Integrative genomic analysis of sporadic colorectal cancer

Inherited genetic mutations cause a small percentage of all cancers in the United States. The combination of risk factors and accumulated low penetrance susceptibility alleles are the determinants of an individual's predisposition. Identifying these risk alleles, particularly in colorectal cancer (CRC), a leading cause of cancer deaths, is of great importance. We report using the laboratory mouse and the powerful classical genetics mapping approach to identify novel susceptibility to colon cancer loci (Scc) and their associated networks. Our study mimics sporadic CRC by exposing a genetically diverse mouse population to a colon specific carcinogen, azoxymethane. In addition, we extend our understanding of CRC susceptibility by applying systems genetics to clarify the genetic interactions and cancer specific networks. The combination of genomics with classical genetics produced the field of genetical genomics, which is now expanding to systems genetics by integrating multiple, systems-level biomolecular data in the context of segregating genetic populations. This new integrative field has the power to elucidate molecular networks associated with biological phenotypes by anchoring variability in networks to natural genetic variants. As initial applications of this technology was transcriptional profiling, which is providing new insights into the genetic networks underlying normal and disease states. Classical and systems genetics have enabled us to elucidate CRC susceptibility networks and the cellular re-wiring that occurs during cancer development. These approaches offer the possibility to identify and pharmaceutically-target networks that are cancer-specific, resulting in more effective, and safer anti-cancer drugs

Genetic mapping and developmental timing of transmission ratio distortion in a mouse interspecific backcross

<p>Abstract</p> <p>Background</p> <p>Transmission ratio distortion (TRD), defined as statistically significant deviation from expected 1:1 Mendelian ratios of allele inheritance, results in a reduction of the expected progeny of a given genotype. Since TRD is a common occurrence within interspecific crosses, a mouse interspecific backcross was used to genetically map regions showing TRD, and a developmental analysis was performed to identify the timing of allele loss.</p> <p>Results</p> <p>Three independent events of statistically significant deviation from the expected 50:50 Mendelian inheritance ratios were observed in an interspecific backcross between the <it>Mus musculus </it>A/J and the <it>Mus spretus </it>SPRET/EiJ inbred strains. At weaning <it>M. musculus </it>alleles are preferentially inherited on Chromosome (Chr) 7, while <it>M. spretus </it>alleles are preferentially inherited on Chrs 10 and 11. Furthermore, alleles on Chr 3 modify the TRD on Chr 11. All TRD loci detected at weaning were present in Mendelian ratios at mid-gestation and at birth.</p> <p>Conclusions</p> <p>Given that Mendelian ratios of inheritance are observed for Chr 7, 10 and 11 during development and at birth, the underlying causes for the interspecific TRD events are the differential post-natal survival of pups with specific genotypes. These results are consistent with the TRD mechanism being deviation from Mendelian inheritance rather than meiotic drive or segregation distortion.</p

Mapping Six New Susceptibility to Colon Cancer ( Scc ) Loci Using a Mouse Interspecific Backcross

Colorectal cancer (CRC) has a complex etiology resulting from the combination of multiple genetic and environmental factors, each with small effects. Interactions among susceptibility modifier loci make many of the loci difficult to detect in human genome-wide association studies. Previous analyses in mice have used classical inbred strains, which share large portions of their genomes due to common ancestry. Herein, we used an interspecific backcross between the Mus musculus strain A/J and the Mus spretus strain SPRET/EiJ to map 6 additional CRC modifier loci (Scc16-21) and 2 suggestive loci. Three loci modify the location of tumors along the proximal-distal axis of the colon. Six CRC modifiers previously mapped in intraspecific crosses were also replicated. This work confirms genetic models suggesting that CRC is caused by many small effect alleles and brings the catalog of reported CRC modifier loci to 23 spread across 13 chromosomes. Furthermore, this work provides the foundation for large population-level epistatic interaction tests to identify combinations of low effect alleles that may have large effects on CRC susceptibility

Impact of asthma on educational attainment in a socioeconomically deprived population: a study linking health, education and social care datasets

