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  • Online Resource  (30)
  • American Association for Cancer Research (AACR)  (30)
  • 1
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 6, No. 9 ( 2016-09-01), p. 1052-1067
    Abstract: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P & lt; 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P & lt; 10−5 in the three-cancer meta-analysis. Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052–67. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 932
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 3, No. 3 ( 2005-03-01), p. 119-129
    Abstract: Tumor cell lines are relied on extensively for cancer investigations, yet cultured cells in an in vitro environment differ considerably in behavior compared with those of the same cancer cells that proliferate and form tumors in vivo. To uncover gene expression changes related to tumor formation, gene expression profiles of human lung adenocarcinoma (A549) cells grown as lung tumors in immune-compromised mice were compared with profiles of the same cells grown in vitro. Additionally, profiles of uninvolved adjacent mouse tissue were determined. A profound interplay between cancer cells and the host was shown that affected a complex protein interaction network involving processes of extracellular interaction, growth factor signaling, hemostasis, immune response, and transcriptional regulation. Growth in vivo of A549 cells, which carry an activating k-ras mutation, induced changes in gene expression that corresponded highly to a pattern characteristic of human lung tumors with k-ras mutation. Cytokines interleukin-4, interleukin-6, and IFN-γ each induced distinct in vitro genomic responses in cancer cells that emulated many of the changes in gene expression observed in vivo. Genes that were both selectively induced in vivo and overexpressed in human lung adenocarcinoma tumors included CSPG2, which has not been associated previously with tumor formation. Knockdown in A549 of CSPG2 by RNA interference significantly inhibited tumor growth in vivo but not in vitro. Thus, analysis of tumor xenografts by gene expression profiling has the potential for identifying genes involved in tumor development that may not be expressed in cancer cells grown in vitro.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
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  • 3
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 11_Supplement ( 2013-11-01), p. B12-B12
    Abstract: Development of resistance is a significant clinical problem for virtually all targeted cancer therapies. We have generated a reproducible, patient derived xenograft (PDX) model of acquired vemurafenib resistance to address these challenges. Continuous treatment of V600E melanoma tumors, caused synchronous tumor stasis for approximately 7 weeks, following which, all tumors displayed simultaneous resistance marked by rapid tumor growth. Additionally, this model maintains the resistance phenotype upon serial transplantation, providing a platform for testing rational drug selection. The fidelity of the PDX models was further confirmed using a BRAF V600V tumor which did not respond to vemurafenib. Onset of vemurafenib resistance is accompanied by increased phosphor-ERK signifying re-engagement of the MAPK signaling pathway and supporting MEK as a potential target. MEK inhibition in vemurafenib resistant tumors using PD0325901, resulted in rapid tumor shrinkage and dramatically reduced phosphor-ERK levels. Treatment of resistant tumors with PD0325901 alone, whilst leading to rapid tumor shrinkage, showed significant host toxicity and onset of acquired MEKi resistance. Interestingly, combination of vemurafenib + PD0325901 was non-toxic, and showed dramatic and sustained tumor suppression. Upon cessation of PD0325901 at 70 days the tumors remained undetectable for the duration of the study ( & gt;100 days). These data support the use of MEK inhibitors post-development of vemurafenib resistance and demonstrate that combination therapy mitigates systemic MEKi toxicity and results in persistent tumor inhibition/eradication. PDX models of acquired resistance provide a unique opportunity to bridge the gap between patients and the basic in vitro biology. Additionally, this PDX system allows the interrogation of the kinetics involved in the development of resistance by longitudinal tumor tissue sampling. Numerous mechanisms have been identified as potential causes of the resistance phenotype. Many have been identified in vitro but not all have been confirmed in patients. We detected no evidence of increased BRAF copy number or expression, although alternative BRAF splicing was identified in resistant tumors. Using differential gene expression accompanied by pathway and network analysis we identified distinct differences in the PDX tumors at various time points during the development of resistance. In particular, a potential role for interferon signaling in resistant tumors was observed. Furthermore, changes in the metabolic profiles were identified with untreated and resistant tumors favoring glycolytic pathways, whereas growth arrested tumors exhibited a preference for oxidative phosphorylation. In conclusion, these results demonstrate the value of PDX models for contributing to clinical cancer management through the decryption of complex drug resistance mechanisms and accelerating the identification of rationally selected drug combinations for bench to bedside applications. