142 results on '"Giuseppe Matullo"'
Search Results
2. Supplementary Figure S1 from Shorter Leukocyte Telomere Length Is Independently Associated with Poor Survival in Patients with Bladder Cancer
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Giuseppe Matullo, Carlotta Sacerdote, Paolo Vineis, Bruno Frea, Dario Fontana, Andrea Zitella, Luigi Rolle, Paolo Gontero, Paolo Destefanis, Giuseppina Cucchiarale, Giovanni Casetta, Andrea Bosio, Rossana Critelli, Alessandra Allione, Clara Viberti, Barbara Pardini, Giovanni Fiorito, Simonetta Guarrera, Federica Modica, and Alessia Russo
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Supplementary Figure S1. Kaplan-Meier OS curves of bladder cancer patients stratified for TL quartiles. OS, overall survival; TL, telomere length.
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- 2023
3. Supplementary Table S3 from Shorter Leukocyte Telomere Length Is Independently Associated with Poor Survival in Patients with Bladder Cancer
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Giuseppe Matullo, Carlotta Sacerdote, Paolo Vineis, Bruno Frea, Dario Fontana, Andrea Zitella, Luigi Rolle, Paolo Gontero, Paolo Destefanis, Giuseppina Cucchiarale, Giovanni Casetta, Andrea Bosio, Rossana Critelli, Alessandra Allione, Clara Viberti, Barbara Pardini, Giovanni Fiorito, Simonetta Guarrera, Federica Modica, and Alessia Russo
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Supplementary Table S3. Multivariate Cox regression survival analysis, including TL, age, TG, BCG, radical cystectomy, radiotherapy and chemotherapy. All cause of death.
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- 2023
4. Supplementary Table S1 from Shorter Leukocyte Telomere Length Is Independently Associated with Poor Survival in Patients with Bladder Cancer
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Giuseppe Matullo, Carlotta Sacerdote, Paolo Vineis, Bruno Frea, Dario Fontana, Andrea Zitella, Luigi Rolle, Paolo Gontero, Paolo Destefanis, Giuseppina Cucchiarale, Giovanni Casetta, Andrea Bosio, Rossana Critelli, Alessandra Allione, Clara Viberti, Barbara Pardini, Giovanni Fiorito, Simonetta Guarrera, Federica Modica, and Alessia Russo
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Supplementary Table S1. Description of populations included and not included in the TL study and comparative analysis.
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- 2023
5. Data from Shorter Leukocyte Telomere Length Is Independently Associated with Poor Survival in Patients with Bladder Cancer
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Giuseppe Matullo, Carlotta Sacerdote, Paolo Vineis, Bruno Frea, Dario Fontana, Andrea Zitella, Luigi Rolle, Paolo Gontero, Paolo Destefanis, Giuseppina Cucchiarale, Giovanni Casetta, Andrea Bosio, Rossana Critelli, Alessandra Allione, Clara Viberti, Barbara Pardini, Giovanni Fiorito, Simonetta Guarrera, Federica Modica, and Alessia Russo
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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.
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- 2023
6. Data from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer
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Montserrat Garcia-Closas, Sung Shim Lani Park, Cecilia Arici, Marcello Campagna, Angela Carta, Stefano Porru, Peter Rudnai, Rajiv Kumar, Kvetoslava Koppova, Eugen Gurzau, Alessandra Allione, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Paolo Vineis, Yu-Tang Gao, Yong-Bing Xiang, Victoria K. Cortessis, Manuela Gago-Dominguez, Amit D. Joshi, Román Corral, Faye Elliot, Jennifer H. Barrett, Ananya Choudhury, Sei Chung Sak, D. Timothy Bishop, Heather H. Nelson, Angeline S. Andrew, Margaret R. Karagas, Xifeng Wu, Stephen Chanock, Nuria Malats, Debra Silverman, Manolis Kogevinas, Nathaniel Rothman, Gunnar Steineck, Zuo-Feng Zhang, Donatella Placidi, Jack A. Taylor, Simone Benhamou, Tony Fletcher, Giuseppe Matullo, Jian-Min Yuan, Anne E. Kiltie, Karl T. Kelsey, Jonine D. Figueroa, Jie Lin, and Mariana C. Stern
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Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01–1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01–1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00–1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. [Cancer Res 2009;69(17):6857–64]
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- 2023
7. Supplementary Tables 1-8 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer
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Montserrat Garcia-Closas, Sung Shim Lani Park, Cecilia Arici, Marcello Campagna, Angela Carta, Stefano Porru, Peter Rudnai, Rajiv Kumar, Kvetoslava Koppova, Eugen Gurzau, Alessandra Allione, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Paolo Vineis, Yu-Tang Gao, Yong-Bing Xiang, Victoria K. Cortessis, Manuela Gago-Dominguez, Amit D. Joshi, Román Corral, Faye Elliot, Jennifer H. Barrett, Ananya Choudhury, Sei Chung Sak, D. Timothy Bishop, Heather H. Nelson, Angeline S. Andrew, Margaret R. Karagas, Xifeng Wu, Stephen Chanock, Nuria Malats, Debra Silverman, Manolis Kogevinas, Nathaniel Rothman, Gunnar Steineck, Zuo-Feng Zhang, Donatella Placidi, Jack A. Taylor, Simone Benhamou, Tony Fletcher, Giuseppe Matullo, Jian-Min Yuan, Anne E. Kiltie, Karl T. Kelsey, Jonine D. Figueroa, Jie Lin, and Mariana C. Stern
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Supplementary Tables 1-8 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer
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- 2023
8. Data from TP53 and KRAS2 Mutations in Plasma DNA of Healthy Subjects and Subsequent Cancer Occurrence: A Prospective Study
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Pierre Hainaut, Elio Riboli, Rudolf Kaaks, Rodolfo Saracci, Timothy J. Key, Nicholas E. Day, Göran Hallmans, José Ramón Quirós, Carmen Navarro, Aurelio Barricarte, Miren Dorronsoro, Carmen Martinez, Guillem Pera, Petra H. Peeters, H. Bas Bueno-de-Mesquita, Salvatore Panico, Rosario Tumino, Vittorio Krogh, Domenico Palli, Antonia Trichopoulou, Heiner Boeing, Françoise Clavel-Chapelon, Eiliv Lund, Anne Tjønneland, Kim Overvad, Alison Dunning, Christian Malaveille, Herman Autrup, Luisa Airoldi, Armelle Munnia, Simonetta Guarrera, Seymour Garte, Marco Peluso, Emilie Le Roux, Elodie Caboux, Fabrizio Veglia, Giuseppe Matullo, Paolo Vineis, and Emmanuelle Gormally
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In cancer patients, plasma often contains mutant DNA released by cancer cells. We have assessed the significance of plasma DNA mutations for subsequent cancer development in healthy subjects in a large longitudinal prospective study. The European Prospective Investigation into Cancer and Nutrition study was analyzed with a nested case-control design. Cases were nonsmokers or ex-smokers for >10 years and newly diagnosed with lung, bladder, or upper aerodigestive tract cancers or leukemia accrued after a median follow-up of 6.3 years. Controls were matched 2:1 for follow-up, age, sex, area of recruitment, and smoking status. KRAS2 mutations were detected by mutant-enriched PCR and sequencing (n = 1,098). TP53 mutations were detected by denaturing high-performance liquid chromatography, temporal temperature gradient electrophoresis, and sequencing (n = 550). KRAS2 or TP53 mutations were detected in 13 of 1,098 (1.2%) and 20 of 550 (3.6%) subjects, respectively, 16 of whom developed cancer on average after 18.3 months of follow-up. Among 137 subjects who developed bladder cancer, 5 had KRAS2 mutations [odds ratio (OR), 4.25; 95% confidence interval (95% CI), 1.27-14.15] and 7 had TP53 mutations (OR, 1.81; 95% CI, 0.66-4.97). There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17). This is the first report of TP53 or KRAS2 mutations in the plasma of healthy subjects in a prospective study, suggesting that KRAS2 mutation is detectable ahead of bladder cancer diagnosis. TP53 mutation may be associated with environmental exposures. These observations have implications for monitoring early steps of carcinogenesis. (Cancer Res 2006; 66(13): 6871-6)
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- 2023
9. Supplementary Figure Legend from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer
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Montserrat Garcia-Closas, Sung Shim Lani Park, Cecilia Arici, Marcello Campagna, Angela Carta, Stefano Porru, Peter Rudnai, Rajiv Kumar, Kvetoslava Koppova, Eugen Gurzau, Alessandra Allione, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Paolo Vineis, Yu-Tang Gao, Yong-Bing Xiang, Victoria K. Cortessis, Manuela Gago-Dominguez, Amit D. Joshi, Román Corral, Faye Elliot, Jennifer H. Barrett, Ananya Choudhury, Sei Chung Sak, D. Timothy Bishop, Heather H. Nelson, Angeline S. Andrew, Margaret R. Karagas, Xifeng Wu, Stephen Chanock, Nuria Malats, Debra Silverman, Manolis Kogevinas, Nathaniel Rothman, Gunnar Steineck, Zuo-Feng Zhang, Donatella Placidi, Jack A. Taylor, Simone Benhamou, Tony Fletcher, Giuseppe Matullo, Jian-Min Yuan, Anne E. Kiltie, Karl T. Kelsey, Jonine D. Figueroa, Jie Lin, and Mariana C. Stern
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Supplementary Figure Legend from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer
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- 2023
10. Supplementary Table 1 from TP53 and KRAS2 Mutations in Plasma DNA of Healthy Subjects and Subsequent Cancer Occurrence: A Prospective Study
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Pierre Hainaut, Elio Riboli, Rudolf Kaaks, Rodolfo Saracci, Timothy J. Key, Nicholas E. Day, Göran Hallmans, José Ramón Quirós, Carmen Navarro, Aurelio Barricarte, Miren Dorronsoro, Carmen Martinez, Guillem Pera, Petra H. Peeters, H. Bas Bueno-de-Mesquita, Salvatore Panico, Rosario Tumino, Vittorio Krogh, Domenico Palli, Antonia Trichopoulou, Heiner Boeing, Françoise Clavel-Chapelon, Eiliv Lund, Anne Tjønneland, Kim Overvad, Alison Dunning, Christian Malaveille, Herman Autrup, Luisa Airoldi, Armelle Munnia, Simonetta Guarrera, Seymour Garte, Marco Peluso, Emilie Le Roux, Elodie Caboux, Fabrizio Veglia, Giuseppe Matullo, Paolo Vineis, and Emmanuelle Gormally
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Supplementary Table 1 from TP53 and KRAS2 Mutations in Plasma DNA of Healthy Subjects and Subsequent Cancer Occurrence: A Prospective Study
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- 2023
11. Supplementary Figure 1 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer
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Montserrat Garcia-Closas, Sung Shim Lani Park, Cecilia Arici, Marcello Campagna, Angela Carta, Stefano Porru, Peter Rudnai, Rajiv Kumar, Kvetoslava Koppova, Eugen Gurzau, Alessandra Allione, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Paolo Vineis, Yu-Tang Gao, Yong-Bing Xiang, Victoria K. Cortessis, Manuela Gago-Dominguez, Amit D. Joshi, Román Corral, Faye Elliot, Jennifer H. Barrett, Ananya Choudhury, Sei Chung Sak, D. Timothy Bishop, Heather H. Nelson, Angeline S. Andrew, Margaret R. Karagas, Xifeng Wu, Stephen Chanock, Nuria Malats, Debra Silverman, Manolis Kogevinas, Nathaniel Rothman, Gunnar Steineck, Zuo-Feng Zhang, Donatella Placidi, Jack A. Taylor, Simone Benhamou, Tony Fletcher, Giuseppe Matullo, Jian-Min Yuan, Anne E. Kiltie, Karl T. Kelsey, Jonine D. Figueroa, Jie Lin, and Mariana C. Stern
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Supplementary Figure 1 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer
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- 2023
12. Malignant pleural mesothelioma: Germline variants in DNA repair genes may steer tailored treatment
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Marika Sculco, Marta La Vecchia, Anna Aspesi, Giulia Pinton, Michela G. Clavenna, Elisabetta Casalone, Alessandra Allione, Federica Grosso, Roberta Libener, Alberto Muzio, Ottavio Rena, Guido Baietto, Sara Parini, Renzo Boldorini, Daniela Giachino, Mauro Papotti, Giorgio V. Scagliotti, Enrica Migliore, Dario Mirabelli, Laura Moro, Corrado Magnani, Daniela Ferrante, Giuseppe Matullo, and Irma Dianzani
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Mesothelioma ,Cancer Research ,Lung Neoplasms ,Synthetic lethality ,DNA Repair ,DNA repair genes ,Pleural Neoplasms ,Mesothelioma, Malignant ,Germline variants ,Tazemetostat ,Germ Cells ,Oncology ,Humans - Abstract
Malignant pleural mesothelioma (MPM) is a tumour associated with asbestos exposure. Approximately, 10% of patients with MPM carry a germline pathogenic variant (PV), mostly in DNA repair genes, suggesting the occurrence of inherited predispositions.This article aimed to 1) search for new predisposing genes and assess the prevalence of PVs in DNA repair genes, by next-generation sequencing (NGS) analysis of germline DNA from 113 unselected patients with MPM and 2) evaluate whether these patients could be sensitive to tailored treatments.NGS was performed using a custom panel of 107 cancer-predisposing genes. To investigate the response to selected drugs in conditions of DNA repair insufficiency, we created a three-dimensional-MPM cell model that had a defect in ataxia telangiectasia mutated (ATM), the master regulator of DNA repair.We identified PVs in approximately 7% of patients with MPM (8/113) and a new PV in BAP1 in a further patient with familial MPM. Most of these PVs were in genes involved or supposedly involved in DNA repair (BRCA1, BRIP1, CHEK2, SLX4, FLCN and BAP1). In vitro studies showed apoptosis induction in ATM-silenced/inhibited MPM spheroids treated with an enhancer of zeste homologue 2 inhibitor (tazemetostat).Overall these data suggest that patients with MPM and DNA repair insufficiency may benefit from this treatment, which induces synthetic lethality.
