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BackgroundUnderstanding the role of circulating proteins in cancer risk can reveal key biological pathways and identify novel therapeutic targets for cancer prevention.MethodsWe investigated the associations of 2,094 circulating proteins with risk of nine common cancers (bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney, and malignant non-melanoma) usingcispQTL Mendelian randomisation (MR) and colocalization. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalization were replicated using an independent cancer GWAS. Additionally, MR and colocalization phenome-wide association analyses (PHEWAS) were conducted to identify potential adverse side-effects of altering risk proteins. Finally, we mapped cancer risk proteins to drug and ongoing clinical trials targets.ResultsWe identified 40 proteins associated with cancer risk, of which a majority replicated and were novel. Among these were proteins associated with common cancers, such as PLAUR and risk of breast cancer [odds ratio per standard deviation increment (OR): 2.27, 95% CI: 1.88 to 2.74], and with high-mortality cancers, such as CTRB1 and pancreatic cancer [OR: 0.79, 95% CI: 0.73 to 0.85]. PHEWAS highlighted multiple links between proteins and potential adverse effects of protein-altering interventions. Additionally, 18 proteins associated with cancer risk mapped to existing therapeutic interventions, while 15 were not currently known to be under clinical investigation, such as GAS1 and triple negative breast cancer [OR: 1.88, 95% CI: 1.42 to 2.47].ConclusionOur findings emphasize the importance of proteomics for improving our understanding of cancer aetiology. Additionally, we demonstrate the benefit of in-depth protein PHEWAS analyses on risk proteins to identify potential adverse side-effects of protein-altering interventions. Using these methods, we identify a subset of risk proteins as potential drug targets for the prevention and treatment of cancer as well as opportunities for drug repurposing.

Background:Genome-wide association studies (GWASs) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Our study aims to explore the shared genetic basis between these traits and investigate their impact on somatic environment of lung tumours.Methods:We performed genetic correlation, Mendelian randomisation (MR), and colocalisation analyses using the largest available GWASs summary statistics of LTL (N=464,716) and lung cancer (N=29,239 cases and 56,450 controls). Principal components analysis based on RNA-sequencing data was used to summarise gene expression profile in lung adenocarcinoma cases from TCGA (N=343).Results:Although there was no genome-wide genetic correlation between LTL and lung cancer risk, longer LTL conferred an increased risk of lung cancer regardless of smoking status in the MR analyses, particularly for lung adenocarcinoma. Of the 144 LTL genetic instruments, 12 colocalised with lung adenocarcinoma risk and revealed novel susceptibility loci, including MPHOSPH6, PRPF6, and POLI. The polygenic risk score for LTL was associated with a specific gene expression profile (PC2) in lung adenocarcinoma tumours. The aspect of PC2 associated with longer LTL was also associated with being female, never smokers, and earlier tumour stages. PC2 was strongly associated with cell proliferation score and genomic features related to genome stability, including copy number changes and telomerase activity.Conclusions:This study identified an association between longer genetically predicted LTL and lung cancer and sheds light on the potential molecular mechanisms related to LTL in lung adenocarcinomas.Funding:Institut National du Cancer (GeniLuc2017-1-TABAC-03-CIRC-1-TABAC17‐022), INTEGRAL/NIH (5U19CA203654-03), CRUK (C18281/A29019), and Agence Nationale pour la Recherche (ANR-10-INBS-09).

LD between nine functional CYP2A6 variants and top six overlapping associations between MEC & TRICL - among Whites and Overall MEC sample

List of 226 overlapping associations for CYP2A6 in the TRICL & MEC Studies

Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3′-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10−8). CYP2A6 activity was correlated (r = 0.32; P < 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified. Cancer Res; 76(19); 5768–76. ©2016 AACR.

List of 251 globally significant associations (p < 5E-8) for CYP2A6 in the MEC Cohort

Descriptive Characteristics of TRICL participants

Results of the six overlapping globally significant associations (p < 5E-8) with lung cancer risk in TRICL and with CYP2A6 activtiy in MEC stratified by cell type.

