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  • American Association for Cancer Research (AACR)  (6)
  • 1
    Online Resource
    Online Resource
    Shorter Leukocyte Telomere Length Is Independently Associated with Poor Survival in Patients with Bladder Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 23, No. 11 ( 2014-11-01), p. 2439-2446
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 23, No. 11 ( 2014-11-01), p. 2439-2446
    Abstract: Background: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival. Methods: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years. Results: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non–muscle-invasive tumor/high-grade and with non–muscle-invasive tumor/non–high-grade (TL reference 0.7 ± 0.2; vs. respectively, 0.8 ± 0.2, P = 3.4 × 10−2 and 0.8 ± 0.2, P = 3.6 × 10−2). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 × 10−4). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Guérin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7–9.1; P = 1.2 × 10−3). Conclusions: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade. Impact: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2439–46. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-14-0228
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 2
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    Abstract 5367: DNA repair capacity, gene expression and epigenomic profiles in bladder cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5367-5367
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5367-5367
    Abstract: In Europe, bladder cancer (BC) is the sixth most commonly diagnosed tumor and the second most common cause of death among patients with genitourinary tract malignancies. The ability to repair DNA damage is strongly associated with the risk of cancer and inter-individual variation in DNA repair capacity (DRC) might account for different susceptibility of developing cancer. DRC represents a complex marker comprising the sum of several factors such as gene variants, gene expression, stability of gene products, and effect of inhibitors/stimulators. Individuals with low DRC will tend to accumulate more damage than those who have a better ability to repair such damage. This variability is modulated by the genetic background to which SNPs/haplotype combinations in DNA repair genes, as well as epigenetic regulation are likely to contribute. Phenotypic assays to evaluate DNA repair activity (in particular NER comet assay, H2AX phosphorylation and micronucleus assay) were performed on cryopreserved lymphocytes from 159 cases (collected before treatment) and 159 controls matched by age and smoking habits, enrolled in Turin Bladder Cancer Study (TBCS). We aimed at studying the relationship between DRC (evaluated by comet assay, micronuclei and H2AX phosphorylation assay) and bladder cancer integrating, gene expression and epigenetic profile data (methylation levels and microRNA expression). In particular, we performed an integrated analysis on the genotype/phenotype correlation in a population of bladder cancer cases and controls provided with detailed description of the follow-up for response to therapy/recurrence/survival. This integrated approach will help in elucidating the role of DRC (and its determinants) as predictive and prognostic marker and to identify combined biomarkers to be measured in blood cells as non-invasive predictive method. Citation Format: Barbara Pardini, Alessandra Allione, Simonetta Guarrera, Valentina Turinetto, Giovanni Fiorito, Fabio Rosa, Alessia Russo, Federica Modica, Claudia Giachino, Paolo Vineis, Carlotta Sacerdote, Giuseppe Matullo. DNA repair capacity, gene expression and epigenomic profiles in bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5367. doi:10.1158/1538-7445.AM2014-5367
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-5367
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 410466-3
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  • 3
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    Online Resource
    Abstract 4615: H2AX phosphorylation assays, gene expression and epigenomic profiles as markers in bladder cancer: an integrated approach
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4615-4615
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4615-4615
    Abstract: Bladder cancer (BC), which is the fourth most common malignancy among men in the Western world, has a typical aetiology characterized by a multistep carcinogenesis, reflecting that multiple lesions in the DNA are required for tumour development. DNA repair capacity (DRC) is a complex marker comprising the sum of several factors such as gene variants, gene expression, stability of gene products, and effect of inhibitors/stimulators and might account for different susceptibility of developing this cancer. Individuals with low DRC will tend to accumulate more damage than those who have a better ability to repair such damage. The identification of patients with particular DRC and at high-risk of BC and/or recurrence of the disease could help in personalizing both surveillance and treatment. We aimed at studying the relationship between DRC evaluated by H2AX phosphorylation assays and BC, integrating gene expression and epigenetic profile data (methylation levels and microRNA expression) in cryopreserved lymphocytes from 159 BC cases and 159 controls matched by age and smoking habits. We observed a significant association between γ-H2AX basal levels and H2AX dephosphorylation capacity and risk of BC recurrence. Patients with high basal DSB signaling had a better event-free survival (HR 0.35, 95% CI 0. 