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- 2022
13. Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights
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Stella Koutros, Lambertus A. Kiemeney, Parichoy Pal Choudhury, Roger L. Milne, Evangelina Lopez de Maturana, Yuanqing Ye, Vijai Joseph, Oscar Florez-Vargas, Lars Dyrskjøt, Jonine Figueroa, Diptavo Dutta, Graham G. Giles, Michelle A.T. Hildebrandt, Kenneth Offit, Manolis Kogevinas, Elisabete Weiderpass, Marjorie L. McCullough, Neal D. Freedman, Demetrius Albanes, Charles Kooperberg, Victoria K. Cortessis, Margaret R. Karagas, Alison Johnson, Molly R. Schwenn, Dalsu Baris, Helena Furberg, Dean F. Bajorin, Olivier Cussenot, Geraldine Cancel-Tassin, Simone Benhamou, Peter Kraft, Stefano Porru, Angela Carta, Timothy Bishop, Melissa C. Southey, Giuseppe Matullo, Tony Fletcher, Rajiv Kumar, Jack A. Taylor, Philippe Lamy, Frederik Prip, Mark Kalisz, Stephanie J. Weinstein, Jan G. Hengstler, Silvia Selinski, Mark Harland, Mark Teo, Anne E. Kiltie, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina García-Closas, Josep Lloreta, Alan Schned, Petra Lenz, Elio Riboli, Paul Brennan, Anne Tjønneland, Thomas Otto, Daniel Ovsiannikov, Frank Volkert, Sita H. Vermeulen, Katja K. Aben, Tessel E. Galesloot, Constance Turman, Immaculata De Vivo, Edward Giovannucci, David J. Hunter, Chancellor Hohensee, Rebecca Hunt, Alpa V. Patel, Wen-Yi Huang, Gudmar Thorleifsson, Manuela Gago-Dominguez, Pilar Amiano, Klaus Golka, Mariana C. Stern, Wusheng Yan, Jia Liu, Shengchao Alfred Li, Shilpa Katta, Amy Hutchinson, Belynda Hicks, William A. Wheeler, Mark P. Purdue, Katherine A. McGlynn, Cari M. Kitahara, Christopher A. Haiman, Mark H. Greene, Thorunn Rafnar, Nilanjan Chatterjee, Stephen J. Chanock, Xifeng Wu, Francisco X. Real, Debra T. Silverman, Montserrat Garcia-Closas, Kari Stefansson, Ludmila Prokunina-Olsson, Núria Malats, and Nathaniel Rothman
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Genome-Wide Association Study (GWAS) ,Germline genetics ,All institutes and research themes of the Radboud University Medical Center ,Urology ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Bladder cancer ,Gene-environment interaction - Abstract
Contains fulltext : 293880.pdf (Publisher’s version ) (Closed access) BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. DESIGN, SETTING, AND PARTICIPANTS: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p
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- 2023
14. Identification of novel circulating microRNAs in advanced heart failure by next‐generation sequencing
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Alessandro Galluzzo, Serena Bergerone, Giuseppe Matullo, Alessandra Volpe, Giovanni Birolo, Carla Giustetto, Paolo Boretto, Simona Gallo, Stefano Pidello, Dario Celentani, Piero Fariselli, Caterina Peraldo-Neia, Barbara Pardini, Tiziana Crepaldi, Martina Spilinga, Alessandro Bonzano, and Annapia Vitacolonna
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Prohormone ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Original Research Articles ,Internal medicine ,Biomarkers ,Circulating microRNAs ,Heart failure ,Risk stratification ,microRNA ,medicine ,Clinical endpoint ,Diseases of the circulatory (Cardiovascular) system ,Humans ,Original Research Article ,Circulating MicroRNA ,030212 general & internal medicine ,education ,Heart Failure ,Heart transplantation ,education.field_of_study ,business.industry ,High-Throughput Nucleotide Sequencing ,medicine.disease ,Brain natriuretic peptide ,MicroRNAs ,RC666-701 ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
Aims Risk stratification in patients with advanced chronic heart failure (HF) is an unmet need. Circulating microRNA (miRNA) levels have been proposed as diagnostic and prognostic biomarkers in several diseases including HF. The aims of the present study were to characterize HF‐specific miRNA expression profiles and to identify miRNAs with prognostic value in HF patients. Methods and results We performed a global miRNome analysis using next‐generation sequencing in the plasma of 30 advanced chronic HF patients and of matched healthy controls. A small subset of miRNAs was validated by real‐time PCR (P
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- 2021
15. Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization
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Veerle Dam, N Charlotte Onland-Moret, Stephen Burgess, Maria-Dolores Chirlaque, Sanne A E Peters, Ewoud Schuit, Kaja Tikk, Elisabete Weiderpass, Clare Oliver-Williams, Angela M Wood, Anne Tjønneland, Christina C Dahm, Kim Overvad, Marie-Christine Boutron-Ruault, Matthias B Schulze, Antonia Trichopoulou, Pietro Ferrari, Giovanna Masala, Vittorio Krogh, Rosario Tumino, Giuseppe Matullo, Salvatore Panico, Jolanda M A Boer, W M Monique Verschuren, Marit Waaseth, Maria José Sánchez Pérez, Pilar Amiano, Liher Imaz, Conchi Moreno-Iribas, Olle Melander, Sophia Harlid, Maria Nordendahl, Patrik Wennberg, Timothy J Key, Elio Riboli, Carmen Santiuste, Rudolf Kaaks, Verena Katzke, Claudia Langenberg, Nicholas J Wareham, Heribert Schunkert, Jeanette Erdmann, Christina Willenborg, Christian Hengstenberg, Marcus E Kleber, Graciela Delgado, Winfried März, Stavroula Kanoni, George Dedoussis, Panos Deloukas, Majid Nikpay, Ruth McPherson, Markus Scholz, Andrej Teren, Adam S Butterworth, Yvonne T van der Schouw, Dam, Veerle [0000-0002-5982-232X], Onland-Moret, N Charlotte [0000-0002-2360-913X], Burgess, Stephen [0000-0001-5365-8760], Chirlaque, Maria-Dolores [0000-0001-9242-3040], Schuit, Ewoud [0000-0002-9548-3214], Weiderpass, Elisabete [0000-0003-2237-0128], Overvad, Kim [0000-0001-6429-7921], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Trichopoulou, Antonia [0000-0002-7204-6396], Ferrari, Pietro [0000-0001-9358-7338], Masala, Giovanna [0000-0002-5758-9069], Krogh, Vittorio [0000-0003-0122-8624], Panico, Salvatore [0000-0002-5498-8312], Harlid, Sophia [0000-0001-8540-6891], Riboli, Elio [0000-0001-6795-6080], Katzke, Verena [0000-0002-6509-6555], Schunkert, Heribert [0000-0001-6428-3001], Hengstenberg, Christian [0000-0002-8284-2994], Kleber, Marcus E [0000-0003-0663-7275], Deloukas, Panos [0000-0001-9251-070X], Nikpay, Majid [0000-0003-0285-6454], McPherson, Ruth [0000-0002-9087-6107], Scholz, Markus [0000-0002-4059-1779], and Apollo - University of Cambridge Repository
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Male ,MENOPAUSE ,Aging ,IMPACT ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Coronary Disease ,VARIANTS ,Biochemistry ,Polymorphism, Single Nucleotide ,AGE ,Endocrinology ,Mendelian Randomization ,Aging/genetics ,Reproductive aging ,risk factors ,Humans ,cardiovascular diseases ,GENOME-WIDE ASSOCIATION ,coronary heart disease ,Coronary Disease/epidemiology ,RISK ,MORTALITY ,Biochemistry (medical) ,Mendelian Randomization Analysis ,Coronary heart disease ,BIAS ,Risk factors ,reproductive aging ,Genome-Wide Association Study/methods ,Female ,FASTING GLUCOSE ,Genome-Wide Association Study - Abstract
The EPIC-CVD project was supported by the European Union Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (G0800270, MR/L003120/1), the British Heart Foundation (SP/09/002, RG/08/014, RG13/13/30194), and the UK National Institute of Health Research (to EPIC-CVD). The establishment of the subcohort was supported by the EU Sixth Framework Programme (FP6) (grant LSHM_CT_2006_037197 to the InterAct project) and the Medical Research Council Epidemiology Unit (grants MC_ UU_12015/1 and MC_UU_12015/5). The national EPIC cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy) and MIUR "Dipartimenti di Eccellenza"(Project D15D18000410001) to the Department of Medical Sciences; Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skane and Vasterbotten (Sweden); and Cancer Research UK, Medical Research Council (United Kingdom). LIFE-Heart is funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF), and by funds of the Free State of Saxony within the framework of the excellence initiative. This work is supported by the Dutch Heart Foundation (2013T083 to V.D.), by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1 to S.A.E.P.), and by a Sir Henry Dale Fellowship jointly funded by the Welcome Trust and the Royal Society (204623/Z/16/Z to S.B.). None of the funding sources had a role in the collection, analysis, and interpretation of the data, nor in the decision to submit the article for publication., Background: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. Objectives: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. Design: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. Participants: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. Main Outcome Measures: CHD, CHD risk factors, and ANM. Results: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. Conclusion: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men., European Commission HEALTH-F2-2012-279233 European Research Council (ERC) European Commission 268834, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) G0800270 MR/L003120/1 British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), EU Sixth Framework Programme (FP6) LSHM_CT_2006_037197, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_ UU_12015/1 MC_UU_12015/5, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe Federal Ministry of Education & Research (BMBF) Deutsches Krebsforschungszentrum (Germany), Ministry of Health and Social Solidarity (Greece) Stavros Niarchos Foundation (Greece) Hellenic Health Foundation (Greece), Fondazione AIRC per la ricerca sul cancro Consiglio Nazionale delle Ricerche (CNR) MIUR "Dipartimenti di Eccellenza" D15D18000410001, Dutch Ministry of Public Health, Welfare and Sports, LK Research Funds, Dutch Prevention Funds Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund International (WCRF) ERC-2009-AdG 232997, Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Instituto de Salud Carlos III, Junta de Andalucia, Principality of Asturias, Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain), Instituto de Salud Carlos III RD06/0020, Swedish Cancer Society Swedish Scientific Council (Sweden) Regional Government of Skane and Vasterbotten (Sweden), Cancer Research UK UK Research & Innovation (UKRI) Medical Research Council UK (MRC), Leipzig Research Center for Civilization Diseases (LIFE), European Commission, Free State of Saxony, Netherlands Heart Foundation 2013T083, Medical Research Council UK (MRC) MR/P014550/1, Sir Henry Dale Fellowship - Welcome Trust 204623/Z/16/Z, Sir Henry Dale Fellowship - Royal Society 204623/Z/16/Z
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- 2022
16. Interleukin-3-Receptor-α in Triple-Negative Breast Cancer (TNBC): An Additional Novel Biomarker of TNBC Aggressiveness and a Therapeutic Target
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Malvina Koni, Isabella Castellano, Emilio Venturelli, Alessandro Sarcinella, Tatiana Lopatina, Cristina Grange, Massimo Cedrino, Saveria Femminò, Paolo Cossu-Rocca, Sandra Orrù, Fabrizio D’Ascenzo, Ilaria Cotellessa, Cristian Tampieri, Carla Debernardi, Giovanni Cugliari, Giuseppe Matullo, Giovanni Camussi, Maria Rosaria De Miglio, and Maria Felice Brizzi
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Cancer Research ,Oncology ,interleukin-3/interleukin-3 receptor α ,triple-negative breast cancer ,vascular mimicry ,programmed cell death-ligand 1 - Abstract
Tumour molecular annotation is mandatory for biomarker discovery and personalised approaches, particularly in triple-negative breast cancer (TNBC) lacking effective treatment options. In this study, the interleukin-3 receptor α (IL-3Rα) was investigated as a prognostic biomarker and therapeutic target in TNBC. IL-3Rα expression and patients’ clinical and pathological features were retrospectively analysed in 421 TNBC patients. IL-3Rα was expressed in 69% human TNBC samples, and its expression was associated with nodal metastases (p = 0.026) and poor overall survival (hazard ratio = 1.50; 95% CI = 1.01–2.2; p = 0.04). The bioinformatics analysis on the Breast Invasive Carcinoma dataset of The Cancer Genome Atlas (TCGA) proved that IL-3Rα was highly expressed in TNBC compared with luminal breast cancers (p = 0.017, padj = 0.026). Functional studies demonstrated that IL-3Rα activation induced epithelial-to-endothelial and epithelial-to-mesenchymal transition, promoted large blood lacunae and lung metastasis formation, and increased programmed-cell death ligand-1 (PD-L1) in primary tumours and metastases. Based on the TCGA data, IL-3Rα, PD-L1, and EMT coding genes were proposed to discriminate against TNBC aggressiveness (AUC = 0.86 95% CI = 0.82–0.89). Overall, this study identified IL-3Rα as an additional novel biomarker of TNBC aggressiveness and provided the rationale to further investigate its relevance as a therapeutic target.
