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  • American Association for Cancer Research (AACR)  (7)
  • 1
    Online Resource
    Online Resource
    Cancer in People with and without Hepatitis C Virus Infection: Comparison of Risk Before and After Introduction of Direct-Acting Antivirals
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 30, No. 12 ( 2021-12-01), p. 2188-2196
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 30, No. 12 ( 2021-12-01), p. 2188-2196
    Abstract: Chronic hepatitis C virus (HCV) infection is a leading cause of liver cancer. The association of HCV infection with extrahepatic cancers, and the impact of direct-acting antiviral (DAA) treatment on these cancers, is less well known. Methods: We conducted a cohort study in a healthcare delivery system. Using electronic health record data from 2007 to 2017, we determined cancer incidence, overall and by type, in people with HCV infection and by DAA treatment status. All analyses included comparisons with a reference population of people without HCV infection. Covariate-adjusted Poisson models were used to estimate incidence rate ratios. Results: 2,451 people with HCV and 173,548 people without HCV were diagnosed with at least one type of cancer. Compared with people without HCV, those with HCV were at higher risk for liver cancer [adjusted incidence rate ratio (aIRR) = 31.4, 95% confidence interval (CI) = 28.9–34.0], hematologic cancer (aIRR = 1.3, 95% CI = 1.1–1.5), lung cancer (aIRR = 1.3, 95% CI = 1.2–1.5), pancreatic cancer (aIRR = 2.0, 95% CI = 1.6–2.5), oral/oropharynx cancer (aIRR = 1.4, 95% CI = 1.1–1.8), and anal cancer (aIRR = 1.6, 95% CI = 1.1–2.4). Compared with people without HCV, the aIRR for liver cancer was 31.9 (95% CI = 27.9–36.4) among DAA-untreated and 21.2 (95% CI = 16.8–26.6) among DAA-treated, and the aIRR for hematologic cancer was 1.5 (95% CI = 1.1–2.0) among DAA-untreated and 0.6 (95% CI = 0.3–1.2) among DAA-treated. Conclusions: People with HCV infection were at increased risk of liver cancer, hematologic cancer, and some other extrahepatic cancers. DAA treatment was associated with reduced risk of liver cancers and hematologic cancers. Impact: DAA treatment is important for reducing cancer incidence among people with HCV infection.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-21-0742
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Genome-Wide Gene–Diabetes and Gene–Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 9 ( 2020-09-01), p. 1784-1791
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 9 ( 2020-09-01), p. 1784-1791
    Abstract: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P & lt; 1.25 × 10−6) was observed in the meta-analysis (PGxE = 1.2 ×10−6, PJoint = 4.2 ×10−7). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-20-0275
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
    Online Resource
    Online Resource
    Integrative Molecular Characterization of Malignant Pleural Mesothelioma
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Discovery Vol. 8, No. 12 ( 2018-12-01), p. 1548-1565
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 12 ( 2018-12-01), p. 1548-1565
    Abstract: Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. Significance: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM. See related commentary by Aggarwal and Albelda, p. 1508. This article is highlighted in the In This Issue feature, p. 1494
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-18-0804
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
    Online Resource
    Online Resource
    Matrix metalloproteinase–activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity
    American Association for Cancer Research (AACR) ; 2005
    In:  Molecular Cancer Therapeutics Vol. 4, No. 5 ( 2005-05-01), p. 751-760
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 4, No. 5 ( 2005-05-01), p. 751-760
    Abstract: Matrix metalloproteinase (MMP)–activated prodrugs were formed by coupling MMP-cleavable peptides to doxorubicin. The resulting conjugates were excellent in vitro substrates for MMP-2, -9, and -14. HT1080, a fibrosarcoma cell line, was used as a model system to test these prodrugs because these cells, like tumor stromal fibroblasts, expressed several MMPs. In cultured HT1080 cells, simple MMP-cleavable peptides were primarily metabolized by neprilysin, a membrane-bound metalloproteinase. MMP-selective metabolism in cultured HT1080 cells was obtained by designing conjugates that were good MMP substrates but poor neprilysin substrates. To determine how conjugates were metabolized in animals, MMP-selective conjugates were given to mice with HT1080 xenografts and the distribution of doxorubicin was determined. These studies showed that MMP-selective conjugates were preferentially metabolized in HT1080 xenografts, relative to heart and plasma, leading to 10-fold increases in the tumor/heart ratio of doxorubicin. The doxorubicin deposited by a MMP-selective prodrug, compound 6, was more effective than doxorubicin at reducing HT1080 xenograft growth. In particular, compound 6 cured 8 of 10 mice with HT1080 xenografts at doses below the maximum tolerated dose, whereas doxorubicin cured 2 of 20 mice at its maximum tolerated dose. Compound 6 was less toxic than doxorubicin at this efficacious dose because mice treated with compound 6 had no detectable changes in body weight or reticulocytes, a marker for marrow toxicity. Hence, MMP-activated doxorubicin prodrugs have a much higher therapeutic index than doxorubicin using HT1080 xenografts as a preclinical model.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-05-0006
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Anti-CD20 Antibody Promotes Cancer Escape via Enrichment of Tumor-Evoked Regulatory B Cells Expressing Low Levels of CD20 and CD137L
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 7 ( 2013-04-01), p. 2127-2138
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 7 ( 2013-04-01), p. 2127-2138
