Publications by authors named "Sarah J Plummer"

39 Publications

Genetic Effects on Transcriptome Profiles in Colon Epithelium Provide Functional Insights for Genetic Risk Loci.

Cell Mol Gastroenterol Hepatol 2021 Feb 16;12(1):181-197. Epub 2021 Feb 16.

Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain; Colorectal Cancer Group, Molecular Mechanisms and Experimental Therapy in Oncology (ONCOBELL) Program, Bellvitge Biomedical Research Institute, Spain; Consortium for Biomedical Research in Epidemiology and Public Health, Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain. Electronic address:

Background & Aims: The association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait-associated loci and may suggest novel genes implicated in disease. Here, our aims were as follows: (1) to generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse, and descending), (2) to identify expression and splicing quantitative trait loci (QTLs), (3) to find traits for which identified QTLs contribute to single-nucleotide polymorphism (SNP)-based heritability, (4) to propose candidate effector genes, and (5) to provide a web-based visualization resource.

Methods: We collected colonic mucosal biopsy specimens from 485 healthy adults and performed bulk RNA sequencing. We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses.

Results: We provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate effector genes for multiple phenotypes. Finally, we provided the Colon Transcriptome Explorer web application.

Conclusions: We provide a large characterization of gene expression and splicing across colon subsites. Our findings provide greater etiologic insight into complex traits and diseases influenced by transcriptomic changes in colon tissue.
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http://dx.doi.org/10.1016/j.jcmgh.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102177PMC
February 2021

SNPs associated with colorectal cancer at 15q13.3 affect risk enhancers that modulate GREM1 gene expression.

Hum Mutat 2021 Mar 2;42(3):237-245. Epub 2021 Feb 2.

Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

Several genome wide association studies of colorectal cancer (CRC) have identified single nucleotide polymorphisms (SNPs) on chromosome 15q13.3 associated with CRC risk. To identify functional variant(s) underlying this association, we investigated SNPs in linkage disequilibrium with the risk-associated SNP rs4779584 that overlapped regulatory regions/enhancer elements characterized in colon-related tissues and cells. We identified several SNP-containing regulatory regions that exhibited enhancer activity in vitro, including one SNP (rs1406389) that correlated with allele-specific effects on enhancer activity. Deletion of either this enhancer or another enhancer that had previously been reported in this region correlated with decreased expression of GREM1 following CRISPR/Cas9 genome editing. That GREM1 is one target of these enhancers was further supported by an expression quantitative trait loci correlation between rs1406389 and GREM1 expression in the transverse but not sigmoid colon in the Genotype-Tissue Expression dataset. Taken together, we conclude that the 15q13.3 region contains at least two functional variants that map to distinct enhancers and impact CRC risk through modulation of GREM1 expression.
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http://dx.doi.org/10.1002/humu.24166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898835PMC
March 2021

Ethanol exposure drives colon location specific cell composition changes in a normal colon crypt 3D organoid model.

Sci Rep 2021 Jan 11;11(1):432. Epub 2021 Jan 11.

Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.

Alcohol is a consistently identified risk factor for colon cancer. However, the molecular mechanism underlying its effect on normal colon crypt cells remains poorly understood. We employed RNA-sequencing to asses transcriptomic response to ethanol exposure (0.2% vol:vol) in 3D organoid lines derived from healthy colon (n = 34). Paired regression analysis identified 2,162 differentially expressed genes in response to ethanol. When stratified by colon location, a far greater number of differentially expressed genes were identified in organoids derived from the left versus right colon, many of which corresponded to cell-type specific markers. To test the hypothesis that the effects of ethanol treatment on colon organoid populations were in part due to differential cell composition, we incorporated external single cell RNA-sequencing data from normal colon biopsies to estimate cellular proportions following single cell deconvolution. We inferred cell-type-specific changes, and observed an increase in transit amplifying cells following ethanol exposure that was greater in organoids from the left than right colon, with a concomitant decrease in more differentiated cells. If this occurs in the colon following alcohol consumption, this would lead to an increased zone of cells in the lower crypt where conditions are optimal for cell division and the potential to develop mutations.
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http://dx.doi.org/10.1038/s41598-020-80240-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801615PMC
January 2021

A functional variant on 20q13.33 related to glioma risk alters enhancer activity and modulates expression of multiple genes.

Hum Mutat 2021 Jan 22;42(1):77-88. Epub 2020 Nov 22.

Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with glioma risk on 20q13.33, but the biological mechanisms underlying this association are unknown. We tested the hypothesis that a functional SNP on 20q13.33 impacted the activity of an enhancer, leading to an altered expression of nearby genes. To identify candidate functional SNPs, we identified all SNPs in linkage disequilibrium with the risk-associated SNP rs2297440 that mapped to putative enhancers. Putative enhancers containing candidate functional SNPs were tested for allele-specific effects in luciferase enhancer activity assays against glioblastoma multiforme (GBM) cell lines. An enhancer containing SNP rs3761124 exhibited allele-specific effects on activity. Deletion of this enhancer by CRISPR-Cas9 editing in GBM cell lines correlated with an altered expression of multiple genes, including STMN3, RTEL1, RTEL1-TNFRSF6B, GMEB2, and SRMS. Expression quantitative trait loci (eQTL) analyses using nondiseased brain samples, isocitrate dehydrogenase 1 (IDH1) wild-type glioma, and neurodevelopmental tissues showed STMN3 to be a consistent significant eQTL with rs3761124. RTEL1 and GMEB2 were also significant eQTLs in the context of early CNS development and/or in IDH1 wild-type glioma. We provide evidence that rs3761124 is a functional variant on 20q13.33 related to glioma/GBM risk that modulates the expression of STMN3 and potentially other genes across diverse cellular contexts.
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http://dx.doi.org/10.1002/humu.24134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839675PMC
January 2021

Genomic Analysis of Germline Variation Associated with Survival of Patients with Colorectal Cancer Treated with Chemotherapy Plus Biologics in CALGB/SWOG 80405 (Alliance).

