Stephen B Gruber

University of Southern California, Los Ángeles, California, United States

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Publications (221)1938.15 Total impact

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    ABSTRACT: Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted. We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided. We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003). Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    JNCI Journal of the National Cancer Institute 11/2015; 107(11):djv246. DOI:10.1093/jnci/djv246 · 15.16 Impact Factor
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    ABSTRACT: 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.
    Nature Communications 07/2015; 6:7138. DOI:10.1038/ncomms8138 · 10.74 Impact Factor
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    ABSTRACT: Epidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51,725 cases and 62,035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P=6.3x10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P=6.6x10(-6)). Under Mendelian randomization assumptions, the association estimate (odds ratio (OR)=2.78) is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 base pair increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Human Molecular Genetics 07/2015; DOI:10.1093/hmg/ddv252 · 6.68 Impact Factor
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    ABSTRACT: NRAS and BRAF mutations in melanoma inform current treatment paradigms but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. A population-based study with median follow-up of 7.6 years for 912 patients with first primary cutaneous melanoma analyzed for NRAS and BRAF mutations diagnosed in the year 2000 from the United States and Australia in the Genes, Environment and Melanoma Study and followed through 2007. Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype). In a multivariable model including clinicopathologic characteristics, NRAS+ melanoma was associated (P<.05) with mitoses, lower tumor infiltrating lymphocyte (TIL) grade, and anatomic site other than scalp/neck and BRAF+ melanoma was associated with younger age, superficial spreading subtype, and mitoses, relative to wildtype melanoma. There was no significant difference in melanoma-specific survival for melanoma harboring mutations in NRAS (HR 1.7, 95% CI, 0.8-3.4) or BRAF (HR, 1.5, 95% CI, 0.8-2.9) compared to wildtype melanoma adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher risk (T2b or higher stage) tumors with NRAS (HR 2.9; 95% CI 1.1-7.7) or BRAF (HR 3.1; 95% CI 1.2-8.5) mutations but not for lower risk (T2a or lower) tumors (P=.65) adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may impact its response to immunotherapies. Further, the approximately three-fold increased death rate for higher risk tumors harboring NRAS or BRAF mutations compared to wildtype melanomas after adjusting for other prognostic factors indicates that the prognostic implication of NRAS and BRAF mutations deserves further investigation, particularly in higher AJCC stage primary melanomas.
    06/2015; 1(3):359-368. DOI:10.1001/jamaoncol.2015.0493
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    ABSTRACT: Background Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. Methods Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype–phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. Results This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying biallelic truncating mutations. Residual expression of fulllength PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. Conclusions Our genotype–phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention.
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    ABSTRACT: Variation in the melanocortin-1receptor (MC1R) gene is associated with pigmentary phenotypes and risk of malignant melanoma. Few studies have reported on MC1R variation with respect to tumor characteristics, especially clinically important prognostic features. We examined associations between MC1R variants and histopathological melanoma characteristics. Study participants were enrolled from nine geographic regions in Australia, Canada, Italy and the United States and were genotyped for MC1R variants classified as high-risk [R] (D84E, R142H, R151C, R160W, and D294H, all nonsense and insertion/deletion) or low-risk [r] (all other nonsynonymous) variants. Tissue was available for 2,160 white participants of the Genes, Environment and Melanoma (GEM) Study with a first incident primary melanoma diagnosis, and underwent centralized pathologic review. No statistically significant associations were observed between MC1R variants and AJCC established prognostic tumor characteristics: Breslow thickness, presence of mitoses or presence of ulceration. However, MC1R was significantly associated with anatomic site of melanoma (p = 0.002) and a positive association was observed between carriage of more than one [R] variant and melanomas arising on the arms (OR = 2.39; 95% CI: 1.40, 4.09). We also observed statistically significant differences between sun-sensitive and sun-resistant individuals with respect to associations between MC1R genotype and AJCC prognostic tumor characteristics. Our results suggest inherited variation in MC1R may play an influential role in anatomic site presentation of melanomas and may differ with respect to skin pigmentation phenotype.