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- 2022
17. Diagnostics of
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Marika, Sculco, Marta, La Vecchia, Anna, Aspesi, Michela Giulia, Clavenna, Michela, Salvo, Giulia, Borgonovi, Alessandra, Pittaro, Gianluca, Witel, Francesca, Napoli, Angela, Listì, Federica, Grosso, Roberta, Libener, Antonio, Maconi, Ottavio, Rena, Renzo, Boldorini, Daniela, Giachino, Paolo, Bironzo, Antonella, Maffè, Greta, Alì, Lisa, Elefanti, Chiara, Menin, Luisella, Righi, Cristian, Tampieri, Giorgio Vittorio, Scagliotti, Caterina, Dianzani, Daniela, Ferrante, Enrica, Migliore, Corrado, Magnani, Dario, Mirabelli, Giuseppe, Matullo, and Irma, Dianzani
- Abstract
Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (
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- 2022
18. Functional and clinical implications of genetic structure in 1686 Italian exomes
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Elisabetta Casalone, Rosanna Asselta, Elvezia Maria Paraboschi, Giovanni Cugliari, Elisa Giorgio, Alessia Russo, Diego Ardissino, Serena Aneli, Giovanni Birolo, Giuseppe Matullo, Cornelia Di Gaetano, Alessandra Allione, and Stefano Duga
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medicine.medical_specialty ,Population ,Biology ,genetic frequency database ,03 medical and health sciences ,symbols.namesake ,Exome Sequencing ,Genetics ,medicine ,Humans ,Italian population ,Exome ,whole-exome sequencing ,education ,genomic medicine ,pathogenic variants ,rare variants ,Gene ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,030305 genetics & heredity ,Genetic Variation ,Europe ,Italy ,Genetic structure ,Mendelian inheritance ,symbols ,Medical genetics ,DPYD - Abstract
To reconstruct the phenotypical and clinical implications of the Italian genetic structure, we thoroughly analyzed a whole-exome sequencing data set comprised of 1686 healthy Italian individuals. We found six previously unreported variants with remarkable frequency differences between Northern and Southern Italy in the HERC2, OR52R1, ADH1B, and THBS4 genes. We reported 36 clinically relevant variants (submitted as pathogenic, risk factors, or drug response in ClinVar) with significant frequency differences between Italy and Europe. We then explored putatively pathogenic variants in the Italian exome. On average, our Italian individuals carried 16.6 protein-truncating variants (PTVs), with 2.5% of the population having a PTV in one of the 59 American College of Medical Genetics (ACMG) actionable genes. Lastly, we looked for PTVs that are likely to cause Mendelian diseases. We found four heterozygous PTVs in haploinsufficient genes (KAT6A, PTCH1, and STXBP1) and three homozygous PTVs in genes causing recessive diseases (DPYD, FLG, and PYGM). Comparing frequencies from our data set to other public databases, like gnomAD, we showed the importance of population-specific databases for a more accurate assessment of variant pathogenicity. For this reason, we made aggregated frequencies from our data set publicly available as a tool for both clinicians and researchers (http://nigdb.cineca.it; NIG-ExIT).
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- 2021
19. Pathophysiology roles and translational opportunities of miRNAs in bladder cancer
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Barbara Pardini and Giuseppe Matullo
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- 2022
20. Pathophysiology roles and translational opportunities of miRNAs in mesothelioma
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Elisabetta Casalone, Alessandra Allione, and Giuseppe Matullo
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- 2022
21. Contributors
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Samuel Akanksha, Alessandra Allione, Juan Carlos Álvarez-Perez, Alvaro Andrades, Alberto M. Arenas, Carlos Baliñas-Gavira, Dominik A. Barth, Anna Bielowski, Roopa Biswas, Mattia Boeri, Elisabetta Broseghini, George A. Calin, Enrica Calura, Elisabetta Casalone, Vera Constâncio, Giulia Cosentino, Marina C. Costa, Carlo M. Croce, Marta Cuadros, Christine E. Cutucache, Ben Davidson, Emi Dika, Sayra Dilmac, Mihnea P. Dragomir, Rares Drula, Francisco J. Enguita, Zhaohui Feng, Manuela Ferracin, Francesca Fornari, Orazio Fortunato, André F. Gabriel, Daniel J. García, Laura Gramantieri, Rui Henrique, Wenwei Hu, Marilena V. Iorio, Carmen Jerónimo, Sakshi Kamboj, Manoj Kumar, Charles Henderson Lawrie, Ana Lúcia Leitão, Juan Liu, Francesca Lovat, Laura Masatti, Giuseppe Matullo, Pedro P. Medina, Swati Mohapatra, Vlad Moisoiu, Massimo Negrini, Vu Hong Loan Nguyen, Jacob Anderson O’Brien, Bulent Ozpolat, Barbara Pardini, Juan Rodrigo Patiño-Mercau, Laura Pazzaglia, Paola Peinado, Yuri Pekarsky, Chun Peng, George E.D. Petrescu, Martin Pichler, Ilaria Plantamura, Reuven Reich, Maria Isabel Rodriguez, Chiara Romualdi, Juan Sanjuan-Hidalgo, Katia Scotlandi, Ram C. Shankaraiah, Ondrej Slaby, Carla Solé, Dharmendra Kumar Soni, Gabriella Sozzi, Anamika Thakur, Angelo Veronese, Rosa Visone, Petra Vychytilova-Faltejskova, and Cen Zhang
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- 2022
22. Combined miRNA and SERS urine liquid biopsy for the point-of-care diagnosis and molecular stratification of bladder cancer
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Tudor Moisoiu, Mihnea P. Dragomir, Stefania D. Iancu, Simon Schallenberg, Giovanni Birolo, Giulio Ferrero, Dan Burghelea, Andrei Stefancu, Ramona G. Cozan, Emilia Licarete, Alessandra Allione, Giuseppe Matullo, Gheorghita Iacob, Zoltán Bálint, Radu I. Badea, Alessio Naccarati, David Horst, Barbara Pardini, Nicolae Leopold, and Florin Elec
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Tumor ,microRNA ,Molecular subtypes ,SERS ,Point-of-Care Systems ,Bladder cancer ,Liquid Biopsy ,Bayes Theorem ,MicroRNAs ,Urinary Bladder Neoplasms ,Genetics ,Biomarkers, Tumor ,Biomarkers ,Liquid biopsy ,Humans ,Retrospective Studies ,Molecular Medicine ,Molecular Biology ,Genetics (clinical) - Abstract
Background Bladder cancer (BC) has the highest per-patient cost of all cancer types. Hence, we aim to develop a non-invasive, point-of-care tool for the diagnostic and molecular stratification of patients with BC based on combined microRNAs (miRNAs) and surface-enhanced Raman spectroscopy (SERS) profiling of urine. Methods Next-generation sequencing of the whole miRNome and SERS profiling were performed on urine samples collected from 15 patients with BC and 16 control subjects (CTRLs). A retrospective cohort (BC = 66 and CTRL = 50) and RT-qPCR were used to confirm the selected differently expressed miRNAs. Diagnostic accuracy was assessed using machine learning algorithms (logistic regression, naïve Bayes, and random forest), which were trained to discriminate between BC and CTRL, using as input either miRNAs, SERS, or both. The molecular stratification of BC based on miRNA and SERS profiling was performed to discriminate between high-grade and low-grade tumors and between luminal and basal types. Results Combining SERS data with three differentially expressed miRNAs (miR-34a-5p, miR-205-3p, miR-210-3p) yielded an Area Under the Curve (AUC) of 0.92 ± 0.06 in discriminating between BC and CTRL, an accuracy which was superior either to miRNAs (AUC = 0.84 ± 0.03) or SERS data (AUC = 0.84 ± 0.05) individually. When evaluating the classification accuracy for luminal and basal BC, the combination of miRNAs and SERS profiling averaged an AUC of 0.95 ± 0.03 across the three machine learning algorithms, again better than miRNA (AUC = 0.89 ± 0.04) or SERS (AUC = 0.92 ± 0.05) individually, although SERS alone performed better in terms of classification accuracy. Conclusion miRNA profiling synergizes with SERS profiling for point-of-care diagnostic and molecular stratification of BC. By combining the two liquid biopsy methods, a clinically relevant tool that can aid BC patients is envisaged.
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- 2021
23. Serum Extracellular Vesicle-Derived microRNAs as Potential Biomarkers for Pleural Mesothelioma in a European Prospective Study
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Elisabetta Casalone, Giovanni Birolo, Barbara Pardini, Alessandra Allione, Alessia Russo, Chiara Catalano, Manlio Mencoboni, Daniela Ferrante, Corrado Magnani, Marika Sculco, Irma Dianzani, Federica Grosso, Dario Mirabelli, Rosa Angela Filiberti, Ottavio Rena, Carlotta Sacerdote, Miguel Rodriguez-Barranco, Karl Smith-Byrne, Salvatore Panico, Claudia Agnoli, Theron Johnson, Rudolf Kaaks, Rosario Tumino, José María Huerta, Elio Riboli, Alicia K Heath, Camino Trobajo-Sanmartín, Matthias B. Schulze, Calogero Saieva, Pilar Amiano, Antonio Agudo, Elisabete Weiderpass, Paolo Vineis, and Giuseppe Matullo
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Malalties de la pleura ,Mesothelioma ,Pleural disease ,next generation sequencing ,early changes ,malignant pleural mesothelioma ,biomarkers ,microRNAs ,Cancer Research ,Biochemical markers ,Mesotelioma ,Oncology ,Marcadors bioquímics - Abstract
Simple Summary Malignant pleural mesothelioma (MPM) is an aggressive and still incurable cancer. There is an urgent need to identify effective and reliable tools for detecting and diagnosing the early onset of MPM. In our study, we investigated the whole miRNAs expression profile from serum extracellular vesicles to identify early changes related to MPM development. miR-11400, miR-148a-3p, and miR-409-3p levels were increased in pre-clinical MPM patients up to five years before their diagnosis. The three-miRNA pattern showed a good discrimination capacity to distinguish pre-clinical MPM from cancer-free controls. The three miRNAs also displayed high diagnostic capabilities for differentiating between MPM patients and controls. This study identified a potential EV miRNA signature in preclinical MPM up to five years before diagnosis and raises the possibility of early intervention. Malignant pleural mesothelioma (MPM) is an aggressive cancer with a dismal prognosis. Early therapeutic interventions could improve patient outcomes. We aimed to identify a pattern of microRNAs (miRNAs) as potential early non-invasive markers of MPM. In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort, we screened the whole miRNome in serum extracellular vesicles (EVs) of preclinical MPM cases. In a subgroup of 20 preclinical samples collected five years prior MPM diagnosis, we observed an upregulation of miR-11400 (fold change (FC) = 2.6, adjusted p-value = 0.01), miR-148a-3p (FC = 1.5, p-value = 0.001), and miR-409-3p (FC = 1.5, p-value = 0.04) relative to matched controls. The 3-miRNA panel showed a good classification capacity with an area under the receiver operating characteristic curve (AUC) of 0.81 (specificity = 0.75, sensitivity = 0.70). The diagnostic ability of the model was also evaluated in an independent retrospective cohort, yielding a higher predictive power (AUC = 0.86). A signature of EV miRNA can be detected up to five years before MPM; moreover, the identified miRNAs could provide functional insights into the molecular changes related to the late carcinogenic process, preceding MPM development.
