Clalit Health Services National Cancer Control Center

Haifa, Israel

Clalit Health Services National Cancer Control Center

Haifa, Israel
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Schumacher F.R.,University of Southern California | Schmit S.L.,University of Southern California | Jiao S.,Fred Hutchinson Cancer Research Center | Edlund C.K.,University of Southern California | And 110 more authors.
Nature Communications | Year: 2015

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies. © 2015 Macmillan Publishers Limited.

Crous-Bou M.,Bellvitge Biomedical Research Institute IDIBELL | Crous-Bou M.,Catalan Institute of Nanoscience and Nanotechnology | Rennert G.,Clalit Health Services National Cancer Control Center | Salazar R.,Bellvitge Biomedical Research Institute IDIBELL | And 11 more authors.
Mutagenesis | Year: 2012

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included dietary fat intake; consequently, the role of genes in the fatty acid biosynthesis and metabolism pathways is of particular interest. Moreover, hyperlipidaemia has been associated with different type of cancer and serum lipid levels could be affected by genetic factors, including polymorphisms in the lipid metabolism pathway. The aim of this study is to assess the association between single-nucleotide polymorphisms (SNPs) in fatty acid metabolism genes, serum lipid levels, body mass index (BMI) and dietary fat intake and CRC risk; 30 SNPs from 8 candidate genes included in fatty acid biosynthesis and metabolism pathways were genotyped in 1780 CRC cases and 1864 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. Several LIPC (lipase, hepatic) polymorphisms were found to be associated with CRC risk, although no particular haplotype was related to CRC. The SNP rs12299484 showed an association with CRC risk after Bonferroni correction. We replicate the association between the T allele of the LIPC SNP rs1800588 and higher serum high-density lipoprotein levels. Weak associations between selected polymorphism in the LIPC and PPARG genes and BMI were observed. A path analysis based on structural equation modelling showed a direct effect of LIPC gene polymorphisms on colorectal carcinogenesis as well as an indirect effect mediated through serum lipid levels. Genetic polymorphisms in the hepatic lipase gene have a potential role in colorectal carcinogenesis, perhaps though the regulation of serum lipid levels. © 2012 The Author.

Antoniou A.C.,University of Cambridge | Wang X.,Mayo Medical School | Fredericksen Z.S.,Mayo Medical School | McGuffog L.,University of Cambridge | And 189 more authors.
Nature Genetics | Year: 2010

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P trend = 2.3 × 10 9 to P trend = 3.9 × 10 7), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 × 10 7 to P trend = 8 × 10 5; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P trend = 1.1 × 10 7). © 2010 Nature America, Inc. All rights reserved.

Schmit S.L.,University of Southern California | Rennert H.S.,Carmel Medical Center | Rennert G.,Carmel Medical Center | Rennert G.,Clalit Health Services National Cancer Control Center | And 2 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2016

Background: Coffee contains several bioactive compounds relevant to colon physiology. Although coffee intake is a proposed protective factor for colorectal cancer, current evidence remains inconclusive. Methods: We investigated the association between coffee consumption and risk of colorectal cancer in 5,145 cases and 4,097 controls from the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based case-control study in northern Israel. We also examined this association by type of coffee, by cancer site (colon and rectum), and by ethnic subgroup (Ashkenazi Jews, Sephardi Jews, and Arabs). Coffee data were collected by interview using a validated, semi-quantitative food frequency questionnaire. Results: Coffee consumption was associated with 26% lower odds of developing colorectal cancer [OR (drinkers vs. nondrinkers), 0.74; 95% confidence interval (CI), 0.64-0.86; P < 0.001]. The inverse association was also observed for decaffeinated coffee consumption alone (OR, 0.82; 95%CI, 0.68-0.99; P = 0.04) and for boiled coffee (OR, 0.82; 95% CI, 0.71-0.94; P= 0.004). Increasing consumption of coffee was associated with lower odds of developing colorectal cancer. Compared with <1 serving/day, intake of 1 to <2 servings/day (OR, 0.78; 95% CI, 0.68-0.90; P < 0.001), 2 to 2.5 servings/day (OR, 0.59; 95% CI, 0.51-0.68; P < 0.001), and <2.5 servings/day (OR, 0.46; 95% CI, 0.39-0.54; P < 0.001) were associated with significantly lower odds of colorectal cancer (Ptrend < 0.001), and the dose-response trend was statistically significant for both colon and rectal cancers. Conclusions: Coffee consumption may be inversely associated with risk of colorectal cancer in a dose-response manner. Impact: Global coffee consumption patterns suggest potential health benefits of the beverage for reducing the risk of colorectal cancer. © 2016 American Association for Cancer Research.

Lemire M.,Ontario Cancer Institute | Qu C.,Fred Hutchinson Cancer Research Center | Loo L.W.M.,University of Hawaii at Manoa | Zaidi S.H.E.,Ontario Cancer Institute | And 53 more authors.
Human Genetics | Year: 2015

Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10−10; odds ratio estimated by re-including all controls (OR) = 0.87, 95 % confidence interval (CI) 0.83–0.91; minor allele frequency (MAF) = 13 %]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95 % CI 0.77–0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10−8). © 2015, Springer-Verlag Berlin Heidelberg.

Schmit S.L.,University of Southern California | Gollub J.,Affymetrix | Shapero M.H.,Affymetrix | Huang S.-C.,University of Southern California | And 6 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2015

Background: miRNAs act as post-transcriptional regulators of gene expression. Genetic variation in miRNA-encoding sequences or their corresponding binding sites may affect the fidelity of the miRNA-mRNA interaction and subsequently alter the risk of cancer development. Methods: This study expanded the search for miRNA-related polymorphisms contributing to the etiology of colorectal cancer across the genome using a novelplatform, the Axiommi RNA Target Site Genotyping Array (237,858 markers). After quality control, the study included 596 cases and 429 controls from the Molecular Epidemiology of Colorectal Cancer study, a population-based case-control study of colorectal cancer in northern Israel. The association between each marker and colorectal cancer status was examined assuming a log-additive genetic model using logistic regression adjusted for sex, age, and two principal components. Results: Twenty-three markers had P values less than 5.0E-04, and the most statistically significant association involved rs2985 (chr6:34845648; intronic of UHRF1BP1; OR = 0.66; P = 3.7E-05). Furthermore, this study replicated a previously published risk locus, rs1051690, in the 3′-untranslated region of the insulin receptor gene INSR (OR = 1.38; P = 0.03), with strong evidence of differences in INSR gene expression by genotype. Conclusions: This study is the first to examine associations between genetic variation in miRNA target sites and colorectal cancer using a genome-wide approach. Functional studies to identify allele-specific effects on miRNA binding are needed to confirm the regulatory capacity of genetic variation to influence risk of colorectal cancer. Impact: This study demonstrates the potential for an miRNA-targeted genome-wide association study to identify candidate susceptibility loci and prioritize them for functional characterization. © 2014 American Association for Cancer Research.

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