    PLoS ONE 03/2015; 10(3):e0119920. DOI:10.1371/journal.pone.0119920 · 3.23 Impact Factor
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    ABSTRACT: Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype-phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. Our genotype-phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Journal of Medical Genetics 02/2015; 52(5). DOI:10.1136/jmedgenet-2014-102934 · 5.64 Impact Factor
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    ABSTRACT: & Aims: Risk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci. Using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States (US) and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in US. We identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased discriminatory accuracy from 0.51 to 0.59 (P=.0028) for men and from 0.52 to 0.56 (P=.14) for women. We calculated age- and sex-specific 10 y CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score=90%) was 42 y, and for low-risk men (no family history of CRC and genetic risk score=10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women. By incorporating information on CRC risk alleles, we created a model to more accurately determine risk for CRC. This model might be used to develop screening and prevention strategies. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Gastroenterology 02/2015; 148(7). DOI:10.1053/j.gastro.2015.02.010 · 13.93 Impact Factor
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    ABSTRACT: To provide recommendations on prevention, screening, genetics, treatment, and management for people at risk for hereditary colorectal cancer (CRC) syndromes. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. The Familial Risk-Colorectal Cancer: European Society for Medical Oncology Clinical Practice Guideline published in 2013 on behalf of the European Society for Medical Oncology (ESMO) Guidelines Working Group in Annals of Oncology was reviewed for developmental rigor by methodologists, with content and recommendations reviewed by an ASCO endorsement panel. The ASCO endorsement panel determined that the recommendations of the ESMO guidelines are clear, thorough, and based on the most relevant scientific evidence. The ASCO panel endorsed the ESMO guidelines and added a few qualifying statements. Approximately 5% to 6% of patient cases of CRC are associated with germline mutations that confer an inherited predisposition for cancer. The possibility of a hereditary cancer syndrome should be assessed for every patient at the time of CRC diagnosis. A diagnosis of Lynch syndrome, familial adenomatous polyposis, or another genetic syndrome can influence clinical management for patients with CRC and their family members. Screening for hereditary cancer syndromes in patients with CRC should include review of personal and family histories and testing of tumors for DNA mismatch repair deficiency and/or microsatellite instability. Formal genetic evaluation is recommended for individuals who meet defined criteria. © 2014 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 12/2014; 33(2). DOI:10.1200/JCO.2014.58.1322 · 18.43 Impact Factor
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    ABSTRACT: MC1R is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population-based series of single primary melanoma patients enrolled into the GEM study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes with melanoma-specific survival (i.e. death due to melanoma) and overall survival using Cox proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index and age. Additionally, we evaluated haplotypes involving polymorphisms near the ASIP locus for their impacts on survival. Melanoma-specific survival was inversely associated with carriage of MC1R variants in the absence of consensus alleles compared to carriage of at least one consensus allele (HR=0.60; 95%CI: 0.40, 0.90). MC1R results for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma-specific death among carriers of the risk haplotype TG near the ASIP locus (HR=1.37; 95%CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma-specific death (HR=5.11; 95%CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma-specific survival among carriers of two inherited MC1R variants. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 11/2014; 136(11). DOI:10.1002/ijc.29317 · 5.01 Impact Factor
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    ABSTRACT: Background: MicroRNAs (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-messenger RNA interaction and subsequently alter risk of cancer development. Methods: This study expanded the search for miRNA-related polymorphisms contributing to the etiology of colorectal cancer (CRC) across the genome using a novel platform, the Axiom® miRNA 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 CRC in northern Israel. The association between each marker and CRC 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-value=3.7E-05). Further, this study replicated a previously published 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 CRC 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 CRC. Impact:This study demonstrates the potential for a miRNA-targeted genome-wide association study to identify candidate susceptibility loci and prioritize them for functional characterization.
    Cancer Epidemiology Biomarkers & Prevention 10/2014; 24(1). DOI:10.1158/1055-9965.EPI-14-0219 · 4.32 Impact Factor
  • Stephanie Stenzel · Hedy S. Rennert · Gad Rennert · Stephen B. Gruber
    Cancer Research 10/2014; 74(19 Supplement):1267-1267. DOI:10.1158/1538-7445.AM2014-1267 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2194-2194. DOI:10.1158/1538-7445.AM2014-2194 · 9.28 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):2921-2921. DOI:10.1158/1538-7445.AM2014-2921 · 9.28 Impact Factor
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    ABSTRACT: The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P<5 × 10(-8)) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.4 × 10(-9)), providing additional insight into the aetiology of CRC and highlighting the value of association mapping in diverse populations.