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- 2022
24. Combination of urinary fibrinogen β-chain and tyrosine-phosphorylated proteins for the detection of bladder cancer
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Clara Viberti, Amina Khadjavi, Francesca Pecoraro, Mauro Prato, Giuliana Giribaldi, Matteo De Bellis, Giuseppe Matullo, Marco Allasia, Paolo Gontero, Giulia Bonomessi, Gabriele Montefusco, Nicole Finesso, Francesco Soria, Bruno Emilio Bressan, Alessandra Allione, Stefano Turini, Claudia Filippini, and Daniela Ulliers
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Bladder cancer ,Chemistry ,Urinary system ,bladder cancer ,fibrinogen β-chain ,tyrosine-phosphorylated proteins ,urinary markers ,Fibrinogen ,medicine.disease ,medicine ,Cancer research ,Diagnostic biomarker ,Tyrosine ,skin and connective tissue diseases ,Phosphorylated proteins ,Research Article ,Biotechnology ,medicine.drug - Abstract
Aim: To evaluate the performance of urinary fibrinogen β-chain (FBC) – either alone or associated with urinary tyrosine-phosphorylated proteins (UPY) – as bladder cancer (BCa) diagnostic biomarker. Materials & methods: 164 subjects were tested. Results: Significantly different FBC and UPY levels were found between BCa patients and controls, as well as between low-grade and high-grade cancers. The diagnostic accuracy was 0.84 for FBC and 0.87 for UPY. The combination of FBC and UPY improved the accuracy to 0.91. The addition of clinical variables (age, gender, and smoking habit) to FBC and UPY into a model for BCa prediction significantly improved the accuracy to 0.99. The combination of FBC and UPY adjusted for clinical variables associates with the highest sensitivity and good specificity. Conclusion: Urinary FBC and UPY could be used as biomarkers for BCa diagnosis., Lay abstract This research has developed and validated a highly accurate predictive model for BCa diagnosis based on the combination of two urinary biomarkers, fibrinogen β-chain (FBC), and urinary tyrosine-phosphorylated proteins (UPY), and some clinical variables (age, gender and smoking habit). If the preliminary promising results will be confirmed by external validations and prospective trials in selected clinical scenarios, our model could be transferred to clinical practice for screening of high-risk population., Graphical abstract
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- 2021
25. Diagnostics of BAP1-Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience
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Marika Sculco, Marta La Vecchia, Anna Aspesi, Michela Giulia Clavenna, Michela Salvo, Giulia Borgonovi, Alessandra Pittaro, Gianluca Witel, Francesca Napoli, Angela Listì, Federica Grosso, Roberta Libener, Antonio Maconi, Ottavio Rena, Renzo Boldorini, Daniela Giachino, Paolo Bironzo, Antonella Maffè, Greta Alì, Lisa Elefanti, Chiara Menin, Luisella Righi, Cristian Tampieri, Giorgio Vittorio Scagliotti, Caterina Dianzani, Daniela Ferrante, Enrica Migliore, Corrado Magnani, Dario Mirabelli, Giuseppe Matullo, and Irma Dianzani
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BAP1-TPDS ,cancer genome ,diagnostics ,germline variants ,immunohistochemistry ,melanoma ,mesothelioma ,Clinical Biochemistry - Abstract
Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 (BAP1) lead to BAP1 tumor predisposition syndrome (BAP1-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of BAP1-TPDS, along with a clinical update and cascade genetic testing of previously reported BAP1-TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected BAP1-TPDS and validated pathogenic variants (PVs) by assessing BAP1 somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline BAP1 PVs, including one novel variant. Consistently, cascade testing revealed a total of seven BAP1 PV carriers. In addition, we explored the mutational burden of BAP1-TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type BAP1 allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous BAP1 in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of BAP1-TPDS patients.
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- 2022
26. Analysis of Italian
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Gisella, Figlioli, Arcangela, De Nicolo, Irene, Catucci, Siranoush, Manoukian, Bernard, Peissel, Jacopo, Azzollini, Benedetta, Beltrami, Bernardo, Bonanni, Mariarosaria, Calvello, Davide, Bondavalli, Barbara, Pasini, Francesca, Vignolo Lutati, Paola, Ogliara, Monica, Zuradelli, Valeria, Pensotti, Giovanna, De Vecchi, Sara, Volorio, Paolo, Verderio, Sara, Pizzamiglio, Giuseppe, Matullo, Serena, Aneli, Giovanni, Birolo, Federica, Zanardi, Carlo, Tondini, Alberto, Zambelli, Luca, Livraghi, Michela, Franchi, Paolo, Radice, and Paolo, Peterlongo
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breast cancer ,Italy ,cardiovascular system ,Bergamo province ,skin and connective tissue diseases ,BRCA1 ,BRCA2 ,pathogenic variants ,Article ,spectrum - Abstract
Simple Summary The Italian population is characterized by a high genetic heterogeneity mostly due to its long history of migration and colonization and to its geographical conformation. Consistently, several BRCA1/2 pathogenic variants (PVs) have been reported to be recurrent or even founder in defined geographical areas including the Bergamo province in Northern Italy. In this study, we retrospectively analyzed the data from 1019 women affected with breast cancer with BRCA1/2 PVs. We compared the BRCA1/2 PVs spectrum found in the carrier individuals from the Bergamo province (BGP) with that of the general Italian population. We found that the majority of the BGP PVs had a local origin and remained confined to the BGP or to the surrounding Lombardy region. We also observed that the BGP BRCA1/2 PV spectrum is private and conserved comprising a smaller number of variants with an average higher frequency with respect to that of carrier individuals from the rest of Italy. Abstract Germline pathogenic variants (PVs) in the BRCA1 or BRCA2 genes cause high breast cancer risk. Recurrent or founder PVs have been described worldwide including some in the Bergamo province in Northern Italy. The aim of this study was to compare the BRCA1/2 PV spectra of the Bergamo and of the general Italian populations. We retrospectively identified at five Italian centers 1019 BRCA1/2 PVs carrier individuals affected with breast cancer and representative of the heterogeneous national population. Each individual was assigned to the Bergamo or non-Bergamo cohort based on self-reported birthplace. Our data indicate that the Bergamo BRCA1/2 PV spectrum shows less heterogeneity with fewer different variants and an average higher frequency compared to that of the rest of Italy. Consistently, four PVs explained about 60% of all carriers. The majority of the Bergamo PVs originated locally with only two PVs clearly imported. The Bergamo BRCA1/2 PV spectrum appears to be private. Hence, the Bergamo population would be ideal to study the disease risk associated with local PVs in breast cancer and other disease-causing genes. Finally, our data suggest that the Bergamo population is a genetic isolate and further analyses are warranted to prove this notion.
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- 2020
27. Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation
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Giuseppe Matullo, John R. B. Perry, Meena Kumari, Gemma C Sharp, Tomáš Paus, E. Giralt-Steinhauer, Marta E. Alarcón-Riquelme, Koen F. Dekkers, F. Gagnon, Simonetta Guarrera, Cilla Söderhäll, Rosie M. Walker, Therese Tillin, M. Smarts, Juan E. Castillo-Fernandez, John M. Starr, Jean Shin, Dan Mason, T Esko, Christopher Shaw, Hannah R Elliott, Manon Bernard, David L. Corcoran, Yvonne Awaloff, Ahmad Al Khleifat, Bert Brunekreef, Clara Viberti, John Wright, Gibran Hemani, Kathryn L. Evans, Camilla Schmidt Morgen, Jouke J. Hottenga, Susan M. Ring, Terrie E. Moffitt, Silva Kasela, C. Hale, Idil Yet, Katri Räikkönen, René Luijk, Vanessa Schmoll, Kimberley Burrows, Annelot M. Dekker, D. VanHeemst, Jordana T. Bell, Jordi Jimenez-Conde, Carlotta Sacerdote, Salvatore Panico, Lili Milani, Nabila Kazmi, Torben Hansen, Aleksey Shatunov, J L Min, Richa Gupta, Henning Tiemeier, Grant W. Montgomery, Vincent W. V. Jaddoe, E.J.C. de Geus, Fernando Rivadeneira, Debbie A Lawlor, Carol A. Wang, Toni-Kim Clarke, Susanne Lucae, Nicholas J. Wareham, Jordi Sunyer, Felix R. Day, C. Soriano-Tarraga, Christoph Bock, Juan R. González, D. Aissi, J.B. van Meurs, Ian J. Deary, Ken K. Ong, Louise Arseneault, Eilis Hannon, Bastiaan T. Heijmans, Philip E. Melton, Ashok Kumar, Pierre-Emmanuel Morange, Zdenka Pausova, T.D. Spector, Nicholas G. Martin, J. Mill, Francesc Català-Moll, Alun D. Hughes, Leonard C. Schalkwyk, Giovanni Cugliari, Carlos Ruiz-Arenas, Elena Carnero-Montoro, Marine Germain, Yanni Zeng, Andrew M. McIntosh, Riccardo E. Marioni, Wilfried Karmaus, Ikram, Gonneke Willemsen, Miina Ollikainen, Karen M Ho, Craig E. Pennell, F.I. Rezwan, Darina Czamara, Ramona A. J. Zwamborn, Dorret I. Boomsma, Wendy L. McArdle, J. M. van Dongen, Guillermo Barturen, Matthew Suderman, Richie Poulton, Daniel Lawson, A. Metspalu, David-Alexandre Trégouët, Marian Beekman, Andrew D. Bretherick, Johanna Klughammer, Hongmei Zhang, M.H. van IJzendoorn, Nish Chaturvedi, Jari Lahti, Karen Sugden, Jan H. Veldink, Mariona Bustamante, Avshalom Caspi, Pooja R. Mandaviya, Judith M. Vonk, Tom R. Gaunt, Cheng-Jian Xu, John W. Holloway, Tian Lin, Tom G. Richardson, Caroline L Relton, Naomi R. Wray, Allan F. McRae, George Davey Smith, Erik Melén, Valentina Iotchkova, Ellen A. Nohr, Jaakko Kaprio, Göran Pershagen, Elisabeth B. Binder, A. al Chalabi, T.J. Gorrie-Stone, K. van Eijk, Gerard H. Koppelman, M. Lerro, Alexia Cardona, Sailalitha Bollepalli, P.E. Slagboom, Thorkild I. A. Sørensen, André G. Uitterlinden, Jaume Roquer, Peter M. Visscher, Janine F. Felix, Martin Kerick, Gail Davies, Rae-Chi Huang, Alfredo Iacoangeli, Alison D. Murray, Helsinki Institute of Life Science HiLIFE, Institute for Molecular Medicine Finland, Epigenetics of Complex Diseases and Traits, Department of Public Health, Department of Psychology and Logopedics, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, APH - Methodology, Groningen Research Institute for Asthma and COPD (GRIAC), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Epidemiology, Internal Medicine, Pediatrics, Child and Adolescent Psychiatry / Psychology, and Clinical Child and Family Studies
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Multifactorial Inheritance ,ADN ,Quantitative Trait Loci ,Genome-wide association study ,VARIANTS ,Biology ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,LINKS ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Quantitative Trait, Heritable ,Genetic variation ,Genetics ,WIDE ASSOCIATION ,GWAS ,Humans ,Genetic Predisposition to Disease ,Genotip ,METAANALYSIS ,EQTL ,030304 developmental biology ,Epigenesis ,SNP ANALYSIS ,0303 health sciences ,COMPLEX ,dNaM ,Chromosome Mapping ,DNA ,DNA Methylation ,Phenotype ,Genetic architecture ,MODEL ,Fenotip ,Gene Expression Regulation ,DNA methylation ,MENDELIAN RANDOMIZATION ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,3111 Biomedicine ,Metilació ,Transcriptome ,Genètica ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs. Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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- 2020
28. DNA Methylation of
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Giovanni, Cugliari, Chiara, Catalano, Simonetta, Guarrera, Alessandra, Allione, Elisabetta, Casalone, Alessia, Russo, Federica, Grosso, Daniela, Ferrante, Clara, Viberti, Anna, Aspesi, Marika, Sculco, Chiara, Pirazzini, Roberta, Libener, Dario, Mirabelli, Corrado, Magnani, Irma, Dianzani, and Giuseppe, Matullo
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asbestos exposure ,DNA methylation ,epigenome-wide analysis ,lymphocyte-to-monocyte ratio ,malignant pleural mesothelioma ,Article ,survival analysis - Abstract
Simple Summary Our study is the first one to investigate DNA methylation changes in white blood cells (WBCs) from easily accessible peripheral blood as malignant pleural mesothelioma (MPM) survival biomarker. The Cox proportional hazards regression model highlighted that the methylation status of the CpG dinucleotide cg03546163 is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Biological validation and replication showed that epigenetic changes at the FKBP5 gene were robustly associated with overall survival (OS) in MPM cases. The identification of simple and valuable prognostic markers for MPM will enable clinicians to select patients who are most likely to benefit from aggressive therapies and avoid subjecting non-responder patients to ineffective treatment. Abstract Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10−9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5′UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value< 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM.