It is unclear why some melanomas aggressively metastasize while others remain indolent. Available studies employing multi-omic profiling of melanomas are based on large primary or metastatic tumors. We examine the genomic landscape of early-stage melanomas diagnosed prior to the modern era of immunological treatments. Untreated cases with Stage II/III cutaneous melanoma were identified from institutions throughout the United States, Australia and Spain. FFPE tumor sections were profiled for mutation, methylation and microRNAs. Preliminary results from mutation profiling and clinical pathologic correlates show the distribution of four driver mutation sub-types: 31% BRAF; 18% NRAS; 21% NF1; 26% Triple Wild Type. BRAF mutant tumors had younger age at diagnosis, more associated nevi, more tumor infiltrating lymphocytes, and fewer thick tumors although at generally more advanced stage. NF1 mutant tumors were frequent on the head/neck in older patients with severe solar elastosis, thicker tumors but in earlier stages. Triple Wild Type tumors were predominantly male, frequently on the leg, with more perineural invasion. Mutations in TERT, TP53, CDKN2A and ARID2 were observed often, with TP53 mutations occurring particularly frequently in the NF1 sub-type. The InterMEL study will provide the most extensive multi-omic profiling of early-stage melanoma to date. Initial results demonstrate a nuanced understanding of the mutational and clinicopathological landscape of these early-stage tumors.

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

The SARS-CoV-2 infection pathogenesis reported a complex interplay between virus and host immune response. In this study, we hypothesized that Omicron variant causes less inflammation and cytokine release than Delta and Alpha variants as measured by the first laboratory biomarkers during hospitalization. This is a retrospective cohort study of veterans who tested positive for COVID-19 and were hospitalized at the Veterans Health Administration due to COVID-19 infection. We defined three groups of patients based on highly likely period representing variants: Alpha (12/01/2020-05/31/2021), Delta (09/01/2021-11/30/2021), and Omicron (02/01/2022-07/11/2022). The risk of abnormality levels in biomarkers (C-reactive protein [CRP], ferritin, albumin, alanine aminotransferase [ALT], aspartate transaminase [AST], and lactate), as well as in-hospital mortality, were calculated using logistic regression adjusted by age, sex, body-mass-index, race, Charlson comorbidity index, VA frailty index, and vaccine record status. Of 414,213 Veterans tested for COVID-19, 74,342 Veterans (age: 67.8±14.3 years, BMI: 29.4±7.1 kg/m2) met the criteria: Alpha, 18,159 (34.4%); Delta, 23,414 (44.4%); Omicron, 11,207 (21.2%). Compared with Omicron, we observed significantly higher odds of abnormality levels in CRP (Alpha, adjusted odds ratio (aOR)=1.38; Delta, aOR=1.74), ferritin (Alpha, aOR=2.02; Delta, aOR=2.33), albumin (Alpha, aOR=1.16; Delta, aOR=1.15), ALT (Alpha, aOR=1.13; Delta, aOR=1.12), AST (Alpha, aOR=1.31; Delta, aOR=1.57), and lactate (Alpha, aOR=1.62; Delta, aOR=2.27) as well as mortality (Alpha, aOR=2.19; Delta, aOR=2.95). Veterans infected with Omicron showed less severe biomarkers’ responses compared to Alpha and Delta and lower mortality risk. Understanding the biomarkers’ responses of each patient across the different variants could be used to enhance acute patients’ management.

AimTo determine whether macular retinal nerve fibre layer (mRNFL) and ganglion cell-inner plexiform layer (GC-IPL) thicknesses vary by ethnicity after accounting for total retinal thickness.MethodsWe included healthy participants from the UK Biobank cohort who underwent macula-centred spectral domain-optical coherence tomography scans. mRNFL and GC-IPL thicknesses were determined for groups from different self-reported ethnic backgrounds. Multivariable regression models adjusting for covariables including age, gender, ethnicity and refractive error were built, with and without adjusting for total retinal thickness.Results20237 participants were analysed. Prior to accounting for total retinal thickness, mRNFL thickness was on average 0.9 μm (−1.2, –0.6; pConclusionsThe previously reported ethnic differences in layer thickness among groups are likely driven by differences in total retinal thickness. Our results suggest using layer thickness ratio (retinal layer thicknesses/total retinal thickness) rather than absolute thickness values when comparing retinal layer thicknesses across groups.