Clin Cancer Res 2021 Jan 21;27(1):267-275. Epub 2020 Sep 21.

Duke Cancer Institute, Duke University, Durham, North Carolina.

Purpose: Irinotecan/5-fluorouracil (5-FU; FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in patients with mCRC treated with these regimens in Cancer and Leukemia Group B/SWOG 80405.

Experimental Design: Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for approximately 700,000 SNPs. The association between SNPs and overall survival (OS) was tested in 613 patients of genetically estimated European ancestry using Cox proportional hazards models.

Results: The four most significant SNPs associated with OS were three haplotypic SNPs between microsomal glutathione S-transferase 1 () and LIM domain only 3 (, representative HR, 1.56; = 1.30 × 10), and rs11644916 in (HR, 1.39, = 4.26 × 10). is a well-established tumor suppressor gene in colorectal cancer, and rs11644916 (G>A) conferred shorter OS. Median OS for patients with the AA, AG, or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 patients with stage IV colorectal cancer from The Cancer Genome Atlas (TCGA), rs11649255 in [in almost complete linkage disequilibrium (LD) with rs11644916], was associated with shorter OS (HR, 2.24, = 0.0096). Using rs11648673 in (in very high LD with rs11644916 and with functional evidence), luciferase activity in three colorectal cancer cell lines was reduced.

Conclusions: This is the first large genome-wide association study ever conducted in patients with mCRC treated with first-line standard treatment in a randomized phase III trial. A common SNP in conferred worse OS and the effect was replicated in TCGA. Further studies in colorectal cancer experimental models are required.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785628PMC
January 2021

Oncogenic Features in Histologically Normal Mucosa: Novel Insights Into Field Effect From a Mega-Analysis of Colorectal Transcriptomes.

Clin Transl Gastroenterol 2020 07;11(7):e00210

Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.

Introduction: Colorectal cancer is a common malignancy that can be cured when detected early, but recurrence among survivors is a persistent risk. A field effect of cancer in the colon has been reported and could have implications for surveillance, but studies to date have been limited. A joint analysis of pooled transcriptomic data from all available bulk RNA-sequencing data sets of healthy, histologically normal tumor-adjacent, and tumor tissues was performed to provide an unbiased assessment of field effect.

Methods: A novel bulk RNA-sequencing data set from biopsies of nondiseased colon from screening colonoscopy along with published data sets from the Genomic Data Commons and Sequence Read Archive were considered for inclusion. Analyses were limited to samples with a quantified read depth of at least 10 million reads. Transcript abundance was estimated with Salmon, and downstream analysis was performed in R.

Results: A total of 1,139 samples were analyzed in 3 cohorts. The primary cohort consisted of 834 independent samples from 8 independent data sets, including 462 healthy, 61 tumor-adjacent, and 311 tumor samples. Tumor-adjacent gene expression was found to represent an intermediate state between healthy and tumor expression. Among differentially expressed genes in tumor-adjacent samples, 1,143 were expressed in patterns similar to tumor samples, and these genes were enriched for cancer-associated pathways.

Discussion: Novel insights into the field effect in colorectal cancer were generated in this mega-analysis of the colorectal transcriptome. Oncogenic features that might help explain metachronous lesions in cancer survivors and could be used for surveillance and risk stratification were identified.
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http://dx.doi.org/10.14309/ctg.0000000000000210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386360PMC
July 2020

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

J Natl Cancer Inst 2019 02;111(2):146-157

Division of Research, Kaiser Permanente Medical Care Program of Northern California, Oakland, CA.

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.

Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.

Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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http://dx.doi.org/10.1093/jnci/djy099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555904PMC
February 2019

Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype.

PLoS One 2014 6;9(11):e111914. Epub 2014 Nov 6.

Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFβ/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A previous study implicated a novel SNP (novel 1 or rs58920878) as a functional variant within an enhancer element in SMAD7 intron 4. In this study, we show that four SNPs including novel 1 (rs6507874, rs6507875, rs8085824, and rs58920878) in linkage disequilibrium (LD) with the index SNP rs4939827 demonstrate allele-specific enhancer effects in a large, multi-component enhancer of SMAD7. All four SNPs demonstrate allele-specific protein binding to nuclear extracts of CRC cell lines. Furthermore, some of the risk-associated alleles correlate with increased expression of SMAD7 in normal colon tissues. Finally, we show that the enhancer is responsive to BMP4 stimulation. Taken together, we propose that the associated CRC risk at 18q21.1 is due to four functional variants that regulate SMAD7 expression and potentially perturb a BMP negative feedback loop in TGFβ/BMP signaling pathways.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111914PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223076PMC
July 2015

Identification and characterization of functional risk variants for colorectal cancer mapping to chromosome 11q23.1.

Hum Mol Genet 2014 Apr 20;23(8):2198-209. Epub 2013 Nov 20.

Department of Preventive Medicine.