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- 2020
29. Genomic and phenomic insights from an atlas of genetic effects on DNA methylation
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Carol A. Wang, Simonetta Guarrera, Avshalom Caspi, Eilis Hannon, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Pooja R. Mandaviya, Koen F. Dekkers, Cheng-Jian Xu, Jari Lahti, Juan E. Castillo-Fernandez, Dan Mason, Dylan Aïssi, Jan H. Veldink, Mariona Bustamante, Melissa C. Smart, Guillermo Barturen, Zdenka Pausova, Jenny van Dongen, Jordi Jimenez-Conde, Craig E. Pennell, Gibran Hemani, Tom R. Gaunt, Camilla Schmidt Morgen, Ken K. Ong, Toni-Kim Clarke, Alexia Cardona, Susanne Lucae, René Luijk, T.J. Gorrie-Stone, Phillip E. Melton, Thorkild I. A. Sørensen, André G. Uitterlinden, Jordana T. Bell, Jouke-Jan Hottenga, Meena Kumari, Francesc Català-Moll, Jonathan Mill, Tõnu Esko, Sailalitha Bollepalli, Dorret I. Boomsma, Torben Hansen, Hongmei Zhang, Yanni Zeng, John Wright, Wilfried Karmaus, Martin Kerick, Carolina Soriano-Tárraga, Jaakko Kaprio, Miina Ollikainen, Eco J. C. de Geus, Jordi Sunyer, Therese Tillin, Juan R. González, Yvonne Awaloff, Faisal I. Rezwan, Karen Sugden, Nicholas G. Martin, Karen M Ho, Andres Metspalu, Marine Germain, Kristel R. van Eijk, Ramona A. J. Zwamborn, George Davey Smith, Judith M. Vonk, Tian Lin, Henning Tiemeier, Grant W. Montgomery, Naomi R. Wray, Rae-Chi Huang, Alfredo Iacoangeli, Wendy L. McArdle, Jean Shin, Michael Lerro, Darina Czamara, Valentina Iotchkova, David-Alexandre Trégouët, Johanna Klughammer, Elena Carnero-Montoro, Pierre-Emmanuel Morange, Andrew M. McIntosh, Gemma C Sharp, Alun D. Hughes, Carlos Ruiz-Arenas, John M. Starr, Riccardo E. Marioni, Peter M. Visscher, Nabila Kazmi, Ian J. Deary, Kathryn L. Evans, Terrie E. Moffitt, Janine F. Felix, Tomáš Paus, Ashok Kumar, Jaume Roquer, Christopher Shaw, Hannah R Elliott, Susan M. Ring, Nish Chaturvedi, Giovanni Cugliari, Ahmad Al Khleifat, Joyce B. J. van Meurs, Kimberley Burrows, Bert Brunekreef, Debbie A Lawlor, Clara Viberti, Louise Arseneault, Silva Kasela, Cilla Söderhäll, Idil Yet, Manon Bernard, Christoph Bock, Vincent W. V. Jaddoe, Felix R. Day, Diana van Heemst, Alison D. Murray, Nicholas J. Wareham, Giuseppe Matullo, John R. B. Perry, Gerard H. Koppelman, M. Arfan Ikram, Ammar Al Chalabi, Gonneke Willemsen, Richie Poulton, Daniel Lawson, Andrew D. Bretherick, Vanessa Schmoll, Carlotta Sacerdote, Annelot M. Dekker, Lili Milani, Fernando Rivadeneira, Erik Melén, John W. Holloway, Gareth E. Davies, Tom G. Richardson, Caroline L Relton, Josine L. Min, Göran Pershagen, Elisabeth B. Binder, Marian Beekman, Chris Haley, Richa Gupta, Bastiaan T. Heijmans, Ellen A. Nohr, Allan F. McRae, Matthew Suderman, Rosie M. Walker, David L. Corcoran, Katri Räikkönen, Marinus H. van IJzendoorn, Eva Giralt-Steinhauer, Leonard C. Schalkwyk, Aleksey Shatunov, and Tim D. Spector
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Genetics ,Regulation of gene expression ,0303 health sciences ,Natural selection ,dNaM ,Biology ,Genetic architecture ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Genetic variation ,DNA methylation ,Trait ,030217 neurology & neurosurgery ,DNA ,030304 developmental biology - Abstract
Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.
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- 2020
30. Adipocyte-derived extracellular vesicles regulate survival and function of pancreatic β cells
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Maria Felice Brizzi, Alessandro Fanciulli, Simone Arolfo, Maria Chiara Deregibus, Rita Nano, Gaia Zocaro, Iacopo Gesmundo, Huy Ong, Enrica Favaro, Stefania Bruno, Maria Alessandra Bocchiotti, Giovanni Birolo, Giacomo Gamba, Barbara Pardini, Giuseppe Matullo, Mario Morino, Justo P. Castaño, Giovanni Camussi, Eleonora Gargantini, Riccarda Granata, Dana Banfi, Ezio Ghigo, Raúl M. Luque, Lorenzo Piemonti, Juan M. Falcón-Pérez, Gabriele Togliatto, Noemi Congiusta, Gesmundo, Iacopo, Pardini, Barbara, Gargantini, Eleonora, Gamba, Giacomo, Birolo, Giovanni, Fanciulli, Alessandro, Banfi, Dana, Congiusta, Noemi, Favaro, Enrica, Deregibus, Maria Chiara, Togliatto, Gabriele, Zocaro, Gaia, Brizzi, Maria Felice, Luque, Raul M, Castaño, Justo P, Bocchiotti, Maria Alessandra, Arolfo, Simone, Bruno, Stefania, Nano, Rita, Morino, Mario, Piemonti, Lorenzo, Ong, Huy, Matullo, Giuseppe, Falcón-Pérez, Juan M, Ghigo, Ezio, Camussi, Giovanni, and Granata, Riccarda
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0301 basic medicine ,Adult ,Male ,Programmed cell death ,Cell ,Adipose tissue ,Beta cells ,Diabetes ,Metabolism ,03 medical and health sciences ,chemistry.chemical_compound ,Extracellular Vesicles ,Islets of Langerhans ,Mice ,0302 clinical medicine ,Adipocyte ,3T3-L1 Cells ,microRNA ,medicine ,Adipocytes ,Animals ,Humans ,Obesity ,Chemistry ,Pancreatic islets ,General Medicine ,In vitro ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Medicine ,Female ,Signal transduction ,Research Article - Abstract
Extracellular vesicles (EVs) are implicated in the crosstalk between adipocytes and other metabolic organs, and an altered biological cargo has been observed in EVs from human obese adipose tissue (AT). Yet, the role of adipocyte-derived EVs in pancreatic β cells remains to be determined. Here, we explored the effects of EVs released from adipocytes isolated from both rodents and humans and human AT explants on survival and function of pancreatic β cells and human pancreatic islets. EVs from healthy 3T3-L1 adipocytes increased survival and proliferation and promoted insulin secretion in INS-1E β cells and human pancreatic islets, both those untreated or exposed to cytokines or glucolipotoxicity, whereas EVs from inflamed adipocytes caused β cell death and dysfunction. Human lean adipocyte-derived EVs produced similar beneficial effects, whereas EVs from obese AT explants were harmful for human EndoC-βH3 β cells. We observed differential expression of miRNAs in EVs from healthy and inflamed adipocytes, as well as alteration in signaling pathways and expression of β cell genes, adipokines, and cytokines in recipient β cells. These in vitro results suggest that, depending on the physiopathological state of AT, adipocyte-derived EVs may influence β cell fate and function.
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- 2020
31. Small Non-Coding RNA Profiling in Plasma Extracellular Vesicles of Bladder Cancer Patients by Next-Generation Sequencing: Expression Levels of miR-126-3p and piR-5936 Increase with Higher Histologic Grades
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Giovanni Birolo, Alessio Naccarati, Paolo Vineis, Serena Aneli, Marco Oderda, Mihnea P. Dragomir, Barbara Pardini, Giuseppe Matullo, Marco Allasia, Paolo Gontero, Alexandru A Sabo, Carlotta Sacerdote, and Alessandra Allione
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0301 basic medicine ,Cancer Research ,small non-coding RNA profiling ,non-invasive biomarkers ,Urinary system ,Urine ,lcsh:RC254-282 ,DNA sequencing ,Article ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,microRNA ,Medicine ,Liquid biopsy ,Bladder cancer ,Extracellular vesicles ,MicroRNAs ,Next-generation sequencing ,Non-invasive biomarkers ,PiRNAs ,Small non-coding RNA profiling ,liquid biopsy ,business.industry ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Non-coding RNA ,medicine.disease ,Cystoscopies ,microRNAs ,030104 developmental biology ,Oncology ,piRNAs ,030220 oncology & carcinogenesis ,bladder cancer ,next-generation sequencing ,business ,extracellular vesicles - Abstract
Bladder cancer (BC) is the tenth most frequent cancer worldwide. Due to the need for recurrent cystoscopies and the lack of non-invasive biomarkers, BC is associated with a high management burden. In this respect, small non-coding RNAs (sncRNAs) have been investigated in urine as possible biomarkers for BC, but in plasma their potential has not yet been defined. The expression levels of sncRNAs contained in plasma extracellular vesicles (EVs) from 47 men with BC and 46 healthy controls were assessed by next-generation sequencing. The sncRNA profiles were compared with urinary profiles from the same subjects. miR-4508 resulted downregulated in plasma EVs of muscle-invasive BC patients, compared to controls (adj-p = 0.04). In World Health Organization (WHO) grade 3 (G3) BC, miR-126-3p was upregulated both in plasma EVs and urine, when compared to controls (for both, adj-p <, 0.05). Interestingly, two sncRNAs were associated with the risk class: miR-4508 with a downward trend going from controls to high risk BC, and piR-hsa-5936 with an upward trend (adj-p = 0.04 and adj-p = 0.05, respectively). Additionally, BC cases with low expression of miR-185-5p and miR-106a-5p or high expression of miR-10b-5p showed shorter survival (adj-p = 0.0013, adj-p = 0.039 and adj-p = 0.047, respectively). SncRNAs from plasma EVs could be diagnostic biomarkers for BC, especially in advanced grade.
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- 2020
32. ACE2gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population
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Mrgherita Baldassarri, Elisa Benetti, Vincenzo Nigro, Giovanni Birolo, Annarita Giliberti, Andrea Ciolfi, Alessandro Bruselles, Anna Maria Pinto, Francesca Mari, Alfonso Trezza, Marco Seri, Annalaura Torella, Marco Tartaglia, Giuseppe Matullo, Gabriella Doddato, Francesco Musacchia, Floriana Valentino, Rosanna Asselta, Cterina Marconi, Bruttini Mirella, Rossella Tita, Alessandra Renieri, Alfredo Brusco, Simone Furini, Ottavia Spiga, and Tommaso Pippucci
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Genetics ,education.field_of_study ,Proteases ,media_common.quotation_subject ,Population ,Disease ,Biology ,Disease cluster ,medicine.disease_cause ,medicine ,Missense mutation ,Internalization ,education ,Exome sequencing ,media_common ,Coronavirus - Abstract
In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus-disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries.It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for inter-individual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome-sequencing data of 6930 Italian control individuals from five different centers looking forACE2variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison ofACE2WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value
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- 2020
33. The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis
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Tom H. Karlsen, Monica Bocciolone, Mareike Wendorff, Mauro D'Amato, Anna Ludovica Fracanzani, Leonardo Terranova, Pietro Invernizzi, Luigia Scudeller, María Hernández-Tejero, Maurizio Cecconi, David Jiménez, Antonio Pesenti, Anna Latiano, Sandra May, Luigi Santoro, Nicole Braun, Valeria Rimoldi, Jeanette Erdmann, Mariella D'Angiò, Giorgio Costantino, Sara Marsal, Antonio Voza, Fatima Aziz, Xiaoli Yi, Wolfgang Peter, Marina Elena Cazzaniga, Giuseppe Foti, Antonio Julià, Lars Wienbrandt, Rosa Nieto, Cristina Cea, Maria Eloina Figuera Basso, Maria Carrabba, Michele Ciccarelli, Javier Martín, Adriana Palom, Paolo Bonfanti, Andrea Caballero-Garralda, Manuel Romero Gómez, Koldo Garcia-Etxebarria, Guido Baselli, Rosanna Asselta, Giuseppe Matullo, Ilaria My, Francisco Mesonero, Serena Aneli, Javier Fernández, Marit Mæhle Grimsrud, Pedro M. Rodrigues, Luis Téllez, Johannes R. Hov, Elvezia Maria Paraboschi, Enrique Navas, Andrea Gori, Flora Peyvandi, Francesco Blasi, Orazio Palmieri, Ana Lleo de Nalda, Marco Schaefer, Anja Tanck, Jan Christian Kässens, José Ferrusquía-Acosta, Giacomo Grasselli, Wolfgang Albrecht, Maria Buti, Tenghao Zheng, Serena Pelusi, Daniele Prati, Laura Rachele Bettini, Nilda Martinez, Silvano Bosari, M.A. Rodríguez-Gandía, Alessandra Bandera, Leticia Moreira, Paoletta Preatoni, Giulia Cardamone, Albert Blanco-Grau, Tanja Wesse, Aaron Blandino Ortiz, Marina Baldini, Hayato Kurihara, Beatriz Mateos, Jesus M. Banales, Alberto Zanella, Roberta Gualtierotti, Salvatore Badalamenti, David Ellinghaus, Tomás Pumarola, Luca Valenti, Maria Grazia Valsecchi, Chiara Milani, Martin Schulzky, Alba-Estela Garcia-Fernandez, Aurora Solier, Pedro Castro, Ferruccio Ceriotti, Beatriz Jiménez, Maria del Mar Riveiro Barciela, Stefano Duga, Carmen Quereda, Luisa Roade, Michael Wittig, Anna Peschuck, Andre Franke, Valter Monzani, Ricardo Ferrer Roca, Luis Bujanda, F. Martinelli-Boneschi, Adolfo Garrido Chercoles, Raúl de Pablo, Laura Izquierdo-Sanchez, Paola Faverio, Alessandro Protti, Hesham ElAbd, Monica Miozzo, Elena Sandoval, Agustín Albillos, Marialbert Acosta-Herrera, David Pestana, Paolo Omodei, Trine Folseraas, Andrea Biondi, Paolo Tentorio, Florian Uellendahl-Werth, Claudio Angelini, Frauke Degenhardt, Alessio Aghemo, Francisco Rodriguez-Frias, German Research Foundation, Canica, Swiss Cancer League, Ministero dell'Istruzione, dell'Università e della Ricerca, Fonds Schleswig-Holstein, Federal Ministry of Education and Research (Germany), Ministerio de Ciencia, Innovación y Universidades (España), and Agencia Estatal de Investigación (España)
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German ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,language ,Genome-Wide Association Analysis ,Library science ,Christian ministry ,Biobank ,language.human_language - Abstract
[Background] Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients., [Methods] We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a metaanalysis of both case-control panels., [Results] We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P, [Conclusions] We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid19 pathophysiology., The IKMB's core facilities received infrastructure support by the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI, EXC2167). The project also received support through a philanthropic donation by Stein Erik Hagen and Canica AS. L.V. was funded by the Fondazione IRCCS Ca’ Granda «COVID-19 Biobank» research grant. This work was also supported by the Ministero dell’Istruzione, dell’Università e della Ricerca – MIUR project "Dipartimenti di Eccellenza 2018 – 2022" (n° D15D18000410001) to the Department of Medical Sciences, University of Torino. The IKMB authors received financial support from the UKSH Foundation "Gutes Tun!" (special thanks to Alexander Eck, Jenspeter Horst and Jens Scholz) and the German Federal Ministry of Education and Research (BMBF; grant ID 01KI20197). HLA-Typing was performed and supported by the Stefan-MorschStiftung. M.A.H was supported by the Spanish Ministry of Science and Innovation ‘JdC fellowship IJC2018-035131-I.