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B12. Citation Format: Noel R. Monks, David J. Monsma, David M. Cherba, Emily Eugster, Dawna Dylewski, Mary E. Winn, Andrew S. Borgman, Paula J. Davidson, Chelsea A. Peterson, Jose M. Pimiento, Alexander E. Ivliev, Yuri Nikolsky, Marina Bessarabova, Valerie S. Calvert, Mariaelena Pierobon, Emanuel F. Petricoin, Craig P. Webb, Brian J. Nickoloff. Overcoming acquired resistance to vemurafenib using clinically relevant PDX models of melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B12.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 19, No. 2 ( 2010-02-01), p. 600-604
    Abstract: Aberrant glycosylation is a well-described hallmark of cancer. In a previous ovarian cancer case control study that examined polymorphisms in 26 glycosylation-associated genes, we found strong statistical evidence (P = 0.00017) that women who inherited two copies of a single-nucleotide polymorphism in the UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase, GALNT1, had decreased ovarian cancer risk. The current study attempted to replicate this observation. The GALNT1 single-nucleotide polymorphism rs17647532 was genotyped in 6,965 cases and 8,377 controls from 14 studies forming the Ovarian Cancer Association Consortium. The fixed effects estimate per rs17647532 allele was null (odds ratio, 0.99; 95% confidence interval, 0.92-1.07). When a recessive model was fit, the results were unchanged. Test for hetero geneity of the odds ratios revealed consistency across the 14 replication sites but significant differences compared with the original study population (P = 0.03). This study underscores the need for replication of putative findings in genetic association studies. Cancer Epidemiol Biomarkers Prev; 19(2); 600–4
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 5
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 19, No. 1 ( 2010-01-01), p. 245-250
    Abstract: We genotyped 13 single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) region in three population-based case-control studies of epithelial ovarian cancer conducted in the United States, comprising a total of 1,128 and 1,866 non-Hispanic white invasive cases and controls, respectively. A SNP 19 kb downstream of ESR1 (rs2295190, G-to-T change) was associated with invasive ovarian cancer risk, with a per-T-allele odds ratio (OR) of 1.24 [95% confidence interval (CI), 1.06-1.44, P = 0.006]. rs2295190 is a nonsynonymous coding SNP in a neighboring gene called spectrin repeat containing, nuclear envelope 1 (SYNE1), which is involved in nuclear organization and structural integrity, function of the Golgi apparatus, and cytokinesis. An isoform encoded by SYNE1 has been reported to be downregulated in ovarian and other cancers. rs2295190 was genotyped in an additional 12 studies through the Ovarian Cancer Association Consortium, with 5,279 invasive epithelial cases and 7,450 controls. The per-T-allele OR for this 12-study set was 1.09 (95% CI, 1.02-1.17; P = 0.017). Results for the serous subtype in the 15 combined studies were similar to those overall (n = 3,545; OR, 1.09; 95% CI, 1.01-1.18; P = 0.025), and our findings were strongest for the mucinous subtype (n = 447; OR, 1.32; 95% CI, 1.11-1.58; P = 0.002). No association was observed for the endometrioid subtype. In an additional analysis of 1,459 borderline ovarian cancer cases and 7,370 controls, rs2295190 was not associated with risk. These data provide suggestive evidence that the rs2295190 T allele, or another allele in linkage disequilibrium with it, may be associated with increased risk of invasive ovarian cancer. Cancer Epidemiol Biomarkers Prev; 19(1); 244–50
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 6
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 25, No. 5 ( 2016-05-01), p. 780-790
    Abstract: Background: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene–environment interactions related to hormone-related risk factors could differ between obese and non-obese women. Methods: We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case–control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed. Results: SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10−6) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10−5). The most notable obesity–gene–hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10−6). Conclusions: We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2. Future work is needed to develop powerful statistical methods able to detect these complex interactions. Impact: Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780–90. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 7