Genome-wide association studies of colorectal cancer (CRC) have identified a number of common variants associated with modest risk, including rs3802842 at chromosome 11q23.1. Several genes map to this region but rs3802842 does not map to any known transcribed or regulatory sequences. We reasoned, therefore, that rs3802842 is not the functional single-nucleotide polymorphism (SNP), but is in linkage disequilibrium (LD) with a functional SNP(s). We performed ChIP-seq for histone modifications in SW480 and HCT-116 CRC cells, and incorporated ChIP-seq and DNase I hypersensitivity data available through ENCODE within a 137-kb genomic region containing rs3802842 on 11q23.1. We identified SNP rs10891246 in LD with rs3802842 that mapped within a bidirectional promoter region of genes C11orf92 and C11orf93. Following mutagenesis to the risk allele, the promoter demonstrated lower levels of reporter gene expression. A second SNP rs7130173 was identified in LD with rs3802842 that mapped to a candidate enhancer region, which showed strong unidirectional activity in both HCT-116 and SW480 CRC cells. The risk allele of rs7130173 demonstrated reduced enhancer activity compared with the common allele, and reduced nuclear protein binding affinity in electromobility shift assays compared with the common allele suggesting differential transcription factor (TF) binding. SNPs rs10891246 and rs7130173 are on the same haplotype, and expression quantitative trait loci (eQTL) analyses of neighboring genes implicate C11orf53, C11orf92 and C11orf93 as candidate target genes. These data imply that rs10891246 and rs7130173 are functional SNPs mapping to 11q23.1 and that C11orf53, C11orf92 and C11orf93 represent novel candidate target genes involved in CRC etiology.
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http://dx.doi.org/10.1093/hmg/ddt584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959808PMC
April 2014

HOXB13 mutation and prostate cancer: studies of siblings and aggressive disease.

Cancer Epidemiol Biomarkers Prev 2013 Apr 8;22(4):675-80. Epub 2013 Feb 8.

Departments of Epidemiology & Biostatistics and Urology, University of California San Francisco, San Francisco, CA 94158, USA.

Background: Recent work detected for the first time a high-risk prostate cancer mutation, in homeobox B13 (HOXB13) among European-Americans.

Methods: We further evaluated this G84E missense mutation (rs138213197) in two genetic association studies of prostate cancer: a family-based study of brothers and a case-control study of more aggressive disease (N = 2,665 total). We then calculated overall impact of this mutation by pooling all published studies of European-Americans.

Results: In our studies, the mutation was found exclusively among men with prostate cancer (carrier frequency = 1.48%) or unaffected brothers of cases carrying the mutation (frequency = 0.34%), and carrying the mutation gave an OR for disease = 4.79 (P = 0.01). The G84E mutation was more common among men with an earlier age of onset (≤55 years) or a family history of prostate cancer. We also observed for the first time an African-American case carrying the G84E mutation, although at HOXB13 both of his chromosomes were of European-American ancestry. The pooled analysis also indicated that carrying the G84E mutation results in an almost five-fold increase in risk of prostate cancer (P = 3.5 × 10(-17)), and this risk is even higher among cases with an early age of prostate cancer onset (≤55 years) or a family history of disease: a test of heterogeneity across these strata gives P < 1 × 10(-5).

Conclusions: The HOXB13 mutation substantially increases risk of early onset, familial prostate cancer in European-American men.

Impact: Testing for the G84E mutation in men with a positive family history may help distinguish those who merit more regular screening for prostate cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-12-1154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617049PMC
April 2013

Association of the innate immunity and inflammation pathway with advanced prostate cancer risk.

PLoS One 2012 14;7(12):e51680. Epub 2012 Dec 14.

Department of Epidemiology, and Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.

Prostate cancer is the most frequent and second most lethal cancer in men in the United States. Innate immunity and inflammation may increase the risk of prostate cancer. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 single nucleotide polymorphisms, located in 46 genes involved in this pathway, with disease risk using 494 cases with advanced disease and 536 controls from Cleveland, Ohio. Taken together, the whole pathway was associated with advanced prostate cancer risk (P = 0.02). Two sub-pathways (intracellular antiviral molecules and extracellular pattern recognition) and four genes in these sub-pathways (TLR1, TLR6, OAS1, and OAS2) were nominally associated with advanced prostate cancer risk and harbor several SNPs nominally associated with advanced prostate cancer risk. Our results suggest that the innate immunity and inflammation pathway may play a modest role in the etiology of advanced prostate cancer through multiple small effects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0051680PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3522730PMC
June 2013

Quality assessment and correlation of microsatellite instability and immunohistochemical markers among population- and clinic-based colorectal tumors results from the Colon Cancer Family Registry.

J Mol Diagn 2011 May;13(3):271-81

Division of Experimental Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

The detection of defective mismatch repair (MMR), as assessed by the presence of tumor microsatellite instability (MSI) and/or loss of MMR protein expression by IHC, has been useful for risk assessment, prognosis, and prediction of treatment in patients with colorectal cancer. We analyzed tumors for the presence of defective MMR from 5927 Colorectal Cancer Family Registry patients recruited at six international consortium sites. We evaluated the appropriate percentage instability cutoff used to distinguish the three MSI phenotypes [ie, stable (MSS), low instability (MSI-L), and high instability (MSI-H)]; the sensitivity, specificity, and performance characteristics of individual markers; and the concordance between MSI and IHC phenotypes. Guided by the results of the IHC testing, our findings indicate that the distinction between an MSI-H phenotype from a low-instability or MSS phenotype can best be accomplished by using a cutoff of 30% or greater of the markers showing instability. The sensitivity and specificity of the mononucleotide markers were higher than those of the dinucleotide markers. Specifically, BAT26 and BAT25 had the highest sensitivity (94%) and specificity (98%), and the use of mononucleotide markers alone identified 97% of the MSI-H cases correctly. As expected, the presence of MSI-H correlated with an older age of diagnosis, the presence of tumor in the proximal colon, and female sex.
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http://dx.doi.org/10.1016/j.jmoldx.2010.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077724PMC
May 2011

FTO polymorphisms are associated with adult body mass index (BMI) and colorectal adenomas in African-Americans.