    Abstract: The possible therapeutic benefits of B-cell depletion in combating tumoral immune escape have been debated. In support of this concept, metastasis of highly aggressive 4T1 breast cancer cells in mice can be abrogated by inactivation of tumor-evoked regulatory B cells (tBreg). Here, we report the unexpected finding that B-cell depletion by CD20 antibody will greatly enhance cancer progression and metastasis. Both murine and human tBregs express low levels of CD20 and, as such, anti-CD20 mostly enriches for these cells. In the 4T1 model of murine breast cancer, this effect of enriching for tBregs suggests that B-cell depletion by anti-CD20 may not be beneficial at all in some cancers. In contrast, we show that in vivo–targeted stimulation of B cells with CXCL13-coupled CpG oligonucleotides (CpG-ODN) can block cancer metastasis by inhibiting CD20Low tBregs. Mechanistic investigations suggested that CpG-ODN upregulates low surface levels of 4-1BBL on tBregs to elicit granzyme B–expressing cytolytic CD8+ T cells, offering some explanative power for the effect. These findings underscore the immunotherapeutic importance of tBreg inactivation as a strategy to enhance cancer therapy by targeting both the regulatory and activating arms of the immune system in vivo. Cancer Res; 73(7); 2127–38. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-4184
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 6
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    Abstract 5723: An in vivo pharmacogenomics platform replicates and extends biomarkers of therapy response identified via causal inference analysis of clinical data
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5723-5723
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5723-5723
    Abstract: Recent development of therapies targeting oncogenes have dramatically improved cancer care for subsets of patients and generated a wave of interest in cancer precision medicine. However, effective targeted therapies are scarce as we have a limited understanding of how drug responses are modulated by tumor genotype. Here, we utilize both human data and in vivo models to identify genetic drivers of therapy response in KRAS-driven non-small cell lung cancer patients treated with chemotherapy. We first present an integrative causal inference analysis of three clinical data resources: (1) the recently released Genomics Evidence Neoplasia Information Exchange, Biopharma Collaboration dataset (GENIE-BPC; n=197), (2) a selected set of patients from the Tempus Clinico-genomic Database (n=330), and (3) an additional cohort from Memorial Sloan Kettering Cancer Center (n=218). Each dataset was first analyzed separately using a causal inference pipeline. Doubly robust estimators for each variant were inferred within a counting process survival analysis model accounting for time-varying treatments and immortal time bias. Meta-analysis of the results from all three cohorts identified three commonly mutated and highly replicable genes with a significant effect on overall survival: KEAP1, SMARCA4, and CDKN2A. As further validation, we used our murine in vivo pharmacogenomics (PGx) platform that can quantify the effects of therapies across thousands of tumors of diverse genotypes. These tumors are initiated de novo in the native microenvironmental context in mice with an intact adaptive immune system. We tested a chemotherapy combination of carboplatin and pemetrexed in mice with KrasG12D-driven lung tumors and inactivation of each of 60 putative tumor suppressors. Treatment led to & gt;75% reduction in tumor sizes relative to tumor suppressor inactivated (matched) vehicle-treated controls. These models identified causal effects for two out of the three candidates above: KEAP1 (resistance) and CDKN2A (sensitive). Moreover, our PGx platform identified additional candidate genes beyond those found using the clinical data, which had insufficient sample size for these rarely mutated genes. Together, we demonstrate how leveraging our PGx platform together with human data within a causal inference framework may improve the stratification of patients by their clinical outcomes, profoundly advancing the promise of precision medicine. Citation Format: David Amar, Erick Scott, Ian P. Winters, Gregory D. Wall, Dmitri A. Petrov, Monte M. Winslow, Joseph Juan, Ian K. Lai, Lafia Sebastian, Edwin A. Apilado, Gabriel Grenot, Vy B. Tran, Charles Rudin, Michael J. Rosen. An in vivo pharmacogenomics platform replicates and extends biomarkers of therapy response identified via causal inference analysis of clinical data. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5723.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5723
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    Online Resource
    Coffee Consumption and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma by Sex: The Liver Cancer Pooling Project
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 24, No. 9 ( 2015-09-01), p. 1398-1406
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 24, No. 9 ( 2015-09-01), p. 1398-1406
    Abstract: Background: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee–HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Methods: In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Results: Higher coffee consumption was associated with lower risk of HCC (HR & gt;3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53–0.99; Ptrend cups/day = & lt;0.0001). More notable reduced risk was seen among women than men (Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26–0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63–1.37). The associations were stronger for caffeinated coffee (HR & gt;3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50–1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55–1.54). There was no association between coffee consumption and ICC. Conclusions: These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC. Impact: Further research into specific coffee compounds and mechanisms that may account for these associations is needed. Cancer Epidemiol Biomarkers Prev; 24(9); 1398–406. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-15-0137
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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