436 results on '"Benelli, Matteo"'
Search Results
152. Expanding the mutational spectrum of LZTR1 in schwannomatosis
- Author
-
Paganini, Irene, primary, Chang, Vivian Y, additional, Capone, Gabriele L, additional, Vitte, Jeremie, additional, Benelli, Matteo, additional, Barbetti, Lorenzo, additional, Sestini, Roberta, additional, Trevisson, Eva, additional, Hulsebos, Theo JM, additional, Giovannini, Marco, additional, Nelson, Stanley F, additional, and Papi, Laura, additional
- Published
- 2014
- Full Text
- View/download PDF
153. H 3 M 2 : detection of runs of homozygosity from whole-exome sequencing data
- Author
-
Magi, Alberto, primary, Tattini, Lorenzo, additional, Palombo, Flavia, additional, Benelli, Matteo, additional, Gialluisi, Alessandro, additional, Giusti, Betti, additional, Abbate, Rosanna, additional, Seri, Marco, additional, Gensini, Gian Franco, additional, Romeo, Giovanni, additional, and Pippucci, Tommaso, additional
- Published
- 2014
- Full Text
- View/download PDF
154. EXCAVATOR: detecting copy number variants from whole-exome sequencing data
- Author
-
Magi, Alberto, primary, Tattini, Lorenzo, additional, Cifola, Ingrid, additional, D’Aurizio, Romina, additional, Benelli, Matteo, additional, Mangano, Eleonora, additional, Battaglia, Cristina, additional, Bonora, Elena, additional, Kurg, Ants, additional, Seri, Marco, additional, Magini, Pamela, additional, Giusti, Betti, additional, Romeo, Giovanni, additional, Pippucci, Tommaso, additional, Bellis, Gianluca De, additional, Abbate, Rosanna, additional, and Gensini, Gian Franco, additional
- Published
- 2013
- Full Text
- View/download PDF
155. Large Scale Gene Expression Meta-Analysis Reveals Tissue-Specific, Sex-Biased Gene Expression in Humans.
- Author
-
Mayne, Benjamin T., Bianco-Miotto, Tina, Buckberry, Sam, Breen, James, Clifton, Vicki, Shoubridge, Cheryl, Roberts, Claire T., Russo, Francesco, and Benelli, Matteo
- Subjects
GENE expression ,SEX factors in disease ,HUMAN sex chromosomes - Abstract
The severity and prevalence of many diseases are known to differ between the sexes. Organ specific sex-biased gene expression may underpin these and other sexually dimorphic traits. To further our understanding of sex differences in transcriptional regulation, we performed meta-analyses of sex biased gene expression in multiple human tissues. We analyzed 22 publicly available human gene expression microarray data sets including over 2500 samples from 15 different tissues and 9 different organs. Briefly, by using an inverse-variance method we determined the effect size difference of gene expression between males and females. We found the greatest sex differences in gene expression in the brain, specifically in the anterior cingulate cortex, (1818 genes), followed by the heart (375 genes), kidney (224 genes), colon (218 genes), and thyroid (163 genes). More interestingly, we found different parts of the brain with varying numbers and identity of sex-biased genes, indicating that specific cortical regions may influence sexually dimorphic traits. The majority of sex-biased genes in other tissues such as the bladder, liver, lungs, and pancreas were on the sex chromosomes or involved in sex hormone production. On average in each tissue, 32% of autosomal genes that were expressed in a sex-biased fashion contained androgen or estrogen hormone response elements. Interestingly, across all tissues, we found approximately two-thirds of autosomal genes that were sex-biased were not under direct influence of sex hormones. To our knowledge this is the largest analysis of sex-biased gene expression in human tissues to date. We identified many sex-biased genes that were not under the direct influence of sex chromosome genes or sex hormones. These may provide targets for future development of sex-specific treatments for diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
156. A systematic analysis of bone marrow cells by flow cytometry defines a specific phenotypic profile beyond GPI deficiency in paroxysmal nocturnal hemoglobinuria
- Author
-