Introduction: Esophageal adenocarcinoma (EAC) is the most common histological subtype of esophageal cancer in western countries and shows poor prognosis and rapid growth. EAC is characterized by a strong male predominance and racial disparity. EAC is up to five-fold more common among whites than Blacks, yet Black patients with EAC have poorer survival rates. The reason for the racial disparity is still largely unknown. Knowledge of somatic mutations in EAC from recent DNA sequencing studies have shown EAC has a high mutation burden and distinct mutational signatures. However, knowledge of mutations in EAC regarding racial disparities is limited. Methods: In this study, we performed whole-exome sequencing of tumors obtained from 10 Black patients and 8 White patients with EAC. We performed Principal Component Analysis (PCA) by using subset of SNPs with FST>0.2. We performed mutational signature analysis using non-negative matrix factorization (NMF) and R package MutationalPatterns. We used the Wilcoxon rank-sum test to compare mutational signature contributions between racial groups and performed Fisher’s exact test to compare the gene-level somatic mutation counts between racial groups. All p-values were two sided and the significant level was 0.05. Results: We identified 5,281 variants for the PCA and found principal component 1 (PC1) was strongly associated with race. We identified 94,482 somatic mutations and found 3 mutational signatures (A, B and C). “Signature A” was strongly correlated with Signature 19 (cosine-similarity: 0.80, unknown etiology), “Signature B” was strongly correlated with Signatures 4 and 29 (cosine-similarity: 0.78 and 0.80 respectively, etiology: smoking and chewing tobacco), and “Signature C” was strongly correlated with Signature 1 (cosine-similarity: 0.82, etiology: aging). There were no statistically significant differences of the 3 mutational signatures between tumors from black and white patients in EAC. When decomposing mutation count matrix into a sum of known components, we identified 25 COSMIC signatures, and found Signature12 (unknown etiology) shows more contribution in Black patients than in White patients and the difference was statistically significant (p=0.0008, q=0.02). For gene-level analysis, we found TP53 was the most frequently mutated in EAC patients and ARID1A and SMAD4 were the second group of driver genes. There was no statistically significant difference between the gene-level mutations among blacks and whites (Fisher exact test, P>0.05). Conclusion: These results demonstrate that EAC from black patients are similar to cancers from white patients with respect to clinically actionable genomic alterations. Mutational signature 12 might be the characteristic gene mutation that contribute to the racial difference between Black and White EAC patients. Citation Format: Jing Zhao, Spiridon Tsavachidis, Christopher Amos, Aaron P. Thrift. Comparison of somatic mutations of whole exome sequencing data from black and white patients with esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2280.

10612 Background: Germline pathogenic variants (PV) in the TP53 gene are associated with Li-Fraumeni syndrome (LFS). Increased use of multi-gene panel testing has identified TP53 variants suspected to have reduced penetrance, a departure from the significantly increased cancer risks expected with LFS, posing challenges in variant classification and clinical management. TP53 c.467G>A (p.Arg156His), R156H, is a variant with over 250 observations across multiple laboratories with prior discordant classification. R156H was recently downgraded by laboratories from likely pathogenic (VLP) to variant of uncertain significance (VUS). Characterization of R156H to clarify clinical significance has the potential to impact care for many. Methods: R156H carriers were identified through the Li-Fraumeni & TP53: Understanding & Progress (LiFT UP) study ( https://liftupstudy.org ) from 2019-2022. Clinical data were collected and reviewed for phenotypic characterization and to determine whether LFS Classic and/or Chompret criteria were met, and to assign Li-Fraumeni spectrum classification (Kratz et al.). Results: Proband/family characteristics are in the Table. Twenty R156H carriers were identified in 11 families. Seventeen carriers had a personal history of cancer; 8 had a LFS core cancer. All core cancers were breast except for an astrocytoma and a pediatric sarcoma. Two breast cancer cases also carried a BRCA2 PV. The average age at first cancer diagnosis was 40.5 years (range 6-71). No families met Classic LFS criteria. One proband met Chompret criteria due to breast cancer