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- 2020
34. Tumor-associated autoantibodies as early detection markers for ovarian cancer? A prospective evaluation
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Sabina Sieri, Dagfinn Aune, Inger T. Gram, Karin Jirström, Kim Overvad, Renée T. Fortner, Rudolf Kaaks, Carlo La Vecchia, Carmen Navarro Sánchez, Rosario Tumino, Eric J. Duell, María José Sánchez, N. Charlotte Onland-Moret, Anika Hüsing, Domenico Palli, Ruth C. Travis, Antonia Trichopoulou, Theron Johnson, Anne Tjønneland, Laure Dossus, Melissa A. Merritt, Vassiliki Benetou, Elisabete Weiderpass, Agnès Fournier, Nerea Larrañaga, Kathryn L. Terry, Eva Ardanaz, Amalia Mattiello, Annika Idahl, Eva Lundin, Louise Hansen, Elio Riboli, Marina Kvaskoff, Karen S. Anderson, Giuseppe Matullo, Björn Nodin, Marie-Christine Boutron-Ruault, Mattias Johansson, Myrto Barrdahl, Heiner Boeing, Daniel W. Cramer, and Marika Hopper
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,biology ,business.industry ,Case-control study ,Autoantibody ,medicine.disease ,03 medical and health sciences ,Serous fluid ,030104 developmental biology ,0302 clinical medicine ,Antigen ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,medicine ,biology.protein ,Antibody ,Ovarian cancer ,business ,Prospective cohort study - Abstract
Immuno-proteomic screening has identified several tumor-associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times ≤6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited.
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- 2018
35. Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations
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Rosario Tumino, Jody van den Ouweland, Kathryn E. Bradbury, Petra H.M. Peeters, Martin Almquist, Fränzel J.B. Van Duijnhoven, Anja Olsen, Giuseppe Matullo, Miren Dorronsoro, Heinz Freisling, Mazda Jenab, Weimin Ye, Eivind Ness-Jensen, Elio Riboli, Maria Dolores Chirlaque, Jonas Manjer, Marina Kvaskoff, Veronika Fedirko, Verena Katzke, H. Bas Bueno-de-Mesquita, Dagfinn Aune, Marie-Christine Boutron-Ruault, Claudia Agnoli, Mireia Obón-Santacana, Frida Renström, Elisabete Weiderpass, Claire Cadeau, Teresa Norat, Cristina Lasheras, Kay-Tee Khaw, Maria Kritikou, Salvatore Panico, Henk J. van Kranen, Karina Standahl Olsen, Nicholas J. Wareham, Anouk Halfweeg, Arnulf Langhammer, María José Sánchez, Heiner Boeing, Kim Overvad, Anne Tjønneland, Domenico Palli, Antonia Trichopoulou, Ellen Kampman, Neil Murphy, Magritt Brustad, Aurelio Barricarte, Kristian Hveem, Eric J. Duell, Peter D. Siersema, Anastasia Kotanidou, and Tilman Kühn
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,25-Hydroxyvitamin D 2 ,Vitamin D and neurology ,Prospective cohort study ,2. Zero hunger ,business.industry ,Case-control study ,3. Good health ,European Prospective Investigation into Cancer and Nutrition ,030104 developmental biology ,Endocrinology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Nested case-control study ,Calcifediol ,business ,Body mass index - Abstract
Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trondelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant.
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- 2017
36. Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer
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Karin B. Michels, Alexandra M. Binder, Benedetta Mussolin, Andrea Cassingena, Alice Vanzati, Mauro Truini, Salvatore Siena, Manel Esteller, Alessio Amatu, William M. Grady, Andrea Sartore-Bianchi, Simonetta Guarrera, Giulia Siravegna, Sebastian Moran, Sara Bustreo, Federica Di Nicolantonio, Alberto Bardelli, Patrizia Racca, Carlotta Cancelliere, Patrizia Zavattari, Daniele Oddo, Agostino Ponzetti, Giuseppe Matullo, Katia Bencardino, Carmen Cristiano, Sean K. Maden, Chiara Falcomatà, and Ludovic Barault
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Male ,0301 basic medicine ,Oncology ,Colorectal cancer ,medicine.medical_treatment ,chemotherapy ,Bioinformatics ,Polymerase Chain Reaction ,Targeted therapy ,0302 clinical medicine ,tumour markers ,Digital polymerase chain reaction ,Longitudinal Studies ,Oligonucleotide Array Sequence Analysis ,education.field_of_study ,Gastroenterology ,Methylation ,Middle Aged ,3. Good health ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Drug Monitoring ,DNA microarray ,Colorectal Neoplasms ,Cell-Free Nucleic Acids ,Adult ,medicine.medical_specialty ,Population ,colorectal cancer ,Antineoplastic Agents ,Biology ,Article ,03 medical and health sciences ,Cell Line, Tumor ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Liquid biopsy ,methylation ,screening ,education ,Aged ,Chemotherapy ,DNA Methylation ,medicine.disease ,030104 developmental biology ,Mutation - Abstract
ObjectiveMutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC).DesignGenome-wide methylation microarrays of CRC cell lines (n=149) identified five cancer-specific methylated loci (EYA4, GRIA4, ITGA4, MAP3K14-AS1, MSC). Digital PCR assays were employed to measure methylation of these genes in tumour tissue DNA (n=82) and cfDNA from patients with mCRC (n=182). Plasma longitudinal assessment was performed in a patient subset treated with chemotherapy or targeted therapy.ResultsMethylation in at least one marker was detected in all tumour tissue samples and in 156 mCRC patient cfDNA samples (85.7%). Plasma marker prevalence was 71.4% for EYA4, 68.5% for GRIA4, 69.7% for ITGA4, 69.1% for MAP3K14-AS1% and 65.1% for MSC. Dynamics of methylation markers was not affected by treatment type and correlated with objective tumour response and progression-free survival.ConclusionThis five-gene methylation panel can be used to circumvent the absence of patient-specific mutations for monitoring tumour burden dynamics in liquid biopsy under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations.
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- 2017
37. Telomerase activity, telomere length andhTERTDNA methylation in peripheral blood mononuclear cells from monozygotic twins with discordant smoking habits
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Giuseppe Matullo, Emanuela Medda, Riccardo Crebelli, Simonetta Guarrera, Cristina Andreoli, Alessandra Allione, Francesca Marcon, Ester Siniscalchi, and Giovanni Fiorito
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0301 basic medicine ,medicine.medical_specialty ,Telomerase ,Epidemiology ,Health, Toxicology and Mutagenesis ,Methylation ,Biology ,medicine.disease ,Tobacco smoke ,Telomere ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,CpG site ,030220 oncology & carcinogenesis ,Internal medicine ,DNA methylation ,Immunology ,medicine ,Telomerase reverse transcriptase ,Lung cancer ,Genetics (clinical) - Abstract
Increased telomerase expression has been implicated in the pathogenesis of lung cancer and, since the primary cause of lung cancer is smoking, an association between telomerase reactivation and tobacco smoke has been proposed. In this work an investigation has been performed to assess the relationship between tobacco smoke exposure and telomerase activity (TA) in peripheral blood mononuclear cells of healthy smokers. The methylation status of the catalytic subunit of telomerase hTERT was concurrently investigated to assess the possible association between epigenetic modifications of hTERT and TA. Besides, the association between smoke and telomere length (TL) has been evaluated. Healthy monozygotic twins with discordant smoking habits were selected as study population to minimize inter-individual differences because of demographic characteristics and genetic heterogeneity. Statistically significant higher values of TA and TL were observed in smokers compared to nonsmoker co-twins. The multivariate analysis of data showed, besides smoking habits (P = 0.02), an influence of gender (P = 0.006) and BMI (P = 0.001) on TA and a borderline effect of gender (P = 0.05) on TL. DNA methylation analysis, focused on 100 CpG sites mapping in hTERT, highlighted nine CpG sites differentially methylated in smokers. When co-twins were contrasted, selecting as variables the intra-twin difference in TA and hTERT DNA methylation, a statistically significant inverse correlation (P = 0.003) was observed between TA and DNA methylation at the cg05521538 site. In conclusion, these results indicate an association of tobacco smoke with TA and TL and suggest a possible association between smoke-induced epigenetic effects and TA in healthy smokers. Environ. Mol. Mutagen. 58:551–559, 2017. © 2017 Wiley Periodicals, Inc.
- Published
- 2017
38. Plasma microRNAs as biomarkers of pancreatic cancer risk in a prospective cohort study
- Author
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Nicholas J. Wareham, Giovanna Tagliabue, Paul Brennan, Salvatore Panico, Miguel Rodríguez-Barranco, Giuseppe Matullo, Alessio Naccarati, Stuart Sherman, Line Moi, Paolo Vineis, María Dolores Chirlaque, Marc J. Gunter, Pagona Lagiou, Rudolf Kaaks, Antonia Trichopoulou, David C. Muller, Verena Katzke, Gianluca Severi, Eva Ardanaz, Ghislaine Scelo, Vinciane Rebours, Murray Korc, H. Bas Bueno-de-Mesquita, Lill-Tove Busund, Elisabete Weiderpass, Samantha Deitz McElyea, Eric J. Duell, Rosario Tumino, Petra H.M. Peeters, Greg Cote, Marie-Christine Boutron-Ruault, Anne Tjønneland, José Ramón Quirós, Anastasia Kotanidou, Núria Sala, Dagfinn Aune, Anja Olsen, Ruth C. Travis, Kim Overvad, Domenico Palli, Leila Lujan-Barroso, Kay-Tee Khaw, Miren Dorronsoro, and Heiner Boeing
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Receiver operating characteristic ,business.industry ,Case-control study ,Cancer ,medicine.disease ,Logistic regression ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Pancreatic cancer ,Internal medicine ,Cohort ,medicine ,business ,Prospective cohort study ,Cohort study - Abstract
Noninvasive biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis and disease risk stratification are greatly needed. We conducted a nested case-control study within the Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate prediagnostic microRNAs (miRs) as biomarkers of subsequent PDAC risk. A panel of eight miRs (miR-10a, -10b, -21-3p, -21-5p, -30c, -106b, -155 and -212) based on previous evidence from our group was evaluated in 225 microscopically confirmed PDAC cases and 225 controls matched on center, sex, fasting status and age/date/time of blood collection. MiR levels in prediagnostic plasma samples were determined by quantitative RT-PCR. Logistic regression was used to model levels and PDAC risk, adjusting for covariates and to estimate area under the receiver operating characteristic curves (AUC). Plasma miR-10b, -21-5p, -30c and -106b levels were significantly higher in cases diagnosed within 2 years of blood collection compared to matched controls (all p-values
- Published
- 2017
39. Improving the prediction of cardiovascular risk with machine-learning and DNA methylation data
- Author
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Simonetta Guarrera, Paolo Vineis, Carlotta Sacerdote, Giuseppe Matullo, Rosario Tumino, Giovanni Cugliari, Vittorio Krogh, Piero Fariselli, Silvia Benevenuta, and Salvatore Panico
- Subjects
0301 basic medicine ,Epigenetic biomarkers ,030109 nutrition & dietetics ,business.industry ,Computer science ,Machine learning ,computer.software_genre ,Random forest ,03 medical and health sciences ,030104 developmental biology ,DNA methylation ,Computational statistics ,Artificial intelligence ,business ,computer ,Reliability (statistics) - Abstract
Classically, the cardiovascular risk of individual is evaluated using phenomenological variables (PV)such as blood pressure, body mass, smoker status, gender, age etc. Here we show that, on prospective study (after 10–15 years)these PV display a poor agreement with case-control samples. We were able to obtain more accurate predictions using both DNA methylation data and PV as input features of a Random Forest model, achieving a ROC-AUC of 0.74. Furthermore, the Random Forest output correlates with the reliability of the predictions producing a ROC-AUC of 0.90 when only the most reliable predictions are taken into consideration.