Mannelli, Francesco, primary, Bencini, Sara, additional, Peruzzi, Benedetta, additional, Cutini, Ilaria, additional, Sanna, Alessandro, additional, Benelli, Matteo, additional, Magi, Alberto, additional, Gianfaldoni, Giacomo, additional, Rotunno, Giada, additional, Carrai, Valentina, additional, Gelli, Anna Maria Grazia, additional, Valle, Veronica, additional, Santini, Valeria, additional, Notaro, Rosario, additional, Luzzatto, Lucio, additional, and Bosi, Alberto, additional
- Published
- 2012
- Full Text
- View/download PDF
157. WNP: A Novel Algorithm for Gene Products Annotation from Weighted Functional Networks
- Author
-
Magi, Alberto, primary, Tattini, Lorenzo, additional, Benelli, Matteo, additional, Giusti, Betti, additional, Abbate, Rosanna, additional, and Ruffo, Stefano, additional
- Published
- 2012
- Full Text
- View/download PDF
158. A novel founder MYO15Aframeshift duplication is the major cause of genetic hearing loss in Oman
- Author
-
Palombo, Flavia, Al-Wardy, Nadia, Ruscone, Guido Alberto Gnecchi, Oppo, Manuela, Kindi, Mohammed Nasser Al, Angius, Andrea, Al Lamki, Khalsa, Girotto, Giorgia, Giangregorio, Tania, Benelli, Matteo, Magi, Alberto, Seri, Marco, Gasparini, Paolo, Cucca, Francesco, Sazzini, Marco, Al Khabori, Mazin, Pippucci, Tommaso, and Romeo, Giovanni
- Abstract
The increased risk for autosomal recessive disorders is one of the most well-known medical implications of consanguinity. In the Sultanate of Oman, a country characterized by one of the highest rates of consanguineous marriages worldwide, prevalence of genetic hearing loss (GHL) is estimated to be 6/10 000. Families of GHL patients have higher consanguinity rates than the general Omani population, indicating a major role for recessive forms. Mutations in GJB2, the most commonly mutated GHL gene, have been sporadically described. We collected 97 DNA samples of GHL probands, affected/unaffected siblings and parents from 26 Omani consanguineous families. Analyzing a first family by whole-exome sequencing, we identified a novel homozygous frameshift duplication (c.1171_1177dupGCCATCT) in MYO15A, the gene linked to the deafness locus DFNB3. This duplication was then found in a total of 8/26 (28%) families, within a 849 kb founder haplotype. Reconstruction of haplotype structure at MYO15Asurrounding genomic regions indicated that the founder haplotype branched out in the past two to three centuries from a haplotype present worldwide. The MYO15Aduplication emerges as the major cause of GHL in Oman. These findings have major implications for the design of GHL diagnosis and prevention policies in Oman.
- Published
- 2017
- Full Text
- View/download PDF
159. A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK- and PI3K-induced malignant growth
- Author
-
Mayrhofer, Marie, Gourain, Victor, Reischl, Markus, Affaticati, Pierre, Jenett, Arnim, Joly, Jean-Stephane, Benelli, Matteo, Demichelis, Francesca, Poliani, Pietro Luigi, Sieger, Dirk, and Mione, Marina
- Abstract
Somatic mutations activating MAPK and PI3K signalling play a pivotal role in both tumours and brain developmental disorders. We developed a zebrafish model of brain tumours based on somatic expression of oncogenes that activate MAPK and PI3K signalling in neural progenitor cells and found that HRASV12 was the most effective in inducing both heterotopia and invasive tumours. Tumours, but not heterotopias, require persistent activation of phospho (p)-ERK and express a gene signature similar to the mesenchymal glioblastoma subtype, with a strong YAP component. Application of an eight-gene signature to human brain tumours establishes that YAP activation distinguishes between mesenchymal glioblastoma and low grade glioma in a wide The Cancer Genome Atlas (TCGA) sample set including gliomas and glioblastomas (GBMs). This suggests that the activation of YAP might be an important event in brain tumour development, promoting malignant versus benign brain lesions. Indeed, co-expression of dominant-active YAP (YAPS5A) and HRASV12 abolishes the development of heterotopias and leads to the sole development of aggressive tumours. Thus, we have developed a model proving that neurodevelopmental disorders and brain tumours might originate from the same activation of oncogenes through somatic mutations, and established that YAP activation is a hallmark of malignant brain tumours.