SummaryThe current spreading novel coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three SARS-CoV-2 host receptors (ACE2, DC-SIGN and L-SIGN) and DC status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of smokers, non-smokers and COVID-19 patients. We found smoking increased DC-SIGN gene expression and inhibited DC maturation and its ability of T cell stimulation. In COVID-19, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Strikingly, DCs shifted from cDCs to pDCs in COVID-19, but the shift was trapped in an immature stage (CD22+ or ANXA1+ DC) with MHCII downregulation in severe cases. This observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically recognize SARS-CoV-2. Our study provides insights into smoking effect on COVID-19 risk and the profound modulation of DC function in severe COVID-19.Graphical AbstractHighlightsSmoking upregulates the expression of ACE2 and CD209 and inhibits DC maturation in lungs. SARS-CoV-2 modulates the DCs proportion and CD209 expression differently in lung and blood.Severe infection is characterized by DCs less capable of maturation, antigen presentation and MHCII expression.DCs shift from cDCs to pDCs with SARS-CoV-2 infection but are trapped in an immature stage in severe cases.

ObjectiveTo evaluate the prevalence of wounds managed by the UK’s National Health Service (NHS) in 2017/2018 and associated health outcomes, resource use and costs.DesignRetrospective cohort analysis of the electronic records of patients from The Health Improvement Network (THIN) database.SettingPrimary and secondary care sectors in the UK.ParticipantsRandomly selected cohort of 3000 patients from the THIN database who had a wound in 2017/2018.Primary and secondary outcome measuresPatients’ characteristics, wound-related health outcomes, healthcare resource use and total NHS cost of patient management.ResultsThere were an estimated 3.8 million patients with a wound managed by the NHS in 2017/2018, of which 70% healed in the study year; 89% and 49% of acute and chronic wounds healed, respectively. An estimated 59% of chronic wounds healed if there was no evidence of infection compared with 45% if there was a definite or suspected infection. Healing rate of acute wounds was unaffected by the presence of infection. Smoking status appeared to only affect the healing rate of chronic wounds. Annual levels of resource use attributable to wound management included 54.4 million district/community nurse visits, 53.6 million healthcare assistant visits and 28.1 million practice nurse visits. The annual NHS cost of wound management was £8.3 billion, of which £2.7 billion and £5.6 billion were associated with managing healed and unhealed wounds, respectively. Eighty-one per cent of the total annual NHS cost was incurred in the community.ConclusionThe annual prevalence of wounds increased by 71% between 2012/2013 and 2017/2018. There was a substantial increase in resource use over this period and patient management cost increased by 48% in real terms. There needs to be a structural change within the NHS in order to manage the increasing demand for wound care and improve patient outcomes.

Introduction: Lung cancer is the leading cause of cancer-related deaths. 10% of never-smokers develop lung cancer. Currently, no genetic-based lung cancer screening tool exists. As a substitute, phenotypic traits can serve as surrogate markers for lung cancer risk. Our study focuses on identifying novel phenotypes associated with lung cancer. Genome-wide association studies (GWAS) are useful in elucidating complex inheritance patterns and genetic architecture. Cross-trait linkage disequilibrium score regression (LDSC) specifically allows for use of GWAS summary statistics to identify genetic correlations between phenotypes of interest. This method allows for accurate calculations of genetic correlation, as it neutralizes effects from population stratification or cryptic relatedness. Methods: We used LDSC to (1) confirm prior phenotypic trait associations with lung cancer and to (2) identify novel associations. We measured pairwise genetic correlation (rg) and SNP heritability (h2) (the proportion of phenotypic variance observed in a population that can be explained genetically) between multiple phenotypes and lung cancer using summary statistics from the UK Biobank and OncoArray lung consortium. In addition, we conducted analysis after removal of genome regions related to smoking effects that enables us to correct the potential confounding effect in lung cancer. Results: Significant negative genetic correlations were found to exist between lung cancer and environmental factors. Overall alcohol use was significantly correlated with lung cancers. The effect observed was split, with a positive correlation for beer and cider intake (rg = 0.2957, p = 3.936 × 10-8) and a negative correlation with wine intake (rg = -0.3281, p = 2.251 × 10-14) for overall lung. Significant correlations existed between lung cancer and health metrics. A positive correlation was found between lung cancer and increased BMI (rg = 0.1986, p = 3.57 × 10-9). This finding was consistent across other BMI related metrics and within histological subtypes of lung cancer, including for lung adenocarcinoma (rg = 0.1059, p = 3.688 × 10-3) and lung small cell carcinoma (rg = 0.2393, p = 6.463 × 10-7). In comparison, physical conditioning metrics such as cycling to work had a negative correlation with lung cancer (rg = -0.2714, p = 5.690 × 10-5). Further, negative correlations were observed between being breastfed as a baby and lung cancer (rg = -0.320, p = 1.554 × 10-6). Each of these associations maintained its significance even after the removal of smoking-related SNPs. Conclusions: This analysis demonstrates a genetic basis for the shared genetic architecture between environmental factors and lung oncogenesis. We identify several novel associations, including a correlation between breastfeeding and lung cancer. Further studies are necessary in order to confirm these associations and investigate driving genetic mechanisms. Citation Format: Rowland West Pettit, Jinyoung Byun, Younghun Han, Jacob Edelson, Quinn Ostrom, Kyle Walsh, Melissa Bondy, James McKay, Christopher Amos, INTEGRAL Consortium. Genetic correlation between lung cancer and environmental exposures [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2121.

