John Sninsky

Celera · Discovery Research

Aims: To investigate the clinical and genetic risk factors associated with hepatocellular carcinoma (HCC) in cirrhotic patients with chronic hepatitis B (CHB). Methods: Nine hundred forty-nine Chinese Han patients with CHB were studied, including noncirrhotic patients without HCC (N = 234), cirrhotic patients without (N = 281) and with HCC (N =...

Background: Several targeted therapies have been approved for treatment of solid tumors. Identification of gene mutations that indicate response to these therapies is rapidly progressing. A 34-gene next-generation sequencing (NGS) panel, developed and validated by us, was evaluated to detect additional mutations in community-based cancer specimens...

Context: Patients with nonalcoholic fatty liver disease (NAFLD) are at increased risk of cardiovascular disease, and atherogenic lipoproteins may play an important role. Objective: To determine the contribution of the severity of steatohepatitis to atherogenic dyslipidemia in patients with NAFLD. Design: Cross-sectional Setting: University hos...

Translation of results from genetic findings to inform medical practice is a highly anticipated goal of human genetics. The aim of this paper is to review and discuss the role of genetics in medically-relevant prediction. Germline genetics presages disease onset and therefore can contribute prognostic signals that augment laboratory tests and clini...

Outcome predictors in use today are prognostic only for hormone receptor-positive (HRpos) breast cancer. Although microarray-derived multigene predictors of hormone receptor-negative (HRneg) and/or triple negative (Tneg) breast cancer recurrence risk are emerging, to date none have been transferred to clinically suitable assay platforms (for exampl...

Background and aims: Recently, genetic association studies have linked a number of single nucleotide polymorphisms (SNPs) with liver fibrosis risk of hepatitis C. The present study was designed to validate the association of emerging SNPs with development of liver cirrhosis and chronicity in a Chinese population infected with hepatitis B virus (HB...

Low-density lipoprotein cholesterol (LDL-C) lowering is the primary objective of patient management for cardiovascular disease. However, large numbers of patients who have achieved their LDL-C goal remain at risk for cardiovascular events. Low-density lipoprotein subfractions may provide insight into this residual risk. Thus, LDL subfraction standa...

47 Background: IHC is the present standard for measuring estrogen (ER) and progesterone receptor (PR) expression for breast cancer. However, the lack of concordance between testing laboratories and the critical patient treatment decisions made with results prompted ASCO/CAP to recommend guidelines and proficiency testing requirements to ensure accu...

Targeting tumour metabolism is becoming a major new area of pharmaceutical endeavour. Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR signalling pathway has a seminal role in regulating...

The glucose dependency of PIK3CA mutant cells cannot be overridden by supplementation with alternative nutrients. MCF10A PI3Kα isogenic cells (+/+ and E545K/+) and HCT116 isogenic cells (+/− and H1047R/+) were grown for 120 hours in media containing 2mM glutamine and the indicated concentrations of glucose (A and B respectively). Additionally, cell...

Glucose sensitivity of HCT116 PI3Kα (H1047R/+) cells was maintained when grown in 0.5 mM glutamine media. HCT116 isogenic cells (+/− and H1047R/+) were grown for 120 hours in media containing 0.5mM glutamine and the indicated concentrations of glucose. Cell growth was assessed using SRB staining. The growth of each cell line is expressed relative t...

Unlabelled: Among several single-nucleotide polymorphisms (SNPs) that correlate with fibrosis progression in chronic HCV, an SNP in the antizyme inhibitor (AzI) gene is most strongly associated with slow fibrosis progression. Our aim was to identify the mechanism(s) underlying this observation by exploring the impact of the AzI SNP on hepatic stel...

Genetic factors may play a role in fibrosis progression in patients with chronic hepatitis C (CHC). A cirrhosis risk score (CRS7) with seven single nucleotide polymorphisms was previously shown to correlate with cirrhosis in patients with CHC. This study aimed to assess the validity of CRS7 as a marker of fibrosis progression and cirrhosis and as a...

Coronary heart disease (CHD) often presents suddenly with little warning. Traditional risk factors are inadequate to identify the asymptomatic high-risk individuals. Early identification of patients with subclinical coronary artery disease using noninvasive imaging modalities would allow the early adoption of aggressive preventative interventions....