- Published
- 2017
- Full Text
- View/download PDF
160. Read count approach for DNA copy number variants detection
- Author
-
Magi, Alberto, primary, Tattini, Lorenzo, additional, Pippucci, Tommaso, additional, Torricelli, Francesca, additional, and Benelli, Matteo, additional
- Published
- 2011
- Full Text
- View/download PDF
161. Sphingosine 1-Phosphate Induces Differentiation of Mesoangioblasts towards Smooth Muscle. A Role for GATA6
- Author
-
Donati, Chiara, primary, Marseglia, Giuseppina, additional, Magi, Alberto, additional, Serratì, Simona, additional, Cencetti, Francesca, additional, Bernacchioni, Caterina, additional, Nannetti, Genni, additional, Benelli, Matteo, additional, Brunelli, Silvia, additional, Torricelli, Francesca, additional, Cossu, Giulio, additional, and Bruni, Paola, additional
- Published
- 2011
- Full Text
- View/download PDF
162. Bioinformatics for Next Generation Sequencing Data
- Author
-
Magi, Alberto, primary, Benelli, Matteo, additional, Gozzini, Alessia, additional, Girolami, Francesca, additional, Torricelli, Francesca, additional, and Brandi, Maria Luisa, additional
- Published
- 2010
- Full Text
- View/download PDF
163. Expanding the mutational spectrum of LZTR1 in schwannomatosis.
- Author
-
Paganini, Irene, Chang, Vivian Y, Capone, Gabriele L, Vitte, Jeremie, Benelli, Matteo, Barbetti, Lorenzo, Sestini, Roberta, Trevisson, Eva, Hulsebos, Theo JM, Giovannini, Marco, Nelson, Stanley F, and Papi, Laura
- Subjects
SCHWANNOMAS ,NUCLEOTIDE sequencing ,GERM cells ,IMMUNOSTAINING ,PROTEIN expression - Abstract
Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
164. Immunotherapy Bridge 2016 and Melanoma Bridge 2016: meeting abstracts
- Author
-
Hirsh, Vera, Pignata, Sandro, Bersanelli, Melissa, Gnetti, Letizia, Azzoni, Cinzia, Bottarelli, Lorena, Gasparro, Donatello, Leonardi, Francesco, Silini, Enrico Maria, Buti, Sebastiano, Wennerberg, Erik, Mediero, Aranzazu, Cronstein, Bruce, Formenti, Silvia, Demaria, Sandra, Vanpouille-Box, Claire, Pilones, Karsten, Rudqvist, Nils, Diamond, Julie, Morris, Zachary S., Guy, Emily I., Francis, David M., Gressett, Monica M., Armstrong, Eric A., Huang, Shyhmin, Gilles, Stephen D., Korman, Alan J., Hank, Jacquelyn A., Hoefges, Anna, Rakhmilevich, Alexander L., Harari, Paul M., Sondel, Paul M., Hailemichael, Yared, Overwijk, Willem W., Straten, Per thor, Lugli, Alessandro, Dawson, Heather, Blank, Annika, Zlobec, Inti, Fattore, Luigi, Costantini, Susan, Acunzo, Mario, Romano, Giulia, Nigita, Giovanni, Laganà, Alessandro, Malpicci, Debora, Ruggiero, Ciro Francesco, Pisanu, Maria Elena, Noto, Alessia, De Vitis, Claudia, Croce, Carlo Maria, Ascierto, Paolo Antonio, Mancini, Rita, Ciliberto, Gennaro, Postow, Michael, Luke, Jason, Stroncek, David, Castiello, Luciano, Chen, Wenjing, Jin, Ping, Ren, Jiaqiang, Sabatino, Marianna, Ferrone, Soldano, Duong, Connie PM, Vetizou, Marie, Zitvogel, Laurence, Occelli, Marcella, Cauchi, Carolina, Sciancalepore, Grazia, Lo Nigro, Cristiana, Rovera, Michela, Varamo, Chiara, Vivenza, Daniela, Seia, Zelda, Palazzini, Stefania, Errico, Fabiana, Basso, Davide, Quaranta, Laura, Forte, Giuseppe, Lavagna, Fulvio, Violante, Silvia, Bosio, Paolo, Lattanzio, Laura, Merlano, Marco