A91though the role of emotional processing is central to contemporary models of risky decision making, to date the role of trait emotional understanding has not been explored experimentally in this context. The current experiment (N = 326) explores the role of alexithymia with respect to performance on the standard Iowa Gambling Task (IGT) and a version where cumulative financial feedback is obscured. Standard learning on the IGT was observed for those low in alexithymia. Those high in alexithymia learned to avoid disadvantageous decks over the first half of the task. However, over the later trials they showed a change in performance, shifting from advantageous to disadvantageous and back to advantageous decks again (termed an "explore-learn-change-return" strategy). It is argued that this is due to an inability to fully consolidate earlier learning and reduced sensitivity to losses. The absence of cumulative feedback independently resulted in reduced performance.

Sel-1-like (SEL1L) is a putative tumor suppressor gene that is significantly downregulated in human pancreatic ductal adenocarcinoma (PDA). The mechanism of the downregulation is unclear. Here, we investigated whether aberrantly upregulated microRNAs (miRNAs) repressed the expression of SEL1L. From reported miRNA microarray studies on PDA and predicted miRNA targets, we identified seven aberrantly upregulated miRNAs that potentially target SEL1L. We assessed the expression levels of SEL1L mRNA and the seven miRNAs in human PDA tumors and normal adjacent tissues using real-time quantitative polymerase chain reaction. Then statistical methods were applied to evaluate the association between SEL1L mRNA and the miRNAs. Furthermore, the interaction was explored by functional analysis, including luciferase assay and transient miRNA overexpression. SEL1L mRNA expression levels were found to correlate inversely with the expression of hsa-mir-143, hsa-mir-155, and hsa-mir-223 (P < 0.0001, P < 0.0001, and P = 0.002, respectively). As the number of these overexpressed miRNAs increased, SEL1L mRNA expression progressively decreased (Ptrend = 0.001). Functional analysis revealed that hsa-mir-155 acted as a suppressor of SEL1L in PDA cell lines. Our study combined statistical analysis with biological approaches to determine the relationships between several miRNAs and the SEL1L gene. The finding that the expression of the putative tumor suppressor SEL1L is repressed by upregulation of hsa-mir-155 helps to elucidate the mechanism for SEL1L downregulation in some human PDA cases. Our results suggest a role for specific miRNAs in the pathogenesis of PDA and indicate that miRNAs have potential as therapeutic targets for PDA.

The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.