Carcinogenesis 2011 May 11;32(5):748-56. Epub 2011 Feb 11.

Department of Epidemiology and Biostatistics, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106-7281, USA.

Obesity is a known risk factor for colon cancer and higher body mass index (BMI) has been associated with colorectal adenomas, which are precursor lesions to most colorectal cancers. Polymorphisms in the fat-mass and obesity-associated (FTO) gene have been associated with BMI and larger effects in older versus younger children have been reported. However, no studies have examined associations between FTO polymorphisms, BMI throughout adulthood and colorectal adenomas. Therefore, we evaluated associations between FTO polymorphisms (rs1421085, rs17817449, rs8050136, rs9939609, rs8044769), adult BMI (at recruitment, 50s, 40s, 30s, 20s age decades) and colorectal adenomas in 759 Caucasians and 469 African-Americans. We found that the highest versus the lowest BMI tertile at recruitment [odds ratio (OR) = 1.82; 95% confidence interval (CI): 1.07-2.16] and in the 30s (OR = 1.50; 95% CI: 1.04-2.15) was associated with higher adenoma risk. Stratification by ethnicity revealed that these associations only remained significant in Caucasians. We found that, in Caucasians, having two versus no copies of the variant allele in rs17817449, rs8050136 and rs9939609, which are all in strong linkage disequilibrium, was associated with higher BMI in the 30s and 40s but none of the polymorphisms were associated with adenomas. In African-Americans, having one or two copies of the variant in rs17817449 (OR = 0.61; 95% CI: 0.39-0.95) and rs8050136 (OR = 0.59; 95% CI: 0.38-0.93) was associated with colorectal adenomas and, having two variant copies in rs17817449 and rs8050136 was associated with higher BMI at recruitment and in the 40s, respectively. Our results are consistent with prior studies and show for the first time that FTO polymorphisms are associated with colorectal adenomas in African-Americans.
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http://dx.doi.org/10.1093/carcin/bgr026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086700PMC
May 2011

Fine-mapping of prostate cancer aggressiveness loci on chromosome 7q22-35.

Prostate 2011 May 13;71(7):682-9. Epub 2010 Oct 13.

Mary Ann and J. Milburn Smith Child Health Research Program, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Background: Deciphering the genetic basis of prostate cancer aggressiveness could provide valuable information for the screening and treatment of this common but complex disease. We previously detected linkage between a broad region on chromosome 7q22-35 and Gleason score-a strong predictor of prostate cancer aggressiveness. To further clarify this finding and focus on the potentially causative gene, we undertook a fine-mapping study across the 7q22-35 region.

Methods: Our study population encompassed 698 siblings diagnosed with prostate cancer. 3,072 single nucleotide polymorphisms (SNPs) spanning the chromosome 7q22-35 region were genotyped using the Illumina GoldenGate assay. The impact of SNPs on Gleason scores were evaluated using affected sibling pair linkage and family-based association tests.

Results: We confirmed the previous linkage signal and narrowed the 7q22-35 prostate cancer aggressiveness locus to a 370 kb region. Centered under the linkage peak is the gene KLRG2 (killer cell lectin-like receptor subfamily G, member 2). Association tests indicated that the potentially functional non-synonymous SNP rs17160911 in KLRG2 was significantly associated with Gleason score (P = 0.0007).

Conclusions: These findings suggest that genetic variants in the gene KLRG2 may affect Gleason score at diagnosis and hence the aggressiveness of prostate cancer.
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http://dx.doi.org/10.1002/pros.21284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027848PMC
May 2011

Prostate cancer susceptibility variants confer increased risk of disease progression.

Cancer Epidemiol Biomarkers Prev 2010 Sep 22;19(9):2124-32. Epub 2010 Jul 22.

Epidemiology Program, Cancer Research Center of Hawai'i, University of Hawai'i, Honolulu, Hawaii, USA.

Background: Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNP) associated with the risk of prostate cancer. Our objective was to determine whether these SNPs affect the progression of prostate cancer.

Methods: We genotyped 26 SNPs previously associated with prostate cancer risk among 788 aggressive prostate cancer patients who were treated by radical prostatectomy or radiation therapy. Prostate cancer progression was defined as biochemical recurrence based on posttreatment prostate-specific antigen levels of >0.3 ng/mL for radical prostatectomy patients or a 2-ng/mL increase above the nadir for radiation therapy patients, initiation of hormone treatment, or metastases. We assessed the association between independent and combined SNPs and disease progression by Cox proportional hazards regression.

Results: Five SNPs showed independent associations with prostate cancer progression (rs12621278, rs629242, rs9364554, rs4430796, and rs5945572) based on stepwise regression analysis. The strongest SNP was rs12621278 in the ITGA6 locus, which was associated with a 2.4-fold increased risk of progression (P = 0.0003). When considering the sum of risk alleles across these five SNPs, each additional allele was associated with a 29% increase in risk of progression (95% confidence interval, 1.12-1-47).