Carlo, Moogk, Duane, Zhong, Shi, Yu, Zhiya, Liadi, Ivan, Rittase, William, Fang, Victoria, Dougherty, Janna, Perez-Garcia, Arianne, Osman, Iman, Zhu, Cheng, Varadarajan, Navin, Restifo, Nicholas P., Frey, Alan, Krogsgaard, Michelle, Balatoni, Timea, Moho, Anita, Sebestyén, Timea, Varga, Anita, Oláh, Judit, Lengyel, Zsuzsanna, Emri, Gabriella, Liszkay, Gabriella, Ladányi, Andrea, Polini, Beatrice, Fogli, Stefano, Carpi, Sara, Pardini, Barbara, Naccarati, Alessio, Dubbini, Nevio, Breschi, Maria Cristina, Romanini, Antonella, Nieri, Paola, Morgese, Francesca, Soldato, Davide, Pagliaretta, Silvia, Giampieri, Riccardo, Brancorsini, Donatella, Rinaldi, Silvia, Torniai, Mariangela, Campanati, Anna, Ganzetti, Giulia, Offidani, Annamaria, Giacchetti, Alfredo, Ricotti, Giuseppe, Savini, Agnese, Onofri, Azzurra, Bianchi, Francesca, Berardi, Rossana, Galdo, Giovanna, Orlandino, Gianfranco, Serio, Salvatore, Massariello, Domenico, Fabrizio, Tommaso, Montagnani, Valentina, Benelli, Matteo, Apollo, Alessandro, Pescucci, Chiara, Licastro, Danilo, Urso, Carmelo, Gerlini, Gianni, Borgognoni, Lorenzo, Luzzatto, Lucio, Stecca, Barbara, Gambale, Elisabetta, Tinari, Camilla, Quinzii, Alberto, Cortellini, Alessio, Carella, Consiglia, De Tursi, Michele, De Francesco, Adele Emanuela, De Fina, Mariarosanna, Zito, Maria Cristina, Bisceglia, Maria Dezia, Esposito, Stefania, Fersini, Giuseppina, Morello, Silvana, Sorrentino, Claudia, Pinto, Aldo, Di Sarno, Antonella, Bianco, Antonella, D’Aniello, Carmine, Andreozzi, Francesca, Festina, Lucia, Vanella, Vito, Montesarchio, Vincenzo, Kotlan, Beatrix, Godeny, Maria, Emil, Farkas, Toth, Laszlo, Horvath, Szabolcs, Eles, Klara, Savolt, Akos, Szollar, Andras, Kasler, Miklós, Yiu, Daniel, Grizzi, Fabio, Patrinicola, Federica, Chiriva-Internati, Maurizio, Motta, Stefania, Monti, Marcello, Benini, Lavinia, Ugel, Stefano, Cingarlini, Sara, Fiore, Alessandra, Grego, Elisabetta, Tortora, Giampaolo, Bronte, Vincenzo, Tondulli, Luca, Di Monta, Gianluca, Caracò, Corrado, Marone, Ugo, Festino, Lucia, and Mozzillo, Nicola
- Published
- 2017
- Full Text
- View/download PDF
165. Risk assessment of disease recurrence in early breast cancer: A serum metabolomic study focused on elderly patients
- Author
-
Risi, Emanuela, Lisanti, Camilla, Vignoli, Alessia, Biagioni, Chiara, Paderi, Agnese, Cappadona, Silvia, Monte, Francesca Del, Moretti, Erica, Sanna, Giuseppina, Livraghi, Luca, Malorni, Luca, Benelli, Matteo, Puglisi, Fabio, Luchinat, Claudio, Tenori, Leonardo, and Biganzoli, Laura
- Abstract
•We reported the results of a retrospective study performed on elderly breast cancer patients enrolled in 3 onco-geriatric trials coordinated by the medical oncology division of the Hospital of Prato. This analysis suggests that a metabolomic signature, identified employing NMR spectral profiling, is able to predict the risk of disease recurrence in elderly patients with early breast cancer, independently from classical clinicopathological features. The metabolomic signature is a prognostic marker that takes into account not only the tumor but also the host. This is particularly relevant in the elderly, due to the heterogeneity of this population, and particularly in older patients with early breast cancer in whom other causes of death can compete with breast cancer in determining patients’ outcome.