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Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables. HALT-C enrolled patients...

Unlabelled: Only 20% of patients with chronic hepatitis C (CHC) will develop cirrhosis, and fibrosis progression remains highly unpredictable. A recent genome-wide association study identified a genetic variant in the patatin-like phospholipase-3 (PNPLA3) gene (rs738409 C>G) associated with steatosis that was further demonstrated to influence seve...

Background: During tumorigenesis, cells acquire mutations that confer selective advantages for growth. These mutations may reprogram cellular metabolism to meet the requirements of rapid proliferation and survival in an environment of fluctuating and scarce nutrients. Phosphoinositide-3-kinases (PI3Ks) play key roles in fundamental cellular process...

A single nucleotide polymorphism 61*G (rs4444903) in the epidermal growth factor (EGF) gene has been associated, in 2 case-control studies, with hepatocellular carcinoma (HCC). We tested associations between demographic, clinical, and genetic data and development of HCC, and developed a simple predictive model in a cohort of patients with chronic h...

A cirrhosis risk score (CRS) comprised of single nucleotide polymorphisms (SNPs) in seven genes that predicts the risk of cirrhosis in Caucasian hepatitis C has been reported. The present study was to evaluate the association of 11 separate but related SNPs and the CRS with cirrhosis risk in Chinese hepatitis B patients. A total of 563 Chinese subj...

Fibrosis progression in patients with chronic hepatitis C (CHC) is highly variable. A Cirrhosis Risk Score (CRS) based on seven genetic variants has been recently developed for identifying patients at risk for cirrhosis. The objective of this study was to assess the role of the CRS for the early prediction of fibrosis progression in CHC patients wi...

Supplemental table S1. Summary of patient characteristics (grade, tumor size and number of samples scored for lymphocytic infiltration) by data source. "na" denotes where this annotation is not available to the public; and "nd" represents cohorts where Tneg status by ERBB2 transcript levels were not determined.

Supplemental table S2. Established multigene signatures assessed in comparison to HRneg/Tneg signatures. Signatures annotated for Affymetrix probe set information (STAT1 and GGI) are mapped to training data using the Affymetrix probe set ID; otherwise, signatures are mapped using gene symbols. Only signature components that can be mapped (as denote...

Supplemental figure S1. Prognostic performance of individual HRneg genes in training cohort. Kaplan-Meier plots of distant metastatic events dichotomized at the median by high (red) or low (green) expression of individual HRneg genes in training cohort of 199 HRneg cases. Significant differences in survival between groups were determined by log ran...

Supplemental figure S3. Prognostic performance of the 11-gene HRneg and 7-gene Tneg indices considered independently. Kaplan-Meier plots of distant-metastatic events dichotomized at the upper 3rd quartile by high (red) or low (green) expression indices of (A) the 11 prognostic gene candidates identified from the 199 HRneg training cases; and (B) th...

Supplemental figure S4. Distribution of HRneg/Tneg scores by cohort and outcome. The histograms of HRneg/Tneg scores among cases with metastatic (red) or non-metastatic (blue) outcome within the (A) training and (B) validation cohorts. Red dotted-line boxes labeled "worst prognosis group" highlight cases within the upper 3rd quartile of HRneg/Tneg...

Supplemental figure S2. Prognostic performance of individual Tneg genes in training cohort. Kaplan-Meier plots of distant metastatic events dichotomized at the median by high (red) or low (green) expression of individual Tneg genes in training cohort subset of 154 Tneg cases. Significant differences in survival between groups were determined by log...

Various multigene predictors of breast cancer clinical outcome have been commercialized, but proved to be prognostic only for hormone receptor (HR) subsets overexpressing estrogen or progesterone receptors. Hormone receptor negative (HRneg) breast cancers, particularly those lacking HER2/ErbB2 overexpression and known as triple-negative (Tneg) case...

Neben dem Hormonrezeptor-Status spielen Gensignaturen eine immer wichtigere Rolle fur die Therapieentscheidung beim Mammakarzinom. In der vorliegenden Studie wurde die Korrelation des Metastasis Scores (MS) (Tutt et al; MAMMAplus®) mit dem Recurrence Score (RS) (Paik et al.; Oncotype DX®) untersucht. Zusatzlich wurde die Korrelation des RS mit den...