    Nature Communications 10/2014; 5(19 Supplement):4613. DOI:10.1158/1538-7445.AM2014-LB-282 · 10.74 Impact Factor
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    ABSTRACT: Importance Previous studies have reported that histopathologically amelanotic melanoma is associated with poorer survival than pigmented melanoma; however, small numbers of amelanotic melanomas, selected populations, lack of centralized pathologic review, or no adjustment for stage limit the interpretation or generalization of results from prior studies.Objective To compare melanoma-specific survival between patients with histopathologically amelanotic and those with pigmented melanoma in a large international population-based study.Design, Setting, and Participants Survival analysis with a median follow-up of 7.6 years. The study population comprised 2995 patients with 3486 invasive primary melanomas centrally scored for histologic pigmentation from the Genes, Environment, and Melanoma (GEM) Study, which enrolled incident cases of melanoma diagnosed in 1998 through 2003 from international population-based cancer registries.Main Outcomes and Measures Clinicopathologic predictors and melanoma-specific survival of histologically amelanotic and pigmented melanoma were compared using generalized estimating equations and Cox regression models, respectively.Results Of 3467 melanomas, 275 (8%) were histopathologically amelanotic. Female sex, nodular and unclassified or other histologic subtypes, increased Breslow thickness, presence of mitoses, severe solar elastosis, and lack of a coexisting nevus were independently associated with amelanotic melanoma (each P < .05). Amelanotic melanoma was generally of a higher American Joint Committee on Cancer (AJCC) tumor stage at diagnosis (odds ratios [ORs] [95% CIs] between 2.9 [1.8-4.6] and 11.1 [5.8-21.2] for tumor stages between T1b and T3b and ORs [95% CIs] of 24.6 [13.6-44.4] for T4a and 29.1 [15.5-54.9] for T4b relative to T1a; P value for trend, <.001) than pigmented melanoma. Hazard of death from melanoma was higher for amelanotic than for pigmented melanoma (hazard ratio [HR], 2.0; 95% CI, 1.4-3.0) (P < .001), adjusted for age, sex, anatomic site, and study design variables, but survival did not differ once AJCC tumor stage was also taken into account (HR, 0.8; 95% CI, 0.5-1.2) (P = .36).Conclusions and Relevance At the population level, survival after diagnosis of amelanotic melanoma is poorer than after pigmented melanoma because of its more advanced stage at diagnosis. It is probable that amelanotic melanomas present at more advanced tumor stages because they are difficult to diagnose. The association of amelanotic melanoma with presence of mitoses independently of Breslow thickness and other clinicopathologic characteristics suggests that amelanotic melanomas might also grow faster than pigmented melanomas. New strategies for early diagnosis and investigation of the biological properties of amelanotic melanoma are warranted.
    JAMA Dermatology 08/2014; 150(12). DOI:10.1001/jamadermatol.2014.1348 · 4.30 Impact Factor
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    ABSTRACT: Background We previously reported a significant association between higher ultraviolet radiation exposure before diagnosis and greater survival with melanoma in a population-based study in Connecticut. We sought to evaluate the hypothesis that sun exposure prior to diagnosis was associated with greater survival in a larger, international population-based study with more detailed exposure information. Methods We conducted a multi-center, international population-based study in four countries - Australia, Italy, Canada and the United States - with 3,578 cases of melanoma with an average of 7.4 years of follow-up. Measures of sun exposure included sunburn, intermittent exposure, hours of holiday sun exposure, hours of water-related outdoor activities, ambient UVB dose, histological solar elastosis and season of diagnosis. Results Results were not strongly supportive of the earlier hypothesis. Having had any sunburn in one year within 10 years of diagnosis was inversely associated with survival; solar elastosis - a measure of lifetime cumulative exposure - was not. Additionally, none of the intermittent exposure measures - water related activities and sunny holidays - were associated with melanoma-specific survival. Estimated ambient UVB dose was not associated with survival. Conclusion Although there was an apparent protective effect of sunburns within 10 years of diagnosis, there was only weak evidence in this large, international, population-based study of melanoma that sun exposure prior to diagnosis is associated with greater melanoma-specific survival. Impact This study adds to the evidence that sun exposure prior to melanoma diagnosis has little effect on survival with melanoma.
    Cancer Epidemiology Biomarkers & Prevention 07/2014; 23(10). DOI:10.1158/1055-9965.EPI-14-0431 · 4.32 Impact Factor
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    ABSTRACT: Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genome-wide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case–control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery–replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10−9; nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.