19-0.63, p = 0.0005). Additionally, there was an association when considering the percentage of dephosphorylation after 3h divided into two categories (above and under the calculated best cut-off). Interestingly, when compared with the lower category (“slow repair”), the other group (“fast repair”) had a better event-free survival (HR 0.41, 95%CI 0.23-0.72, p = 0.002). Our data suggest that γ-H2AX can be considered as a possible molecular biomarker to identify patients with a higher risk of BC recurrence. A subgroup of cases and controls (39 and 44, respectively) was also analyzed for evaluating their gene expression (Illumina HumanHT-12 Expression BeadChip array) and methylation profile data (Illumina HumanMethylation450 BeadChip array). We found a set of CpG islands that were differentially methylated among cases and controls and a set of genes whose expression was deregulated among different subgroups (e.g. cases vs healthy controls, controls vs BC patients with muscle invasive tumor, etc). We performed an integrated analysis on the genotype/phenotype correlation in the analysed BC cases and healthy controls provided with detailed description of the follow-up for response to therapy/recurrence/survival. This integrated approach will help in elucidating the role of DRC (and its determinants) as predictive and prognostic marker and to identify DNA repair phenotypic assays to be performed in blood cells as non-invasive predictive method. Results will be presented at the AACR Annual Meeting. Citation Format: Barbara Pardini, Alessandra Allione, Simonetta Guarrera, Valentina Turinetto, Giovanni Fiorito, Clara Viberti, Alessia Russo, Paolo Vineis, Carlotta Sacerdote, Claudia Giachino, Giuseppe Matullo. H2AX phosphorylation assays, gene expression and epigenomic profiles as markers in bladder cancer: an integrated approach. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4615. doi:10.1158/1538-7445.AM2015-4615
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4615
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 4
    Online Resource
    Online Resource
    Abstract 778: DNA repair capacity, chromosomal damage, methylation and gene expression levels in bladder cancer: An integrated analysis
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 778-778
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 778-778
    Abstract: Bladder cancer (BC) is the sixth most commonly diagnosed tumor worldwide. DNA repair capacity (DRC) refers to the ability of a cell to protect the integrity of the genome and DNA repair pathways have been implicated in BC risk. It has been observed that individuals with low DRC tend to accumulate more damage than those with a more efficient DRC. This inter-individual variability is modulated by the genetic background, as well as differential gene expression and epigenetic regulation. We aimed at studying the relationship between DRC and DNA damage (evaluated by H2AX phosphorylation and micronucleus assays) and BC risk and clinical outcome, integrating with gene expression and epigenetic profile data in 159 BC cases and 159 matched controls, enrolled in the Turin Bladder Cancer Study (TBCS). We investigated ã-H2AX phosphorylation levels and MN frequencies in cryopreserved peripheral blood mononuclear cells. We found significant differences in micronuclei and nuclear buds frequencies, with higher number of these damages in cases compared to controls (p = 0.0002 and p = 0.002 respectively). On the other hand, we observed a significant association between ã-H2AX basal levels and risk of disease recurrence/progression in both BC patients as a whole and the subgroup of non-muscle invasive BC (NMIBC) (for all BC HR 0.70, 95% CI 0.52-0.94, p = 0.02; for NMIBC HR 0.68, 95% CI 0.50-0.92, p = 0.01): this suggests a protective effect of DNA double strand breaks signalling in terms of preventing BC recurrence or progression. In order to evaluate the genetic and epigenetic role in modulation of DRC we performed whole genome methylation and gene expression analyses on the same BC cases and controls. Preliminary analyses on methylation levels did not show any significant difference between cases and controls. Two metalloproteinases (MMP23A and MMP23B) resulted significantly under-expressed in BC compared to healthy controls (logFC = -0.23, p = 0.01; logFC = -0.37, p = 0.007, respectively). Interestingly, the expression levels of these genes were also significantly correlated with the relative CpGs methylation. Further analyses focusing on the integration of whole genome data with DRC assays are ongoing to unravel new prognostic biomarkers of disease. Citation Format: Giuseppe Matullo, Clara Viberti, Barbara Pardini, Alessandra Allione, Simonetta Guarrera, Valentina Turinetto, Claudia Giachino, Giovanni Fiorito, Alessio Naccarati, Alessia Russo, Rossana Critelli, Paolo Destefanis, Marco Oderda, Paolo Gontero, Paolo Vineis, Carlotta Sacerdote. DNA repair capacity, chromosomal damage, methylation and gene expression levels in bladder cancer: An integrated analysis. [abstract] . In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 778.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-778