- Published
- 2023
- Full Text
- View/download PDF
166. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer
- Author
-
Beltran, Himisha, Prandi, Davide, Mosquera, Juan Miguel, Benelli, Matteo, Puca, Loredana, Cyrta, Joanna, Marotz, Clarisse, Giannopoulou, Eugenia, Chakravarthi, Balabhadrapatruni V S K, Varambally, Sooryanarayana, Tomlins, Scott A, Nanus, David M, Tagawa, Scott T, Van Allen, Eliezer M, Elemento, Olivier, Sboner, Andrea, Garraway, Levi A, Rubin, Mark A, and Demichelis, Francesca
- Abstract
An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, in which tumor cells demonstrate low to absent AR expression and often have neuroendocrine features. The etiology and molecular basis for this 'alternative' treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.
- Published
- 2016
- Full Text
- View/download PDF
167. A systematic analysis of bone marrow cells by flow cytometry defines a specific phenotypic profile beyond GPI deficiency in paroxysmal nocturnal hemoglobinuria.
- Author
-
Mannelli, Francesco, Bencini, Sara, Peruzzi, Benedetta, Cutini, Ilaria, Sanna, Alessandro, Benelli, Matteo, Magi, Alberto, Gianfaldoni, Giacomo, Rotunno, Giada, Carrai, Valentina, Gelli, Anna Maria Grazia, Valle, Veronica, Santini, Valeria, Notaro, Rosario, Luzzatto, Lucio, and Bosi, Alberto
- Published
- 2013
- Full Text
- View/download PDF
168. Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity.
- Author
-
Cyrta, Joanna, Augspach, Anke, De Filippo, Maria Rosaria, Prandi, Davide, Thienger, Phillip, Benelli, Matteo, Cooley, Victoria, Bareja, Rohan, Wilkes, David, Chae, Sung-Suk, Cavaliere, Paola, Dephoure, Noah, Uldry, Anne-Christine, Lagache, Sophie Braga, Roma, Luca, Cohen, Sandra, Jaquet, Muriel, Brandt, Laura P., Alshalalfa, Mohammed, and Puca, Loredana
- Subjects
PROSTATE cancer ,CHROMATIN-remodeling complexes ,NURSING care facilities ,NEUROENDOCRINE cells ,CELL lines - Abstract
Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10–20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors. The differentiation of prostate adenocarcinoma to neuroendocrine prostate cancer (CRPC-NE) is a mechanism of resistance to androgen deprivation therapy. Here the authors show that SWI/SNF chromatin-remodeling complex is deregulated in CRPC-NE and that the complex interacts with different lineage specific factors throughout prostate cancer transdifferentiation. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
169. Clinical outcomes after palbociclib with or without endocrine therapy in postmenopausal women with hormone receptor positive and HER2-negative metastatic breast cancer enrolled in the TREnd trial.
