diagnosed worldwide yearly. A family history of CRC is a major risk factor for CRC. The total genetic contribution to disease development is estimated to be 35%. High-risk syndromes caused by known genes such as familial adenomatous polyposis (FAP) and Lynch Syndrome (LS) explain less than 5% of that number. Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. In total, germline mutations in known genes and moderate- and low risk variants are today suggested to explain 10-15% of the total genetic burden. Hence, predisposed genetic factor are still left to be found. The aim of paper I was to investigate if 11 published loci reported to be associated with an increased or decreased risk of colorectal cancer could be confirmed in a Swedish-based cohort. The cohort was composed of 1786 cases and 1749 controls that were genotyped and analyzed statistically. Genotype– phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumor location, was performed. Of 11 loci, 5 showed statistically significant odds ratios similar to previously published findings. Most of the remaining loci showed similar OR to previous publications. Four statistically significant genotype–phenotype associations were reported. The aim of paper II was to further study these 11 SNPs and their possible correlation with morphological features in tumors. We analyzed 15 histological features in 1572 CRC cases. Five SNPs showed statistically significant associations with morphological parameters. The parameters were poor differentiation, mucin production, decreased frequency of Crohn-like peritumoral reaction and desmoplastic response. The aim of paper III was to identify new CRC loci using a genome wide linkage analysis. We used 121 non-FAP/LS colorectal cancer families and genotyped 600 subjects using SNP array chips. No statistically significant result was found. However, suggestive linkage was found in the parametric analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2) and one on 17p13.2 (LOD/HLOD=2.0). Our linkage study adds support for the previously suggested region on chromosome 9 and suggests three additional loci to be involved in colorectal cancer risk. It is debated whether CRC is a single entity or two different entities, colon- and rectal cancer. Studies have recognized their molecular differences. The aim of paper IV was to identify novel colon- and rectal loci. We performed a genome wide linkage analysis using 32 colon- and 56 rectal cancer families. No LOD or HLOD score above three was observed. However, results close to three could be demonstrated. A maximum HLOD= 2.49 at locus 6p21.1-p12.1 and HLOD= 2.55 at locus 18p11.2 was observed for the colon- and rectal cancer families respectively. Exome sequencing was done, on colon and rectal patients, in these regions of interest. We report 25 variants mutated in family members on chromosome 6 and 27 variants on chromosome 18. Further studies are ongoing to elucidate the importance of these variants

Fluorescence in situ hybridisation analysis of chromosomal aberrations in gastric tissue: the potential involvement of Helicobacter pylori

In this series of experiments, a novel protocol was developed whereby gastric cells were collected using endoscopic cytology brush techniques, and prepared, such that interphase fluorescence in situ hybridization (FISH) could be performed. In total, 80 distinct histological samples from 37 patients were studied using four chromosome probes (over 32 000 cells analysed). Studies have previously identified abnormalities of these four chromosomes in upper GI tumours. Using premalignant tissues, we aimed to determine how early in Correa's pathway to gastric cancer these chromosome abnormalities occurred. Aneuploidy of chromosomes 4, 8, 20 and 17(p53) was detected in histologically normal gastric mucosa, as well as in gastritis, intestinal metaplasia, dysplasia and cancer samples. The levels of aneuploidy increased as disease severity increased. Amplification of chromosome 4 and chromosome 20, and deletion of chromosome 17(p53) were the more common findings. Hence, a role for these abnormalities may exist in the initiation of, and the progression to, gastric cancer. Helicobactor pylori infection was determined in premalignant tissue using histological analysis and PCR technology. Detection rates were comparable. PCR was used to subtype H. pylori for CagA status. The amplification of chromosome 4 in gastric tissue was significantly more prevalent in H. pylori-positive patients (n=7) compared to H. pylori-negative patients (n=11), possibly reflecting a role for chromosome 4 amplification in H. pylori-induced gastric cancer. The more virulent CagA strain of H. pylori was associated with increased disease pathology and chromosomal abnormalities, although numbers were small (CagA+ n=3, CagA− n=4). Finally, in vitro work demonstrated that the aneuploidy induced in a human cell line after exposure to the reactive oxygen species (ROS) hydrogen peroxide was similar to that already shown in the gastric cancer pathway, and may further strengthen the hypothesis that H. pylori causes gastric cancer progression via an ROS-mediated mechanism

NSAIDs Modulate CDKN2A, TP53, and DNA Content Risk for Progression to Esophageal Adenocarcinoma

BACKGROUND: Somatic genetic CDKN2A, TP53, and DNA content abnormalities are common in many human cancers and their precursors, including esophageal adenocarcinoma (EA) and Barrett's esophagus (BE), conditions for which aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as possible chemopreventive agents; however, little is known about the ability of a biomarker panel to predict progression to cancer nor how NSAID use may modulate progression. We aimed to evaluate somatic genetic abnormalities with NSAIDs as predictors of EA in a prospective cohort study of patients with BE. METHODS AND FINDINGS: Esophageal biopsies from 243 patients with BE were evaluated at baseline for TP53 and CDKN2A (p16) alterations, tetraploidy, and aneuploidy using sequencing; loss of heterozygosity (LOH); methylation-specific PCR; and flow cytometry. At 10 y, all abnormalities, except CDKN2A mutation and methylation, contributed to EA risk significantly by univariate analysis, ranging from 17p LOH (relative risk [RR] = 10.6; 95% confidence interval [CI] 5.2–21.3, p < 0.001) to 9p LOH (RR = 2.6; 95% CI 1.1–6.0, p = 0.03). A panel of abnormalities including 17p LOH, DNA content tetraploidy and aneuploidy, and 9p LOH was the best predictor of EA (RR = 38.7; 95% CI 10.8–138.5, p < 0.001). Patients with no baseline abnormality had a 12% 10-y cumulative EA incidence, whereas patients with 17p LOH, DNA content abnormalities, and 9p LOH had at least a 79.1% 10-y EA incidence. In patients with zero, one, two, or three baseline panel abnormalities, there was a significant trend toward EA risk reduction among NSAID users compared to nonusers (p = 0.01). The strongest protective effect was seen in participants with multiple genetic abnormalities, with NSAID nonusers having an observed 10-y EA risk of 79%, compared to 30% for NSAID users (p < 0.001). CONCLUSIONS: A combination of 17p LOH, 9p LOH, and DNA content abnormalities provided better EA risk prediction than any single TP53, CDKN2A, or DNA content lesion alone. NSAIDs are associated with reduced EA risk, especially in patients with multiple high-risk molecular abnormalities