BACKGROUND: Asthma has the potential to adversely affect children's school examination performance, and hence longer term life chances. Asthma morbidity is especially high amongst UK ethnic minority children and those experiencing social adversity, populations which also have poor educational outcomes. We tested the hypothesis that asthma adversely affects performance in national school examinations in a large cohort from an area of ethnic diversity and social deprivation. METHODS AND FINDINGS: With a novel method (using patient and address-matching algorithms) we linked administrative and clinical data for 2002-2005 for children in east London aged 5-14 years to contemporaneous education and social care datasets. We modelled children's performance in school examinations in relation to socio-demographic and clinical variables. The dataset captured examination performance for 12,136 children who sat at least one national examination at Key Stages 1-3. For illustration, estimates are presented as percentage changes in Key Stage 2 results. Having asthma was associated with a 1.1% increase in examination scores (95%CI 0.4 to 1.7)%,p = 0.02. Worse scores were associated with Bangladeshi ethnicity -1.3%(-2.5 to -0.1)%,p = 0.03; special educational need -14.6%(-15.7 to -13.5)%,p = 0.02; mental health problems -2.5%(-4.1 to -0.9)%,p = 0.003, and social adversity: living in a smoking household -1.2(-1.7 to -0.6)%,p<0.001; living in social housing -0.8%(-1.3 to -0.2)% p = 0.01, and entitlement to free school meals -0.8%(-1.5 to -0.1)%,p<0.001. CONCLUSIONS: Social adversity and ethnicity, but not asthma, are associated with poorer performance in national school examinations. Policies to improve educational attainment in socially deprived areas should focus on these factors

Quality of life among Latina breast cancer patients: a systematic review of the literature

Introduction The Latino population is the most rapidly growing ethnic minority in the United States and Latinas have higher rates of advanced breast cancer and more rigorous treatments than White women. However, the literature lacks reviews on quality of life among this population of breast cancer patients. Methods A systematic review of the breast cancer quality of life (QOL) literature was conducted among studies that provided a comparison of mental, physical, social, or sexual QOL between Latinas and other racial/ethnic groups. Of the 375 studies reviewed, 20 quantitative studies and two qualitative studies met criteria for inclusion. Results Latinas were more likely to report poor mental, physical, and social QOL, relative to non-Latinas. Only four studies assessed sexual QOL, making it difficult to draw any conclusions. Of these four QOL domains, the largest disparity was found in the area of mental health in which Latinas reported poorer QOL compared to non-Latina Whites and Blacks. Discussion/conclusions Most quantitative studies revealed either that Latinas consistently evidenced significantly lower QOL than non-Latinas on all measures (6 studies) or reported mixed findings in which Latinas generally demonstrated significantly worse QOL on most, but not all, measures (12 studies) included in the study. Explanatory mechanisms including socio-demographic, treatment-related, and culturally-relevant factors are discussed. Implications for research design, measurement, and clinical work are also included. Implications for cancer survivors Although not entirely consistent, data suggest that Latina breast cancer survivors on average experience worse QOL than non-Latina Whites. Understanding ethnic differences in QOL among breast cancer survivors can inform interventions targeted at improving health status for Latinas

Caribbean synthesis report on the implementation of the Lisbon Declaration on Youth Policies and Programmes

The Subregional review of youth policies and strategies in the Caribbean offers an overview of national policies on youth in 29 Caribbean states and territories that are members or associate members of ECLAC. The report aims at providing a comprehensive review of the state of youth policies and programmes in the Caribbean, its current operational status, and the involvement of youth in guiding future implementation, including enhancing the understanding of the complex and multifaceted challenges facing youth empowerment, based on a set of international and subregional standards for youth policies.Abstract .-- Introduction .-- I. Overview of the current situation regarding youth in the Caribbean. A. Demographic snapshot. B. Youth unemployment. C. Poverty among the youth. D. Youth and education. E. Impact of crime on youth. F. Adolescent fertility rates in the Caribbean. G. HIV/AIDS among young women and adolescent girls. H. Youth development in the Caribbean. I. The role of youth policy in youth development