    Carcinogenesis 07/2014; 35(11). DOI:10.1093/carcin/bgu148 · 5.27 Impact Factor
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    ABSTRACT: Importance Sebaceous neoplasms (SNs) define the Muir-Torre syndrome variant of Lynch syndrome (LS), which is associated with increased risk for colon and other cancers necessitating earlier and more frequent screening to reduce morbidity and mortality. Immunohistochemical (IHC) staining for mismatch repair (MMR) proteins in SNs can be used to screen for LS, but data on subsequent germline genetic testing to confirm LS diagnosis are limited.Objective To characterize the utility of IHC screening of SNs in identification of germline MMR mutations confirming LS.Design, Setting, and Participants Retrospective study at 2 academic cancer centers of 86 adult patients referred for clinical genetics evaluation after diagnosis of SN.Main Outcomes and Measures Results of tumor IHC testing and germline genetic testing were reviewed to determine positive predictive value and sensitivity of IHC testing in diagnosis of LS. Clinical variables, including age at diagnosis of SN, clinical diagnostic criteria for LS and Muir-Torre syndrome, and family history characteristics were compared between mutation carriers and noncarriers.Results Of 86 patients with SNs, 25 (29%) had germline MMR mutations confirming LS. Among 77 patients with IHC testing on SNs, 38 (49%) had loss of staining of 1 or more MMR proteins and 14 had germline MMR mutations. Immunohistochemical analysis correctly identified 13 of 16 MMR mutation carriers, corresponding to 81% sensitivity. Ten of 12 patients (83%) with more than 1 SN had MMR mutations. Fifty-two percent of MMR mutation carriers did not meet clinical diagnostic criteria for LS, and 11 of 25 (44%) did not meet the clinical definition of Muir-Torre syndrome.Conclusions and Relevance Immunohistochemical screening of SNs is effective in identifying patients with germline MMR mutations and can be used as a first-line test when LS is suspected. Abnormal IHC results, including absence of MSH2, are not diagnostic of LS and should be interpreted cautiously in conjunction with family history and germline genetic testing. Use of family history to select patients for IHC screening has substantial limitations, suggesting that universal IHC screening of SNs merits further study. Clinical genetics evaluation is warranted for patients with abnormal IHC test results, normal IHC test results with personal or family history of other LS-associated neoplasms, and/or multiple SNs.
    JAMA Dermatology 07/2014; 150(12). DOI:10.1001/jamadermatol.2014.1217 · 4.30 Impact Factor
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    ABSTRACT: With limited funding and biological specimen availability, choosing an optimal sampling design to maximize power for detecting gene-by-environment (G–E) interactions is critical. Exposure-enriched sampling is often used to select subjects with rare exposures for genotyping to enhance power for tests of G–E effects. However, exposure misclassification (MC) combined with biased sampling can affect characteristics of tests for G–E interaction and joint tests for marginal association and G–E interaction. Here, we characterize the impact of exposure-biased sampling under conditions of perfect exposure information and exposure MC on properties of several methods for conducting inference. We assess the Type I error, power, bias, and mean squared error properties of case-only, case–control, and empirical Bayes methods for testing/estimating G–E interaction and a joint test for marginal G (or E) effect and G–E interaction across three biased sampling schemes. Properties are evaluated via empirical simulation studies. With perfect exposure information, exposure-enriched sampling schemes enhance power as compared to random selection of subjects irrespective of exposure prevalence but yield bias in estimation of the G–E interaction and marginal E parameters. Exposure MC modifies the relative performance of sampling designs when compared to the case of perfect exposure information. Those conducting G–E interaction studies should be aware of exposure MC properties and the prevalence of exposure when choosing an ideal sampling scheme and method for characterizing G–E interactions and joint effects.
    European Journal of Epidemiology 06/2014; 30(5). DOI:10.1007/s10654-014-9908-1 · 5.15 Impact Factor

Publication Stats

8k Citations
1,938.15 Total Impact Points


  • 2014–2015
    • University of Southern California
      • Department of Preventive Medicine
      Los Ángeles, California, United States
  • 2012–2014
    • University of California, Los Angeles
      Los Ángeles, California, United States
    • Keck School of Medicine USC
      Los Angeles, California, United States
  • 1999–2013
    • University of Michigan
      • • Medical School
      • • Department of Human Genetics
      • • Department of Epidemiology
      • • Department of Internal Medicine
      • • Department of Pathology
      • • Division of Molecular Medicine & Genetics
      Ann Arbor, Michigan, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2004–2012
    • Fred Hutchinson Cancer Research Center
      • Division of Public Health Sciences
      Seattle, WA, United States
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
  • 2003–2012
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2009–2011
    • Technion - Israel Institute of Technology
      • Ruth and Bruce Rappaport Faculty of Medicine
      Haifa, Haifa District, Israel
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2007
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Pathology
      Amsterdamo, North Holland, Netherlands
  • 2006
    • Memorial Sloan-Kettering Cancer Center
      • Department of Surgery
      New York, New York, United States
    • University of North Carolina at Chapel Hill
      • Department of Epidemiology
      Chapel Hill, NC, United States
  • 2004–2005
    • University of California, Irvine
      • Department of Medicine
      Irvine, California, United States
  • 2002
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States