Conclusions: We found that five of the recently highlighted prostate cancer susceptibility loci also influence prostate cancer progression beyond the known clinicopathologic predictors. If confirmed, these genetic variants might help clarify which tumors are likely to progress and require more aggressive treatment in contrast to those that might not have substantial effects on morbidity or mortality.

Impact: Genetic susceptibility variants for prostate cancer development may also inform disease progression.
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http://dx.doi.org/10.1158/1055-9965.EPI-10-0268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950095PMC
September 2010

Interleukin-22 genetic polymorphisms and risk of colon cancer.

Cancer Causes Control 2010 Aug 26;21(8):1165-70. Epub 2010 Mar 26.

Department of Family Medicine-Research Division, Case Western Reserve University/University Hospitals of Cleveland, 11001 Cedar Ave., Suite 306, Cleveland, OH 44106-7136, USA.

Interleukin-22 (IL-22) is a member of the IL-10 family of anti-inflammatory cytokines that mediates epithelial immunity. IL-22 expression is enhanced in inflamed colon mucosa in individuals with inflammatory bowel disease. We carried out an association study to examine the hypothesis that common variation in the IL-22 gene is associated with risk of colon cancer. Seven tagging SNPs were genotyped in 561 colon cancer cases and 722 population controls. Information on lifestyle risk factors was collected via a self-administered questionnaire. The rs1179251 SNP conferred an estimated odds ratio (OR) of 1.46 (95% CI = 1.04-2.05) and 2.10 (95% CI = 0.66-6.66), respectively, for those heterozygous and homozygous for the G variant (p (additive) = 0.013) after adjustment for age, gender, and race; the OR assuming a dominant model was 1.50 (95% CI = 1.05-2.08, p (dominant) = 0.016). No other SNP was statistically significantly associated with colon cancer risk. Haplotype analysis found that one haplotype containing the rs1179251 G allele gave an estimated 52% increase in risk of colon cancer for individuals with at least one copy (OR = 1.52, 95% CI = 1.12-2.06, p = 0.0073). Our findings suggest that the rs1179251 SNP in IL-22 is associated with risk of colon cancer.
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http://dx.doi.org/10.1007/s10552-010-9542-5DOI Listing
August 2010

No Association of Obesity and Type 2 Diabetes Mellitus Related Genetic Variants With Colon Cancer.

Gastroenterology Res 2009 Dec 20;2(6):311-316. Epub 2009 Nov 20.

Departments of Family Medicine, Case Western Reserve University/University Hospitals of Cleveland, 10900 Euclid Ave, Cleveland, OH 44106, USA; Epidemiology and Biostatistics, Case Western Reserve University/University Hospitals of Cleveland, 10900 Euclid Ave, Cleveland, OH 44106, USA; The Case Center for Transdisciplinary Research on Energetics and Cancer, Case Comprehensive Cancer Center, 10900 Euclid Ave, Cleveland, OH 44106, USA.

Background: Obesity and type 2 diabetes mellitus (T2D) are known risk factors for colon cancer. Recent reports from a number of genome wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with obesity and T2D. Here we tested the hypothesis that these SNPs may also be associated with risk of colon cancer.

Methods: We genotyped nine SNPs reported in GWAS of obesity and/or T2D, including SNPs in HHEX, KCNJ11, SLC30A8, FTO, CDKN2, CDKAL1, TCF2, and the rs9300039 SNP in an intergenic region, in 561 colon cancer cases and 721 population controls.

Results: None of these SNPs were statistically significantly associated with colon cancer in our sample.

Conclusions: Overall, these results suggest that these obesity and T2D genetic susceptibility loci are unlikely to influence the risk of colon cancer.
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http://dx.doi.org/10.4021/gr2009.11.1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5139690PMC
December 2009

No association between phosphatase and tensin homolog genetic polymorphisms and colon cancer.

World J Gastroenterol 2009 Aug;15(30):3771-5

Department of Epidemiology and Biostatistics and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106-7136, United States.

Aim: To investigate the association between single nucleotide polymorphisms (SNPs) in the phosphatase and tensin homolog (PTEN) tumor suppressor gene and risk of colon cancer.

Methods: We utilized a population-based case-control study of incident colon cancer individuals (n = 421) and controls (n = 483) aged > or = 30 years to conduct a comprehensive tagSNP association analysis of the PTEN gene.

Results: None of the PTEN SNPs were statistically significantly associated with colon cancer when controlled for age, gender, and race, or when additionally adjusted for other known risk factors (P > 0.05). Haplotype analyses similarly showed no association between the PTEN gene and colon cancer.

Conclusion: Our study does not support PTEN as a colon cancer susceptibility gene.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726455PMC
http://dx.doi.org/10.3748/wjg.15.3771DOI Listing
August 2009

No association between cyclooxygenase-2 and uridine diphosphate glucuronosyltransferase 1A6 genetic polymorphisms and colon cancer risk.

World J Gastroenterol 2009 May;15(18):2240-4

Department of Family Medicine, Research Division, Case Western Reserve University, 11001 Cedar Ave., Suite 306, Cleveland, Ohio 44106-7136, United States.

Aim: To investigate the association of variations in the cyclooxygenase-2 (COX2) and uridine diphosphate glucuronosyltransferase 1A6 (UGT1A6) genes and non-steroidal anti-inflammatory drugs (NSAIDs) use with risk of colon cancer.

Methods: NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly, enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGT1A6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms (SNPs) in the COX2 and UGT1A6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.

Results: No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk (P > 0.05), and we did not observe that these variants modify the protective effect of NSAIDs (P > 0.05). We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.