The natural history of breast cancer is not well understood. Access to data sets with well-characterized tumor information and long-term follow-up, prior to the era of adjuvant therapy, are rare. Understanding outcomes after surgical treatment alone is critical to understanding the value of prognostic and predictive markers for breast cancer. The G...

We recently identified a missense single nucleotide polymorphism (SNP) in DDX5 (rs1140409, p.S480A) that enhances the risk of developing cirrhosis. DDX5 is an ATP-dependent RNA helicase and transcriptional modulator. We hypothesized that the activity of DDX5 in regulating fibrogenic gene transcription in hepatic stellate cells (HSCs) is altered by...

Analysis of polymorphism and divergence in the non-coding portion of the human genome yields crucial information about factors driving the evolution of gene regulation. Candidate cis-regulatory regions spanning more than 15,000 genes in 15 African Americans and 20 European Americans were re-sequenced and aligned to the chimpanzee genome in order to...

The effect of using pooled vs local synonymous sites on estimates of the probability of negative selection (above) and the probability of positive selection (below) for candidate cis-regulatory regions in the African American sample. The effect of pooling synonymous sites on estimates of γ is small, as in both cases mkprf uses only the information...

Observed versus critical values of the χ2 goodness of fit test statistic using ms (Hudson 2002) with linkage to determine the test statistic distribution based on 1,000 runs of 22 chromosomes. (A) African expansion model: ms 24 22000 -t 269.4 -r 500 500 -en 0.0664 1 0.3034. (B) European simple bottleneck model: ms 32 22000 -t 308.9 -r 500 500 -en 0...

The effects of applying a demographic correction in mkprf on the inference of selection in candidate cis-regulatory regions in African Americans. The inclusion of a demographic model increases the variance in the posterior distribution of γ, which widens the distribution of estimated values of γ at a locus, inflating the probability that γ<−0.5 (to...

Distribution of estimated mean γ for simulated neutral and positively selected loci analyzed in mkprf with an increasing number of loci simulated under negative selection (see Table 4 in the main text) when there is no fixed variance on the prior distribution of γ. The distributions are significantly different between the neut+pos and the neut+stde...

The effect of analyzing different classes of sites in a separate, independent run of mkprf vs. a concurrent run including all classes of sites. Simulations suggest that the difference across runs is due to the effects of varying degrees of selection in the background loci, which if not controlled for may be a confounding factor when comparing the e...

Boxplots showing the log of the ratio of the number of polymorphisms to the number of human-chimpanzee fixed differences for unfiltered and HMCS simulated data. (2.24 MB TIF)

The effect of using a fixed variance of 8 vs. no fixed variance on the prior distribution of γ in candidate cis-regulatory regions. The probability of negative selection (top) is reduced above ∼20%, while the probability of positive selection (middle) is reduced above ∼50% when the variance is unfixed. Estimates of mean γ (bottom) demonstrate how n...

Distribution of mean γ estimated with mkprf for loci simulated under negative (top), positive (middle), and neutral evolution (bottom) in the neut+del+pos dataset (see Table 4 in the main text). “Informative” genes are those with at least 4 fixed or polymorphic sites, and “noninformative” genes are those with <4 fixed or polymorphic sites. Most of...

McDonald-Kreitman tables for protein-coding regions in EAs. (0.33 MB TXT)

GeneAtlas2 results for protein coding regions. (0.05 MB XLS)

Gene Ontology data for candidate cis-regulatory regions. (0.12 MB XLS)

Comparison of the probability of negative selection (above) and the probability of positive selection (below) when only CNCs in the 5′ upstream regions of genes are considered, as compared to when all CNCs are pooled for African Americans in mkprf. (4.11 MB TIF)

The effects of applying a demographic correction in mkprf on the inference of selection on neutral loci simulated under a model of population expansion inferred from synonymous sites in African Americans. The inclusion of a demographic model increases the variance in the posterior distribution of γ, which widens the distribution of estimated values...