Contribuciones para la customización de viviendas de interés social a partir de las intervenciones realizadas por los usuarios en la etapa de uso

En general el diseño de las políticas habitacionales ha prescindido del conocimiento de la demanda específica. La producción del hábitat popular ha sido a través del uso de técnicas constructivas industrializadas, adoptando estrategias de producción masiva, con una eficiente utilización de los recursos, pero ignorando las exigencias individuales de cada familia, la pluralidad y el dinamismo de la sociedad. En consecuencia surgen complejos que no se adecuan a las necesidades de la población, donde los usuarios intervienen incorporando necesidades no previstas en el desarrollo del producto. A partir de un escenario industrial competitivo donde la diversidad del mercado es un nuevo factor para las empresas, surge la customización masiva como una nueva estrategia, capaz de satisfacer a los consumidores con diferentes productos sin aumentar significativamente los costos y el tiempo de entrega. En programas habitacionales la oferta de customización es muy limitada debido principalmente a lograr una economía de escala de la producción. El objetivo principal de esta investigación fue proponer formas de retroalimentar el proceso de desarrollo del producto a partir de las intervenciones realizadas por los usuarios. Fueron realizados dos estudios de casos de programas residenciales, donde la participación del usuario en el desarrollo del producto es diferente. La investigación se realizó en tres etapas, siendo la primera etapa A de comprensión del proceso de desarrollo del producto, caracterizando la empresa y los emprendimientos. Fueron realizadas entrevistas con informantes calificados, visitas a los emprendimientos y análisis de documentos técnicos. La etapa B tuvo como objetivo la planificación del levantamiento de datos para capturar las informaciones de las intervenciones de los usuarios en la etapa de uso de las unidades. Para esto se realizóla colecta de datos a través de entrevistas, y cuestionarios estructurados a los usuarios, y análisis de las intervenciones a través de fotografías satelitales. La etapa C busco identificar oportunidades de procesamiento de los datos, para entender los requisitos de los usuarios y contribuir a mejorar el PDP. Se identificaron estrategias en el proceso de producción de un sistema industrializado de producción de viviendas, encontrando oportunidades de implementar mejoras en la capacidad de adaptabilidad del sistema a los cambios producidos por los usuarios, aumentando la variabilidad y flexibilidad de las opciones de viviendas ofrecidas por la empresa. Conjuntamente con la empresa fueron analizadas las intervenciones y se identificaron oportunidades para adoptar distintos grados de customización. Las principales contribuciones del trabajo es comprender cuales son los requisitos de los usuarios en la etapa de uso de las viviendas, para lograr un producto customizable en proyectos de vivienda de interés social y contribuir al desarrollo de productos industrializados que incorporen estos requisitos.In general, housing policies have ignored knowledge on the specific needs of families in the design of housing projects. In fact, several industrialized building techniques have been used in social housing, often connected to the adoption of mass production ideas, with the aim of achieving a highly efficient use of resources, but ignoring the individual needs of each family, and the plurality and dynamism of the society. Consequently, there are many housing estates that do not fulfill the needs of the population, resulting in changes in the housing units carried out by the users so that their requirements can be properly considered. In an industrial setting that has growing competition, the diversity in the client needs has become a key factor for several companies in the manufacturing sector. In this context, mass customization has emerged as a new strategy, with the aim of satisfying users with different needs without significantly increasing costs and delivery time. However, in the social housing sector, very few programs offer the possibility of customization, mainly due to the need to achieve economies of scale. Thus, the aim of this research work is to propose guidelines for providing feedback to the product development process of social housing projects, based on product changes that have been made by the users after delivery. Two case studies were conducted in different residential projects, developed by the same company, in which the degree of user involvement in product development was different. The research method was divided into three stages. In stage A, the aim was to understand the product development process, the housing company involved in this investigation, as well as the three projects. The main sources of evidences used were interviews with company representatives, visits to the housing estates, and document analysis. Phase B involved the collection of data related to the product changes carried out by users in the three projects. The main sources of evidence used were interviews with a sample of users, direct observation of those changes, and analysis of interventions by using satellite photos. Phase C sought to propose guidelines for processing user requirement data, and to identify improvement opportunities in the product development process. Regarding the industrialized building system developed by the company, some improvements were proposed, mostly related to the capacity of adaptation of the system to the product changes often made by the users, increasing the variety and flexibility of the housing options offered by the company. In collaboration with company representatives, different degrees of customization were devised. The main contributions of this research work are concerned with how to capture and process requirements based on multiple sources of evidence, as well as to understand the nature of product changes demanded by the users, which can be useful for designing customized houses