Conclusion: Our study does not support a role of COX2 and UGT1A6 genetic variations in the development of colon cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2682239PMC
http://dx.doi.org/10.3748/wjg.15.2240DOI Listing
May 2009

Association of common genetic variants in SMAD7 and risk of colon cancer.

Carcinogenesis 2009 Jun 8;30(6):982-6. Epub 2009 Apr 8.

Department of Family Medicine, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, OH 44106, USA.

Two recent genome-wide association studies (GWAS) identified three common variants in SMAD7 (rs4464148, rs4939827 and rs12953717) that confer modest susceptibility to colorectal cancer. Here, we replicated the association of rs4464148 with colon cancer in a population-based case-control study (561 cases and 721 controls). Compared with the TT genotype, those with CT and CC had an adjusted odds ratio (OR) and 95% confidence interval of 1.06 (0.82-1.38) and 1.86 (1.17-2.96), respectively (P(trend) = 0.04). However, stratified analyses revealed that this association was limited to women only [OR = 1.25 (0.88-1.78) for CT and OR = 2.76 (1.53-4.98) for CC, P(trend) = 0.002, P(interaction) = 0.08], which was not noted in any GWAS. Similarly, we found evidence for association with both rs4939827 and rs12953717 in women only (P = 0.007 in dominant rs4939827 model and P = 0.015 in recessive rs12953717 model), but not in men (P > 0.05) and evidence of an interaction with gender (P = 0.015 for rs4939827 and P = 0.061 for rs12953717). Similar effect modification was found in haplotype analyses. Our data add evidence supporting these genetic variants as markers predisposing to colon cancer, specifically in women.
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http://dx.doi.org/10.1093/carcin/bgp086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691142PMC
June 2009

Association of vitamin D receptor gene variants, adiposity and colon cancer.

Carcinogenesis 2008 Sep 14;29(9):1788-93. Epub 2008 Jul 14.

Department of Social and Preventive Medicine, State University of New York at Buffalo, Buffalo, NY, USA.

Vitamin D receptor (VDR) gene variants have been variably associated with risk of colon cancer in epidemiologic studies. We sought to further clarify the relationship between colon cancer and three single-nucleotide polymorphisms (SNPs) in the VDR gene (Cdx-2, FokI and TaqI) in a population-based case-control study of 250 incident cases and 246 controls. Colon cancer cases were more frequently homozygous for the Cdx-2 A allele (9.2 versus 4.1%, P = 0.06). Cdx-2 AA homozygotes were at increased risk with an unadjusted odds ratio (OR) of 2.47 [95% confidence interval (CI): 1.13-5.37, P = 0.022]; adjustment for age, sex, body mass index (BMI), non-steroidal anti-inflammatory use and family history of colorectal cancer yielded an OR of 2.27 (CI: 0.95-5.41, P = 0.065). Carriers of the FokI TT genotype were also at increased risk with an adjusted OR of 1.87 (CI: 1.03-3.38, P = 0.038). Haplotype analyses showed significant increased colon cancer risk for carriers of the Cdx-2-FokI A-T haplotype and the FokI-TaqI T-G haplotype. The three-SNP Cdx-2-FokI-TaqI (A-T-G) haplotype showed a similar association with an adjusted OR of 3.63 (CI: 1.01-13.07). A strong positive association was observed for the Cdx-2 variant among individuals with low BMI or low waist circumference. Our results suggest that genetic variation at the VDR locus, in particular Cdx-2 and FokI SNPs, may influence colon cancer risk and these associations may be modified by adiposity.
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http://dx.doi.org/10.1093/carcin/bgn166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722851PMC
September 2008

Pathological aggressiveness of prostatic carcinomas related to RNASEL R462Q allelic variants.

J Urol 2008 Apr 4;179(4):1344-8. Epub 2008 Mar 4.

Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio, USA.

Purpose: Allelic variations in the HPC1/RNASEL gene, especially the R462Q single nucleotide polymorphism, have been associated with increased susceptibility to prostate cancer. Prior studies have suggested that HPC1 or R462Q associated tumors present with more aggressive clinical features. We assessed a series of men undergoing radical prostatectomy for clinical and pathological measures of tumor aggressiveness according to the RNASEL R462Q genotype.

Materials And Methods: A prospective analysis of 232 men treated for prostate cancer with radical prostatectomy was performed. Disease aggressiveness at diagnosis was assessed by age at disease onset, biopsy Gleason score, clinical T stage and pretreatment prostate specific antigen. Tumor aggressiveness was assessed pathologically by tumor volume, extraprostatic extension, seminal vesicle involvement and lymph node metastasis. Clinical and pathological characteristics were then correlated with RNASEL genotype.

Results: Of the 232 men studied 104 (45%) were homozygous WT, 101 (43%) were heterozygous and 27 (12%) were homozygous for the R462Q variant, mirroring the distribution in the general population. No significant differences were seen between genotypes in age at disease onset, pretreatment characteristics or pathological features, as assessed by surgical grade and pathological stage. Tumors homozygous for the R462Q variant were of smaller volume than other genotypes (p = 0.02).

Conclusions: This prospective study suggests that prostate cancer in patients with the R462Q allelic variant of the HPC1/RNASEL gene is not associated with more aggressive clinical or pathological features in radical prostatectomy specimens.
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http://dx.doi.org/10.1016/j.juro.2007.11.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293030PMC
April 2008

A common 8q24 variant and the risk of colon cancer: a population-based case-control study.