- Published
- 2019
40. Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease A Longitudinal Study of 11 461 Participants From Population-Based Cohorts
- Author
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Symen Ligthart, Luigi Ferrucci, Rosario Tumino, Kerri L. Wiggins, Bruce M. Psaty, Dena G. Hernandez, Philip S. Tsao, Kelly M. Bakulski, Roby Joehanes, Tianxiao Huan, Steven Horvath, Luke C. Pilling, Eric Boerwinkle, Simone Wahl, Annette Peters, Vittorio Krogh, Devin Absher, Myriam Fornage, M. Daniele Fallin, Cavin K. Ward-Caviness, Elena Colicino, Nona Sotoodehnia, Michael M. Mendelson, Lifang Hou, Chunyu Liu, Pantel S. Vokonas, Carlotta Sacerdote, Abbas Dehghan, Andrew P. Feinberg, Jerome I. Rotter, Yun Li, Themistocles L. Assimes, Jennifer A. Brody, Rahul Gondalia, Andrea A. Baccarelli, Christian Gieger, Guosheng Zhang, Jan Bressler, Salvatore Panico, Stefania Bandinelli, Amy R. Vandiver, James S. Floyd, Michael L. Multhaup, Brian H. Chen, Elias Salfati, Giuseppe Matullo, James D. Stewart, Toshiko Tanaka, Joel Schwartz, Daniel Levy, Simonetta Guarrera, Allan C. Just, Andrew B. Singleton, Golareh Agha, Joel N. Hirschhorn, Eric A. Whitsel, Giovanni Fiorito, and Epidemiology
- Subjects
Regulation of gene expression ,0303 health sciences ,medicine.medical_specialty ,business.industry ,Genomics ,030204 cardiovascular system & hematology ,medicine.disease ,Coronary heart disease ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Coronary Artery Disease ,Coronary Heart Disease ,Epigenetics ,Gene Expression Regulation ,Physiology (medical) ,Internal medicine ,DNA methylation ,medicine ,Cardiology ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,030304 developmental biology - Abstract
Background: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. Methods: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. Results: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate Conclusion: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
- Published
- 2019
41. Genetics and Epigenetics of Mesothelioma
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Marika Sculco, Simonetta Guarrera, Corrado Magnani, Giuseppe Matullo, Elisabetta Casalone, Irma Dianzani, Laura Moro, and Anna Aspesi
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Genetics ,BAP1 ,Germline mutation ,DNA repair ,CDKN2A ,Point mutation ,medicine ,Mesothelioma ,Epigenetics ,Biology ,Carcinogenesis ,medicine.disease_cause ,medicine.disease - Abstract
The definition of the mesothelioma genome is expected to have a great impact toward the development of new drugs and therapeutic approaches with a view to precision medicine. A few studies reported that the malignant pleural mesothelioma (MPM) genomic landscape is characterized by a much greater number of genomic losses than point mutations. Inactivating gene fusions, copy losses, and protein-truncating variants (PTVs) mostly affect tumor suppressor genes, above all BAP1, NF2, CDKN2A, and SETD2. Some of them may be exploited to design novel therapeutic strategies. Germline mutations in some of these genes represent MPM-predisposing risk factors. These mutations require a second hit, i.e., asbestos exposure, to induce carcinogenesis. The most studied of these genes is BAP1. Germline mutations in other tumor suppressor genes, mostly involved in DNA repair, have also been identified in about 10% of MPM patients. These patients are more sensitive to asbestos exposure than those who do not carry such mutations and may benefit of specific treatments. Additionally, epigenetic mechanisms, such as methylation or miRNA alterations, may modify gene expression and drive carcinogenesis. The same abnormalities may be used as disease biomarkers or therapeutic targets.
- Published
- 2019
42. DNA Methylation of FKBP5 as Predictor of Overall Survival in Malignant Pleural Mesothelioma
- Author
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Roberta Libener, Chiara Catalano, Anna Aspesi, Federica Grosso, Dario Mirabelli, Irma Dianzani, Clara Viberti, Giuseppe Matullo, Alessia Russo, Marika Sculco, Corrado Magnani, Elisabetta Casalone, Alessandra Allione, Giovanni Cugliari, Chiara Pirazzini, Simonetta Guarrera, and Daniela Ferrante
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,lymphocyte-to-monocyte ratio ,medicine.disease_cause ,lcsh:RC254-282 ,Asbestos ,survival analysis ,asbestos exposure ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,malignant pleural mesothelioma ,Medicine ,Mesothelioma ,Epigenetics ,Survival analysis ,DNA methylation ,business.industry ,dNaM ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,030104 developmental biology ,epigenome-wide analysis ,030220 oncology & carcinogenesis ,Cohort ,FKBP5 ,business ,Asbestos exposure ,Epigenome-wide analysis ,Lymphocyte-to-monocyte ratio ,Malignant pleural mesothelioma - Abstract
Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 ×, 10&minus, 9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5&prime, UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm <, 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm &ge, 0.45 (mean: 243 versus 534 days, p value<, 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM.
- Published
- 2020
43. Plasma Riboflavin and Vitamin B-6, but Not Homocysteine, Folate, or Vitamin B-12, Are Inversely Associated with Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition-Varese Cohort
- Author
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Ilaria Cancarini, Giovanna Tagliabue, Giuseppe Matullo, Adalberto Cavalleri, Claudia Agnoli, Giulia Garrone, Alessandra Allione, Sara Grioni, Cornelia Di Gaetano, Sabina Sieri, Valeria Pala, Samuele Pedraglio, and Vittorio Krogh
- Subjects
Adult ,0301 basic medicine ,medicine.medical_specialty ,B vitamins ,Riboflavin ,Nutritional Status ,Medicine (miscellaneous) ,Breast Neoplasms ,Lower risk ,Gastroenterology ,Body Mass Index ,03 medical and health sciences ,breast cancer ,Folic Acid ,0302 clinical medicine ,Breast cancer ,nested case-control study ,Risk Factors ,Surveys and Questionnaires ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Homocysteine ,030109 nutrition & dietetics ,Nutrition and Dietetics ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Vitamin B 6 ,EPIC ,homocysteine ,European Prospective Investigation into Cancer and Nutrition ,Vitamin B 12 ,Logistic Models ,Italy ,Premenopause ,Case-Control Studies ,030220 oncology & carcinogenesis ,Nested case-control study ,Female ,Median body ,business - Abstract
BACKGROUND One-carbon metabolism-important for DNA stability and integrity-may play a role in breast carcinogenesis. However, epidemiologic studies addressing this issue have yielded inconsistent results. OBJECTIVE We prospectively investigated associations between breast cancer and plasma folate, riboflavin, vitamin B-6, vitamin B-12, and homocysteine in women recruited to the Varese (Italy) cohort of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. METHODS We performed a nested case-control study on women aged 35-65 y at recruitment with a median body mass index of 25.3 kg/m(2) who gave blood samples in 1987-1992 and again in 1993-1998. Breast cancer cases identified by 31 December 2009 were individually matched to controls. RRs of breast cancer (and subtypes defined by hormone receptor status) with 95% CIs were estimated by unconditional logistic regression, controlling for matching factors and breast cancer risk factors. RESULTS After a median of 14.9 y, 276 breast cancer cases were identified and matched to 276 controls. Increasing plasma vitamin B-6 was associated with decreased risk of overall (RR: 0.78; 95% CI: 0.63, 0.96 for 1-SD increase), premenopausal (RR: 0.66; 95% CI: 0.48, 0.92 for 1-SD increase), estrogen receptor-positive (RR: 0.79; 95% CI: 0.63, 1.00 for 1-SD increase), and progesterone receptor-positive (RR: 0.72; 95% CI: 0.55, 0.95 for 1-SD increase) breast cancers. Increased plasma vitamin B-6 was also associated with decreased breast cancer risk in alcohol consumers (≥7 g/d) compared with consumption of
- Published
- 2016
44. Association between Beta1-Adrenergic Receptor Polymorphism and Risk of ICD Shock in Heart Failure Patients
- Author
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Luisa Zanolla, Corrado Vassanelli, Giuseppe Matullo, Luca Tomasi, Simonetta Guarrera, Giovanni Fiorito, Roberto Zanini, Paola Guarise, and Nicola Cicorella
- Subjects
medicine.medical_specialty ,animal structures ,Ejection fraction ,Adrenergic receptor ,Proportional hazards model ,business.industry ,Hazard ratio ,General Medicine ,030204 cardiovascular system & hematology ,medicine.disease ,Sudden death ,Sudden cardiac death ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Heart failure ,medicine ,Cardiology ,030212 general & internal medicine ,Allele ,Cardiology and Cardiovascular Medicine ,business - Abstract
BACKGROUND Sympathetic activation in heart failure patients favors the development of ventricular arrhythmias, thus leading to an increased risk of sudden cardiac death. β1 - and β2 -adrenergic receptor polymorphisms have been linked to the risk of sudden death. Implantable cardioverter-defibrillators (ICD) are implanted in a large percentage of heart failure patients, and beyond preventing sudden cardiac death they provide a continuous monitoring of major ventricular arrhythmias and of their own interventions. We investigated whether functionally relevant β1 - and β2 -adrenergic receptor polymorphisms are associated with risk of ICD shocks, as evidenced in ICD memory. METHODS 311 patients with systolic heart failure were enrolled, and number and timing of shocks in ICD memory were recorded. Four selected polymorphisms were determined: β1 -adrenergic receptor polymorphisms Ser(49) Gly and Arg(389) Gly and β2 -adrenergic receptor polymorphisms Arg(16) Gly and Gln(27) Glu. RESULTS Only Ser(49) Gly was significantly correlated with time free from ICD shocks, both considering time to the first event in a Cox model (hazard ratio 2.117), and modeling repeated events with the Andersen-Gill method (hazard ratio 2.088). Gly allele carriers had a higher probability of ICD shock. The relationship remained significant even after adjusting for ejection fraction and beta-blocker dosage (hazard ratio 1.910). CONCLUSIONS Data from our study suggest that the β adrenoreceptor Gly 49 allele of the β1 -adrenergic receptor Ser(49) Gly polymorphisms may increase the risk of ICD shock in patients with heart failure, independent of beta-blocker dosage.