Despite great success of GWAS in identification of common genetic variants associated with complex diseases, the current GWAS have focused on single SNP analysis. However, single SNP analysis often identifies a number of the most significant SNPs that account for only a small proportion of the genetic variants and offers limited understanding of complex diseases. To overcome these limitations, we propose gene and pathway-based association analysis as a new paradigm for GWAS. As a proof of concept, we performed a comprehensive gene and pathway-based association analysis for thirteen published GWAS. Our results showed that the proposed new paradigm for GWAS not only identified the genes that include significant SNPs found by single SNP analysis, but also detected new genes in which each single SNP conferred small disease risk, but their joint actions were implicated in the development of diseases. The results also demonstrated that the new paradigm for GWAS was able to identify biologically meaningful pathways associated with the diseases which were confirmed by gene-set rich analysis using gene expression data.

The poster outlines the development of a breast cancer risk assessment tool for the World-Wide-Web based on well-established epidemiological, clinical, and genetic risk factors.

Healthcare websites that are influential in healthcare decision-making must be evaluated for accuracy, readability and understandability by the average population. Most existing frameworks for designing and evaluating interactive websites focus on the utility and usability of the site. Although these are significant to the design of the basic site, they are not sufficient. We have developed an iterative framework that considers additional attributes.

We outline the methodology used to develop an Internet-based cancer risk assessment tool and describe factors needed to create and post credible risk assessment tools or risk calculators.

International audience; Objective To evaluate the contribution of the SPP1 rs11439060 and rs9138 polymorphisms, previously reported as autoimmune risk variants, in the RA genetic background according to anti-citrullinated protein antibodies (ACPAs) status of RA individuals. Methods We analyzed a total of 11,715 RA cases and 26,493 controls from 9 independent cohorts, all individuals were genotyped or had imputed genotypes for SPP1 rs11439060 and rs9138. The effect of the SPP1 rs11439060 and rs9138 risk-allele combination on OPN expression in macrophages and OPN serum levels was investigated. Results We provide evidence for a distinct contribution of SPP1 to RA susceptibility according to ACPA status: the combination of ≥ 3 SPP1 rs11439060 and rs9138 common alleles was associated mainly with ACPA negativity (P = 1.29x10-5, ORACPA-negative 1.257 1.135–1.394) and less with ACPA positivity (P = 0.0148, ORACPA-positive 1.072 1.014–1.134]). The odds ratios between these subgroups (i.e., ACPA-positive and -negative) significantly differed (P = 7.33x10-3). Expression quantitative trait locus analysis revealed an association of the SPP1 risk-allele combination with decreased SPP1 expression in peripheral macrophages from 599 individuals. To corroborate these findings, we found an association of the SPP1 risk-allele combination and low serum level of secreted OPN (P = 0.0157) as well as serum level of secreted OPN correlated positively with ACPA production (P = 0.005; r = 0.483). Conclusion We demonstrate a significant contribution of the combination of SPP1 rs11439060 and rs9138 frequent alleles to risk of RA, the magnitude of the association greater in patients negative for ACPAs.

The distribution and occurrence of Staphylococcus aureus in a non-hospital open community was studied by examining weekly groups of 50 healthy adults and children. Isolations were made from the nose, throat and hand, all the subjects (with the exception of one adult) yielded Staphylococcus aureus, children wore generally persistent carriers and adults transient carriers. There was a significant correlation between isolation rate and ambient temperature and evidence that cross infection occurs between adults and children. 1,357 staphylococci were isolated from adults and 2,479 cultured from children : 60.1 per cent, from children and 49.1 per cent, from adults were susceptible to standard bacteriophages, generally being lysed by group I phages, less frequently phages of raised groups or, in the case of strains from children, group II. Forty eight per cent, of labiates were resistant to penicillin, whilst 6 to 7 per cent, resisted fucidin and streptomycin. Approximately 2 per cent, of isolates resisted methicillin, chloramphenicol, novobiocin and erythromycin, 810 strains were tested with further antibiotics and 0.9 to 7.3 per cent, were resistant to vancomycin, lincomycin, kanamycin and chlortetracycline. No association between pattern of phage susceptibility and antibiotic resistance emerged. Seven strains resistant to methicillin and typable with phages of group I complex (52, 52A, 80, 8I) or group II (55/71; 7l), were isolated from adults and children. Multiple antibiotic resistant strains were isolated occasionally during the survey from adults and children. The presence of plasmids, detected by curing techniques, appeared to be a significant mechanism determining multiple antibiotic resistance; a high proportion of these strains produced penioillinase.