Cancer Epidemiol Biomarkers Prev 2008 Feb;17(2):339-42

Department of Family Medicine-Research Division, Case Western Reserve University, 11001 Cedar Avenue, Suite 306, Cleveland, OH 44106-7136, USA.

Three recent studies identified common variants on 8q24 that confer modestly increased susceptibility to colorectal cancer. Here, we replicate the association in a population-based case-control study of colon cancer, including 561 cases and 721 unrelated controls. The rs6983267 marker was significantly associated with colon cancer risk. Compared with those homozygous for the T allele, the heterozygous and homozygous carriers for the G allele had an age-adjusted odds ratio of 1.39 (95% confidence interval, 1.03-1.88) and 1.68 (95% confidence interval, 1.21-2.33), respectively. An additive model showed strong evidence for a gene-dose response relationship (P(trend) = 0.0022). The association remained statistically significant when restricted to Caucasians only (527 cases and 679 controls; P(trend) = 0.0056). Further adjustment for other known risk factors did not alter the results. Stratified analysis revealed no evidence for effect modification by family history of colorectal cancer, age, or gender. These data replicate the association identified from recent studies, providing additional evidence supporting the rs6983267 genetic polymorphism as a marker predisposing to colon cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-07-0713DOI Listing
February 2008

Association between phosphatidylinositol 3-kinase regulatory subunit p85alpha Met326Ile genetic polymorphism and colon cancer risk.

Clin Cancer Res 2008 Feb;14(3):633-7

Department of Family Medicine-Research Division, Case Western Reserve University, Cleveland, OH 44106-7136, USA.

Purpose: The phosphatidylinositol 3-kinase signaling pathway is frequently activated in cancer. Emerging evidence supports the p85alpha regulatory subunit gene, PIK3R1, as a novel oncogene.

Experimental Design: We examined the association of a functional missense polymorphism (Met326Ile) of PIK3R1 with colon cancer risk in a population-based case-control study of 421 incident cases and 483 controls.

Results: In our base unconditional logistic regression model controlling for age, gender, and race, we observed a 47% increase in risk among those carrying one or two copies of the 326Ile variant (P = 0.01). Further adjustment for family history of colorectal cancer, body mass index, nonsteroidal anti-inflammatory drugs, smoking, alcohol consumption, and physical activity strengthened the association [odds ratio (OR), 1.73; 95% confidence interval (CI), 1.24-2.42, P = 0.001]. The association was more pronounced among those older than 64 years (OR, 2.10; 95% CI, 1.19-3.70, P = 0.01). Evaluation of the genotypes assuming an additive mode of inheritance showed a significant trend for gene-dose response, where compared with Met/Met, the OR estimates for Ile/Met and Ile/Ile were 1.68 (95% CI, 1.19-2.37) and 2.27 (95% CI, 0.98-5.29), respectively (P for trend = 0.001).

Conclusions: This study is the first to describe a significant association between a germ line functional variant in PIK3R1 and cancer, providing new evidence supporting a role for PIK3R1 in the development of colon cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-1211DOI Listing
February 2008

8q24 and prostate cancer: association with advanced disease and meta-analysis.

Eur J Hum Genet 2008 Apr 30;16(4):496-505. Epub 2008 Jan 30.

Department of Epidemiology and Biostatistics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143-0794, USA.

Compelling evidence demonstrates chromosome 8q24 as a prostate cancer susceptibility locus. Multiple variants within three adjacent regions at 8q24 have recently been identified to impact the risk of prostate cancer. Yet, the role of these variants in more advanced disease has not been rigorously assessed. To examine the relationship between 8q24 variants and advanced disease, we tested 10 previously associated 8q24 variants in a case-control study of advanced prostate cancer (N=1012). Of these ten 8q24 variants, six were associated with the risk of advanced prostate cancer (P=0.001-0.038). Three of these variants (rs10090154-region 1, rs16901979-region 2, and rs6983267-region 3), each variant residing in one of the three previously reported 8q24 regions, could account for our 8q24 effects on advanced disease. A meta-analysis across 10 studies including our results of four 8q24 variants (rs1442295 and DG8S737-region 1, rs16901979-region 2, and rs6983267-region 3) and prostate cancer risk demonstrated strong associations across a wide array of study designs and populations. Our findings provide the first confirmation that the three 8q24 regions independently influence the risk of prostate cancer and, in particular, advanced disease.
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http://dx.doi.org/10.1038/sj.ejhg.5201959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819154PMC
April 2008

Plasma lysophosphatidylcholine levels: potential biomarkers for colorectal cancer.

J Clin Oncol 2007 Jul;25(19):2696-701

Department of Cancer Biology, Lerner Research Institute, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.

Purpose: Plasma levels of lysophospholipids were evaluated as potential biomarkers for colorectal cancer (CRC), where a highly reliable and minimally invasive blood test is lacking.

Patients And Methods: Patients with CRC (n = 133) and control subjects (n = 125) were recruited through the Cleveland Clinic. Preoperative plasma samples were analyzed for lysophospholipid levels using liquid chromatography mass spectrometry in a blinded fashion. Participants were randomly divided in a 2:1 ratio into a "training set" (TS) and a "validation set" (VS). Logistic regression models were used in the TS to identify markers that best discriminated between CRC and controls. A cutoff point for the final discriminating model was developed using the receiver operating characteristic curve to achieve 95% specificity. All analyses were then independently validated in the VS.