Distribution of the number of sites resequenced in candidate cis-regulatory and nonsynonymous sites. (3.98 MB TIF)

The distribution of LI for the simulated HMCS and unfiltered datasets. (2.24 MB TIF)

mkprf results for candidate cis-regulatory regions in AAs. (1.08 MB TXT)

mkprf results for candidate cis-regulatory regions in EAs. (1.07 MB TXT)

mkprf results for nonsynonymous sites in EAs. (0.97 MB TXT)

Gene Ontology data for nonsynonymous sites. (0.12 MB XLS)

Summary statistics for the log of the ratio of polymorphism/divergence in simulated human-mouse conserved sequences versus unfiltered sequences. (0.04 MB PDF)

Proportion of simulations with no polymorphisms or human-chimpanzee fixed differences in simulated human-mouse conserved sequences and unfiltered sequences. (0.04 MB PDF)

Correlations between simulated and estimated mean γ obtained from mkprf (see Table 4 in the main text). Kendall's tau rank correlation tests all have p-values<10−16 (except for neut). Loci simulated under positive selection show a stronger correlation than loci simulated under negative selection in the neut+del+pos dataset: tau = 0.38 for positivel...

The relationship between the total number of sites resequenced in candidate cis-regulatory regions (total sites), and the total number of fixed and polymorphic sites (informative sites). We find a significant correlation between estimates of γ and total sites when all genes are considered (Kendall's tau = 0.043, p = 3.3×10−11). The correlation disa...

The relationship between GC content and the probability of positive and negative selection in candidate cis-regulatory regions, nonsynonymous, and synonymous sites in AAs. GC content in candidate cis-regulatory regions shows a weak, but significant negative rank correlation with the probability of negative selection (Kendall's tau = −0.014, p = 0.0...

McDonald-Kreitman tables for candidate cis-regulatory regions in AAs. (0.24 MB TXT)

McDonald-Kreitman tables for candidate cis-regulatory regions in EAs. (0.24 MB TXT)

mkprf results for nonsynonymous sites in AAs. (0.98 MB TXT)

GeneAtlas2 results for candidate cis-regulatory regions. (0.05 MB XLS)

Summary statistics for the distribution of the log of the neutrality index for simulated human-mouse conserved sequences versus unfiltered sequences. (0.04 MB PDF)

Supplemental methods. (0.11 MB PDF)

Flowchart of the bioinformatic pipeline. (9.44 MB TIF)

McDonald-Kreitman tables for protein-coding regions in AAs. (0.33 MB TXT)

Seven genomic loci, implicated by single nucleotide polymorphisms (SNPs), have recently been associated with progression to advanced fibrosis (fibrosis risk) in patients with chronic hepatitis C virus. Other variants in these loci have not been examined but may be associated with fibrosis risk independently of or due to linkage disequilibrium with...

Knowledge of estrogen receptor (ER) and progesterone receptor (PR) status has been critical in the evolution of modern targeted therapy of breast cancer and remains essential for making informed therapeutic decisions. Recently, growth factor receptor HER2/neu (ERBB2) status has made it possible to provide another form of targeted therapy linked to...

Unlabelled: In a recent study, a single nucleotide polymorphism (SNP) of the Toll-like receptor 4 (TLR4) gene (c.1196C>T [rs4986791, p.T399I]) emerged as conferring protection from fibrosis progression compared to a major, wild-type (WT) CC allele (p.T399). The present study examined the functional linkage of this SNP, along with another common, h...

Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-...

Selection of Candidate Genes profiled in the training set. We selected 197 candidate genes from the published literature and microarray-based gene expression profiling experiments. The candidate genes included the 70-gene panel described in van't Veer et al, 104 genes further analyzed from Rosetta dataset (Dai et al), the Paik et al reported 16-gen...

Normalization gene selection. The expression level of 6 housekeeping genes (HSK) was determined on 150 breast cancer tissue samples. Gene stability was evaluated using the geNorm program [Ref. [2]] which relies on the principle that the expression ratio of two ideal reference genes would be identical in all samples, regardless of experimental condi...

Coefficients of the 14 genes in the principle component. Table and graphs of coefficients of the 14 genes in the principle component

Selection bias assessment. Selection bias assessment in the training set and validation set.

Algorithm for computing Metastasis Score (MS). Algorithm for computing Metastasis Score (MS). The relative changes in gene expression are calculated by ΔΔCt method.

Genes selected by supervised principal component procedure. Table of genes selected by supervised principal component procedure.