- Published
- 2016
45. Detection of multiple mutations in urinary exfoliated cells from male bladder cancer patients at diagnosis and during follow-up
- Author
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Paolo Vineis, Paolo Gontero, Irene Lurkin, Silvia Polidoro, Mirko Preto, Giuseppe Matullo, Francesca Fasanelli, Rossana Critelli, Giuseppina Cucchiarale, Ellen C. Zwarthoff, Marco Oderda, Manuela Bianca Assumma, Clara Viberti, Alessio Naccarati, Carlotta Sacerdote, and Pathology
- Subjects
0301 basic medicine ,Oncology ,Male ,Pathology ,DNA Mutational Analysis ,Disease ,GROWTH-FACTOR RECEPTOR-3 ,0302 clinical medicine ,Recurrence ,Epidemiology of cancer ,PATH ,FGFR3 MUTATION ,medicine.diagnostic_test ,VOIDED URINE ,Bladder cancer ,TERT ,Urine mutation analyses ,Middle Aged ,TERT PROMOTER MUTATIONS ,GRADE ,030220 oncology & carcinogenesis ,Area Under Curve ,SURVIVAL ,DISEASE RECURRENCE ,Life Sciences & Biomedicine ,Research Paper ,Adult ,medicine.medical_specialty ,Urinary system ,BIOMARKERS ,Sensitivity and Specificity ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Internal medicine ,SURVEILLANCE ,medicine ,Biomarkers, Tumor ,Humans ,Aged ,Carcinoma, Transitional Cell ,Science & Technology ,Cancer prevention ,business.industry ,Cell Biology ,Cystoscopy ,medicine.disease ,030104 developmental biology ,Genetic epidemiology ,ROC Curve ,Urinary Bladder Neoplasms ,Concomitant ,Mutation ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
// Rossana Critelli 1 , Francesca Fasanelli 2 , Marco Oderda 3 , Silvia Polidoro 1 , Manuela Bianca Assumma 1 , Clara Viberti 2, 4 , Mirko Preto 3 , Paolo Gontero 3 , Giuseppina Cucchiarale 5 , Irene Lurkin 6 , Ellen C. Zwarthoff 6 , Paolo Vineis 1, 7 , Carlotta Sacerdote 8 , Giuseppe Matullo 2, 4 , Alessio Naccarati 1 1 Molecular and Genetic Epidemiology Unit, Human Genetics Foundation, Turin, Italy 2 Department of Medical Sciences, University of Turin, Turin, Italy 3 Department of Surgical Sciences, Urology, University of Turin, Turin, Italy 4 Genomic Variation in Human Populations and Complex Diseases Unit, Human Genetics Foundation, Turin, Italy 5 Department of Urology, Humanitas Cellini, Turin, Italy 6 Department of Pathology, Erasmus MC, Rotterdam, The Netherlands 7 Department of Surgery and Cancer, Imperial College London, London, UK 8 Unit of Cancer Epidemiology, Centre for Cancer Prevention (CPO-Piemonte), Turin, Italy Correspondence to: Alessio Naccarati, email: alessio.naccarati@hugef-torino.org Keywords: bladder cancer, urine mutation analyses, TERT, recurrence Received: May 27, 2016 Accepted: August 25, 2016 Published: September 07, 2016 ABSTRACT Most bladder cancer (BC) patients need life-long, invasive and expensive monitoring and treatment, making it a serious burden on the health system. Thus, there is a pressing need for an accurate test to assist diagnosis and surveillance of BC as an alternative to cystoscopy. Mutations in human TERT , FGFR3 , PIK3CA, and RAS genes have been proposed as potential molecular markers in bladder tumor. Their concomitant presence in urine samples has not been fully explored. We investigated a panel of mutations in DNA from exfoliated urinary cells of 255 BC patients at diagnosis. Forty-one mutations in TERT, FGFR3, PIK3CA, and RAS were analyzed by SNaPshot assay in relation to clinical outcome. In 81 of these patients under surveillance, the same set of mutations was screened in additional 324 samples prospectively collected. The most common mutations detected in urine at diagnosis were in the TERT promoter. In non-invasive BC, these mutations were related to high risk and grade (p
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- 2016
46. H2AX phosphorylation level in peripheral blood mononuclear cells as an event-free survival predictor for bladder cancer
- Author
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Giovanni Casetta, Marco Oderda, Claudia Giachino, Alessia Russo, Simonetta Guarrera, Paolo Gontero, Paolo Destefanis, Giuseppina Cucchiarale, Maria Grazia Ruo Redda, Clara Viberti, Barbara Pardini, Giovanni Fiorito, Valentina Turinetto, Carlotta Sacerdote, Luigi Rolle, Alessandra Allione, Bruno Frea, Giuseppe Matullo, Paolo Vineis, and Silvia Maria Anglesio
- Subjects
0301 basic medicine ,Cancer Research ,Bladder cancer ,DNA repair ,Case-control study ,Disease ,Biology ,medicine.disease ,Peripheral blood mononuclear cell ,03 medical and health sciences ,Basal (phylogenetics) ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Immunology ,Genetic predisposition ,medicine ,Cancer research ,Molecular Biology ,Survival analysis - Abstract
Bladder cancer (BC) has a typical aetiology characterized by a multistep carcinogenesis due to environmental exposures, genetic susceptibility, and their interaction. Several lines of evidence suggest that DNA repair plays a role in the development and progression of BC. In particular, the study of individual susceptibility to DNA double strand breaks (DSBs) may provide valuable information on BC risk, and help to identify those patients at high-risk of either recurrence or progression of the disease, possibly personalizing both surveillance and treatment. Among the different DSB markers, the most well characterized is phosphorylation of the histone H2AX (γ-H2AX). We assessed any potential role of γ-H2AX as a molecular biomarker in a case-control study (146 cases and 146 controls) to identify individuals with increased BC risk and at high-risk of disease recurrence or progression. We investigated γ-H2AX levels in peripheral blood mononuclear cells before and after their exposure to ionizing radiation (IR). We did not find any significant difference among cases and controls. However, we observed a significant association between γ-H2AX basal levels and risk of disease recurrence or progression. In particular, both BC patients as a whole and the subgroup of non-muscle invasive BC (NMIBC) with high basal H2AX phosphorylation levels had a decreased risk of recurrence or progression (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), suggesting a protective effect of basal DSB signaling. Our data suggest that γ-H2AX can be considered as a potential molecular biomarker to identify patients with a higher risk of BC recurrence. © 2015 Wiley Periodicals, Inc.
- Published
- 2015
47. The Italian genome reflects the history of Europe and the Mediterranean basin
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Simonetta Guarrera, Marcus W. Feldman, Giovanni Fiorito, Alberto Piazza, Cornelia Di Gaetano, Giuseppe Matullo, and Fabio Rosa
- Subjects
0301 basic medicine ,Genetics (clinical) ,Genetics ,Human Migration ,Population ,Black People ,Mediterranean Basin ,White People ,Article ,Gene flow ,03 medical and health sciences ,Peninsula ,Humans ,Genetic variability ,education ,education.field_of_study ,geography.geographical_feature_category ,Middle East ,Genome, Human ,Mediterranean Region ,Human migration ,business.industry ,Genetic Variation ,030104 developmental biology ,Geography ,Italy ,Ethnology ,business ,History of Europe - Abstract
Recent scientific literature has highlighted the relevance of population genetic studies both for disease association mapping in admixed populations and for understanding the history of human migrations. Deeper insight into the history of the Italian population is critical for understanding the peopling of Europe. Because of its crucial position at the centre of the Mediterranean basin, the Italian peninsula has experienced a complex history of colonization and migration whose genetic signatures are still present in contemporary Italians. In this study, we investigated genomic variation in the Italian population using 2.5 million single-nucleotide polymorphisms in a sample of more than 300 unrelated Italian subjects with well-defined geographical origins. We combined several analytical approaches to interpret genome-wide data on 1272 individuals from European, Middle Eastern, and North African populations. We detected three major ancestral components contributing different proportions across the Italian peninsula, and signatures of continuous gene flow within Italy, which have produced remarkable genetic variability among contemporary Italians. In addition, we have extracted novel details about the Italian population's ancestry, identifying the genetic signatures of major historical events in Europe and the Mediterranean basin from the Neolithic (e.g., peopling of Sardinia) to recent times (e.g., ‘barbarian invasion' of Northern and Central Italy). These results are valuable for further genetic, epidemiological and forensic studies in Italy and in Europe.
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- 2015
48. MicroRNA expression profiling in bladder cancer: the challenge of next-generation sequencing in tissues and biofluids
- Author
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Barbara Pardini, Alessio Naccarati, and Giuseppe Matullo
- Subjects
0301 basic medicine ,Cancer Research ,Treatment response ,Bladder cancer ,Biology ,medicine.disease ,Bioinformatics ,Microvesicles ,DNA sequencing ,Transcriptome ,Gene expression profiling ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,microRNA ,medicine ,RNA extraction - Abstract
Bladder cancer (BC) is a heterogeneous disease characterized by a high recurrence rate that necessitates continuous cystoscopic surveillance. MicroRNAs (miRNAs) are detectable in tissues and biofluids such as plasma/serum and urine. They represent promising biomarkers with potential not only for detecting BC but also informing on prognosis and monitoring treatment response. In this review, the many aspects of the application of next-generation sequencing (NGS) to evaluate miRNA expression in BC is discussed, including technical issues as well as a comparison with results obtained by qRT-PCR. The available studies investigating miRNA profiling in BC by NGS are described, with particular attention to the potential applicability on biofluids. Altered miRNA levels have been observed in BC tissues by NGS, but these results so far only partially overlapped among studies and with previous data obtained by qRT-PCR. The discrepancies can be ascribed to the small groups of BC patients sequenced. The few available studies on biofluids are mainly focused on implementing RNA isolation and sequencing workflow. Using NGS to analyze miRNAs in biofluids can potentially provide results comparable to tissues with no invasive procedures for the patients. In particular, the analyses performed on exosomes/microvesicles appear to be more informative. Thanks to the improvement of both wet-lab procedures and pipelines/tools for data analyses, NGS studies on biofluids will be performed on a larger scale. MiRNAs detected in urine and serum/plasma will demonstrate their potentiality to describe the variegated scenario of BC and to become relevant clinical markers.
- Published
- 2015
49. Investigation of extended Y chromosome STR haplotypes in Sardinia
- Author
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Renato Robledo, Giuseppe Matullo, Alberto Piazza, Serena Aneli, Carla Maria Calò, Daniela Lacerenza, Claudia Culigioni, Rossana Critelli, C. Di Gaetano, and Carlo Robino
- Subjects
Male ,0301 basic medicine ,Italy ,Sardinia ,Y chromosome ,Y-SNP ,Y-STR ,2734 ,Genetics ,Population ,Single-nucleotide polymorphism ,Biology ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Analysis of molecular variance ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Humans ,030216 legal & forensic medicine ,education ,education.field_of_study ,Chromosomes, Human, Y ,Haplotype ,DNA Fingerprinting ,humanities ,Genetics, Population ,030104 developmental biology ,Haplotypes ,DNA profiling ,Microsatellite ,Microsatellite Repeats - Abstract
Y-chromosomal variation of selected single nucleotide polymorphisms (SNPs) and 32 short tandem repeat (STR) loci was evaluated in Sardinia in three open population groups (Northern Sardinia, n=40; Central Sardinia, n=56; Southern Sardinia, n=91) and three isolates (Desulo, n=34; Benetutti, n=45, Carloforte, n=42). The tested Y-STRs consisted of Yfiler® Plus markers and the seven rapidly mutating (RM) loci not included in the YFiler® Plus kit (DYF399S1, DYF403S1ab, DYF404S1, DYS526ab, DYS547, DYS612, and DYS626). As expected, inclusion of additional Y-STR loci increased haplotype diversity (h), though complete differentiation of male lineages was impossible even by means of RM Y-STRs (h=0.99997). Analysis of molecular variance indicated that the three open populations were fairly homogeneous, whereas signs of genetic heterogeneity could be detected when the three isolates were also included in the analysis. Multidimensional scaling analysis showed that, even for extended haplotypes including RM Y-STR markers, Sardinians were clearly differentiated from populations of the Italian peninsula and Sicily. The only exception was represented by the Carloforte sample that, in accordance with its peculiar population history, clustered with Northern/Central Italian populations. The introduction of extended forensic Y-STR panels, including highly variable RM Y-STR markers, is expected to reduce the impact of population structure on haplotype frequency estimations. However, our results show that the availability of geographically detailed reference databases is still important for the assessment of the evidential value of a Y-haplotype match.
- Published
- 2017
50. WITHDRAWN: Corrigendum to ‘Development of an Italian RM Y-STR haplotype database: results of the 2013 GEFI collaborative exercise’ [Forensic. Sci. Int. Genet. 15 (2015) 56-63]
- Author
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Marilidia Piglionica, Francesca Scarnicci, S Pasino, Carlo Previderè, Carlo Robino, Gregorio Seidita, M. De Marchi, A. Gonzalez, Andrea Piccinini, Solange Sorçaburu-Cigliero, Kaye N. Ballantyne, Carla Bini, A.L. Nutini, L. Casarino, Emiliano Giardina, Nicoletta Resta, Giuseppe Matullo, Manfred Kayser, Onofri, Stefania Turrina, Andrea Verzeletti, Gianmarco Ferri, Arwin Ralf, A. Barbaro, Eugenia Carnevali, Matteo Fabbri, C. Di Gaetano, and E. Ponzano
- Subjects
Genetics ,User group ,Haplotype ,Y-STR ,Biology ,Pathology and Forensic Medicine - Abstract
An inconsistency in the nomenclature used for the rapidly mutating (RM) Y-chromosomal short tandem repeat (Y-STR) marker DYS449 was noted in the above paper. In this paper, the DYS449 allele nomenclature introduced by Ballantyne et al. was used, instead of that described by Redd et al. and subsequently adopted by the International RM Y-STR User Group and in the AMPFlSTR® YFiler Plus kit.
- Published
- 2018
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