Results: Plasma levels of several lysophosphatidylcholines (LPCs), including 18:1- and 18:2-LPC, were significantly decreased in CRC patients compared with controls (P < .001). A model based on total saturated LPC and the difference between the proportional amounts of 18:2-LPC and 18:1-LPC in the unsaturated LPC fraction was derived from the TS. This model achieved a sensitivity and specificity of 82% and 93%, respectively, in the VS. Overall, 118 (94%) of 125 control subjects and 113 (85%) of 133 CRC cases were correctly identified, including eight (89%) of nine CRC cases with stage T1 disease.

Conclusion: Percentage of 18:1-LPC or 18:2-LPC plasma levels compared with total saturated LPC levels, either individually or in combination, may represent potential biomarkers for CRC.
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http://dx.doi.org/10.1200/JCO.2006.08.5571DOI Listing
July 2007

MIC1 and IL1RN genetic variation and advanced prostate cancer risk.

Cancer Epidemiol Biomarkers Prev 2007 Jun;16(6):1309-11

Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143-0794, USA.

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http://dx.doi.org/10.1158/1055-9965.EPI-07-0165DOI Listing
June 2007

Reduced expression of autotaxin predicts survival in uveal melanoma.

Br J Ophthalmol 2007 Oct 2;91(10):1385-92. Epub 2007 May 2.

Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Aim: In an effort to identify patients with uveal melanoma at high risk of metastasis, the authors undertook correlation of gene expression profiles with histopathology data and tumour-related mortality.

Methods: The RNA was isolated from 27 samples of uveal melanoma from patients who had consented to undergo enucleation, and transcripts profiled using a cDNA array comprised of sequence-verified cDNA clones representing approximately 4000 genes implicated in cancer development. Two multivariate data mining techniques--hierarchical cluster analysis and multidimensional scaling--were used to investigate the grouping structure in the gene expression data. Cluster analysis was performed with a subset of 10,000 randomly selected genes and the cumulative contribution of all the genes in making the correct grouping was recorded.

Results: Hierarchical cluster analysis and multidimensional scaling revealed two distinct classes. When correlated with the data on metastasis, the two molecular classes corresponded very well to the survival data for the 27 patients. Thirty two discrete genes (corresponding to 44 probe sets) that correctly defined the molecular classes were selected. A single gene (ectonucleotide pyrophosphatase/phosphodiesterase 2; autotaxin) could classify the molecular types. The expression pattern was confirmed using real-time quantitative PCR.

Conclusions: Gene expression profiling identifies two distinct prognostic classes of uveal melanoma. Underexpression of autotaxin in class 2 uveal melanoma with a poor prognosis needs to be explored further.
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http://dx.doi.org/10.1136/bjo.2007.116947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2001033PMC
October 2007

Toll-like receptor 4 genetic variation and advanced prostate cancer risk.

Cancer Epidemiol Biomarkers Prev 2007 Feb;16(2):352-5

Department of Epidemiology and Biostatistics and Center of Human Genetics, University of California at San Francisco, 94143-0794, USA.

Toll-like receptor 4 (TLR4) is a key innate immunity receptor that initiates an inflammatory response primarily against Gram-negative bacteria. Two recent publications reported that variants in TLR4 were associated with risk of prostate cancer. To further investigate the role of TLR4 in prostate cancer susceptibility, we identified six tagging single-nucleotide polymorphisms that comprehensively captured the common genetic variation of the locus and tested these polymorphisms in our case-control study of 1,012 men. Two single-nucleotide polymorphisms showed nominally statistically significant associations with prostate cancer risk, with the strongest (rs10759932) associated with a 4-fold increased risk of disease (P = 0.006). We estimated through permutation analysis that a similarly strong result would occur by chance 2.5% of the time. Our findings support previous studies and suggest that inherited differences in TLR4 influence prostate cancer risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-06-0429DOI Listing
February 2007

Association of testis derived transcript gene variants and prostate cancer risk.

J Urol 2007 Mar;177(3):894-8

Department of Epidemiology and Biostatistics, and Institute for Human Genetics, University of California, San Francisco, San Francisco, California 94143-0794, USA.

Purpose: The testis derived transcript gene has been suggested as a tumor suppressor gene for prostate cancer at 7q31. To investigate this concept we evaluated the effects of 7 tagging single nucleotide polymorphisms that comprehensively captured the common genetic variants in TES on aggressive prostate cancer in a case-control study.

Materials And Methods: A total of 506 cases diagnosed with aggressive prostate cancer, and an equal number of age, institute and ethnicity matched controls, were recruited from the major medical institutions in Cleveland, Ohio. A logistic regression model was used to evaluate the association between SNPs/multimarker haplotypes and prostate cancer.

Results: When looking at all study subjects and white men only, no statistically significant associations were observed between any variants and more aggressive disease. However, 3 variants showed inverse associations with disease in black men (178), including 2 intronic SNPs (rs2402056, rs1004109) and 1 SNP close to the 3' untranslated region (rs4730721) with ORs of 0.57 (95% CI 0.36-0.90, under an additive mode of inheritance), 0.57 (95% CI 0.36-0.91, under an additive mode of inheritance) and 0.45 (95% CI 0.21-0.98, under a dominant mode of inheritance), respectively. Variants rs2402056 and rs1004109 are in tight linkage disequilibrium (r2=0.8) and the reconstructed haplotype did not provide any additional evidence for association than their genotype level results.

Conclusions: Our findings suggest that the variants in TES, or in a nearby gene, may be associated with prostate cancer in black men.
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http://dx.doi.org/10.1016/j.juro.2006.10.057DOI Listing
March 2007