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 5
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    Online Resource
    Stochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasms
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 10 ( 2020-10-01), p. 2026-2037
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 10 ( 2020-10-01), p. 2026-2037
    Abstract: Age-related epigenetic dysregulations are associated with several diseases, including cancer. The number of stochastic epigenetic mutations (SEM) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated. Methods: A SEM, at a given CpG site, was defined as an extreme outlier of DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case–control pairs nested in three prospective cohorts. Furthermore, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions. Results: In the three-study meta-analysis, the estimated ORs per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% confidence interval (CI), 1.11–1.41 for breast cancer, and 1.23; 95% CI, 1.07–1.42 for lung cancer. In the Melbourne Collaborative Cohort Study, the OR for mature B-cell neoplasm was 1.46; 95% CI, 1.25–1.71. Enrichment analyses indicated that SEMs frequently occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 (P & lt; 0.0001 and P = 0.0005, respectively): two components of the polycomb repressive complex 2 (PCR2). Finally, we showed that PCR2-specific SEMs are generally more stable over time compared with SEMs occurring in the whole genome. Conclusions: The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples. Impact: We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-20-0451
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 6
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    Abstract LB-188: Epigenome-wide study in prediagnostic samples from the European Prospective Investigation into Nutrition and Cancer (EPIC-Italy) cohort: Differentially methylated microRNAs in subjects who developed breast cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. LB-188-LB-188
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. LB-188-LB-188
    Abstract: The crosstalk between microRNAs (miRNAs) and other epigenetic factors may lead to novel hypotheses about carcinogenesis identifying new targets for research. Since a single miRNA can regulate multiple downstream target genes, its altered expression may potentially be a very sensitive biomarker to detect early malignant transformation and improve diagnosis and prognosis. In the current study, we used a genome-wide approach to test the hypothesis that altered methylation of miRNA encoding genes may be related to dietary and lifestyle factors and may be associated with deregulated mature miRNA expression ultimately leading to cancer. In a case-control study nested in a prospective cohort (EPIC-Italy), we analysed DNA methylation levels of miRNA encoding genes (2,191 CpG probes related to 517 genes) that are present in the Infinium Human Methylation450 BeadChip array in prediagnostic peripheral white blood cells of subjects who developed Colorectal Cancer (CRC, n = 159) and Breast Cancer (BC, n = 166) and matched subjects who remained clinically healthy. In the whole cohort, several differentially methylated miRNA genes were observed in association with age, sex, smoking habits and physical activity. Interestingly, in the case-control study, 8 differentially methylated miRNAs were identified in subjects who went on to develop BC (miR-328, miR-675, miR-1307, miR-1286, miR-1275, miR-1910, miR-24-1, and miR-548a-1; all Bonferroni-adjusted p-values & lt; 0.05). No significant associations were found with CRC. Assuming that altered methylation of miRNAs may be present before diagnosis, it may represent a biomarker for early detection or risk of cancer and may help to understand the cascade of events preceding tumour onset. Citation Format: Alessio Naccarati, Silvia Polidoro, Giovanni Fiorito, Francesca Cordero, Giulio Ferrero, Gianluca Campanella, Carlotta Sacerdote, Amalia Mattiello, Salvatore Panico, Giovanna Masala, Domenico Palli, Claudia Agnoli, Vittorio Krogh, Graziella Frasca, Rosario Tumino, Paolo Vineis. Epigenome-wide study in prediagnostic samples from the European Prospective Investigation into Nutrition and Cancer (EPIC-Italy) cohort: Differentially methylated microRNAs in subjects who developed breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-188. doi:10.1158/1538-7445.AM2015-LB-188
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-LB-188
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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