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 21, No. 10_Supplement ( 2012-10-01), p. B83-B83
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 21, No. 10_Supplement ( 2012-10-01), p. B83-B83
    Abstract: Background/Objective: Head and neck squamous cell carcinoma (HNSCC) is a debilitating and deadly disease, particularly among African Americans. Cure rates increase from 30% to 80% if the disease is detected early. This study evaluated the acceptability of a non-invasive, easy to administer, very affordable, and innovative rinse technique that assays the soluble form of CD44 and total protein as HNSCC early detection markers in a sample of African American men and women. The aim of the study was to determine whether the rinse was acceptable and whether the outcome of the rinse was likely to promote screening behavior. Methods: Participants (N=127) were from underserved, low-income (83% of sample reported annual income of less than $15,000), African American backgrounds (mean age = 51.24). Men (n=73) and women (n=53) were administered a questionnaire to capture satisfaction, intention to repeat the test, and whether the results of the test would affect screening behavior after using the rinse. Nearly 100% of the sample was currently smoking or using nicotine products. Descriptive statistics, t-tests and Analysis of Variance (ANOVA) were employed using SPSS 19 (IBM). Results: Findings showed that using the rinse was highly acceptable to African American men and women (i.e., philosophy behind use, ease of rinse, willingness to repeat, perceived willingness of others in their social group to use rinse, all mean scores = strongly agree). With regard to the rinse's potential effects of behavior, mean scores indicate that participants strongly agreed that: (a) they would act on a positive cancer finding based on the rinse by scheduling an appointment for treatment, (b) they would perform the rinse as prescribed, (c) they would engage in preventative behaviors if the rinse indicated a high probability of getting HNC, (d) they would stop smoking if the rinse indicated a high probability of getting HNC, and (e) people who are at high risk of HNC should stop smoking. Acceptability of the rinse and the rinse's potential effects on behavior did not differ between males and females (all p-values of t-tests & gt; .05) or based on educational attainment categories (all p-values of ANOVAs & gt; .05). Compared to currently unemployed participants, those who were employed reported that: the rinse was harder to do (t(1,124)=-2.37, p=.019); were more likely to schedule a treatment appointment based on the rinse's outcome (t(1,124)=3.54, p=.001); they were more likely to rinse as prescribed (t(1,124)=2.84, p=.003); and they were more likely to take action to prevent HNSCC based on the determination of the rinse (t(1,124)=3.04, p=.003). Interestingly, individuals with health care coverage reported that the test was harder to do (F(2, 123)=4.92, p=.009), but did not differ from uninsured participants on any other variables (all p-values of ANOVAs & gt; .05). Discussion: Findings indicate that a simple, easy to use rinse technique is acceptable to patients and is highly likely to promote screening behavior among African Americans at risk for HNSCC. Differences were noted between insured versus uninsured participants, employed versus unemployed participants but no differences were observed between men and women and between groups based on educational attainment. Citation Format: Suzanne C. Lechner, Lutecia H. Mateus Pereira, Erika Reategui, Claudia Gordon, Jamie Studts, Margaret Byrne, Monica Webb Hooper, David J. Lee, Elizabeth J. Franzmann. Acceptability of a rinse technique for diagnosing head and neck squamous cell carcinoma among African Americans. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B83.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 18 ( 2018-09-15), p. 5419-5430
    Abstract: Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P & lt; 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P & lt; 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 6 ( 2009-03-15), p. 2349-2357
    Abstract: The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r2 = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07–1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01–1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region. [Cancer Res 2009;69(6):2349–57]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 10
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 30, No. 1 ( 2021-01-01), p. 217-228
    Abstract: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni & lt; 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P & lt; 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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