- Author
-
Rossi, Lorenzo, Biagioni, Chiara, McCartney, Amelia, Migliaccio, Ilenia, Curigliano, Giuseppe, Sanna, Giuseppina, Moretti, Erica, Minisini, Alessandro M., Cinieri, Saverio, Tondini, Carlo, Arpino, Grazia, Bernardo, Antonio, Martignetti, Angelo, Risi, Emanuela, Pestrin, Marta, Boni, Luca, Benelli, Matteo, Biganzoli, Laura, Di Leo, Angelo, and Malorni, Luca
- Subjects
METASTATIC breast cancer ,HORMONE therapy ,HORMONE receptors ,THERAPEUTICS - Abstract
Currently, there is limited data regarding the effectiveness of standard subsequent line therapies such as endocrine therapy, chemotherapy, or targeted agents after progression on CDK4/6 inhibitor-based regimens. This paper describes time-to-treatment failure beyond progression on palbociclib or palbociclib+endocrine therapy in patients enrolled in the phase II, multicenter TREnd trial. Our results indicate that there is limited benefit from post-palbociclib treatment, regardless of the type of therapy received. A small population of long responders were identified who demonstrated ongoing benefit from a subsequent line of endocrine therapy after progression to palbociclib-based regimens. A translational research program is ongoing on this population of outliers. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
170. LEADeR role of miR-205 host gene as long noncoding RNA in prostate basal cell differentiation.
- Author
-
Profumo, Valentina, Forte, Barbara, Percio, Stefano, Rotundo, Federica, Doldi, Valentina, Ferrari, Elena, Fenderico, Nicola, Dugo, Matteo, Romagnoli, Dario, Benelli, Matteo, Valdagni, Riccardo, Dolfini, Diletta, Zaffaroni, Nadia, and Gandellini, Paolo
- Abstract
Though miR-205 function has been largely characterized, the nature of its host gene, MIR205HG, is still completely unknown. Here, we show that only lowly expressed alternatively spliced MIR205HG transcripts act as de facto pri-miRNAs, through a process that involves Drosha to prevent unfavorable splicing and directly mediate miR-205 excision. Notably, MIR205HG-specific processed transcripts revealed to be functional per se as nuclear long noncoding RNA capable of regulating differentiation of human prostate basal cells through control of the interferon pathway. At molecular level, MIR205HG directly binds the promoters of its target genes, which have an Alu element in proximity of the Interferon-Regulatory Factor (IRF) binding site, and represses their transcription likely buffering IRF1 activity, with the ultimate effect of preventing luminal differentiation. As MIR205HG functions autonomously from (albeit complementing) miR-205 in preserving the basal identity of prostate epithelial cells, it warrants reannotation as LEADeR (Long Epithelial Alu-interacting Differentiation-related RNA). miR-205 is known to have context-dependent tumor suppressive or oncogenic roles. Here, the authors report the host gene of miR-205, MIR205HG as a nuclear lincRNA that maintains the basal identity of prostate cell and prevents luminal cell differentiation via the repression of interferon responsive genes. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
171. Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer.
- Author
-
Guarducci, Cristina, Bonechi, Martina, Benelli, Matteo, Biagioni, Chiara, Boccalini, Giulia, Romagnoli, Dario, Verardo, Roberto, Schiff, Rachel, Osborne, C. Kent, De Angelis, Carmine, Di Leo, Angelo, Malorni, Luca, and Migliaccio, Ilenia
- Published
- 2018
- Full Text
- View/download PDF
172. Genomic correlates of clinical outcome in advanced prostate cancer
- Author
-
Abida, Wassim, Cyrta, Joanna, Heller, Glenn, Prandi, Davide, Armenia, Joshua, Coleman, Ilsa, Cieslik, Marcin, Benelli, Matteo, Robinson, Dan, Van Allen, Eliezer M, Sboner, Andrea, Fedrizzi, Tarcisio, Mosquera, Juan Miguel, Robinson, Brian D, De Sarkar, Navonil, Kunju, Lakshmi P, Tomlins, Scott, Wu, Yi Mi, Nava Rodrigues, Daniel, Loda, Massimo, Gopalan, Anuradha, Reuter, Victor E, Pritchard, Colin C, Mateo, Joaquin, Bianchini, Diletta, Miranda, Susana, Carreira, Suzanne, Rescigno, Pasquale, Filipenko, Julie, Vinson, Jacob, Montgomery, Robert B, Beltran, Himisha, Heath, Elisabeth I, Scher, Howard I, Kantoff, Philip W, Taplin, Mary-Ellen, Schultz, Nikolaus, DeBono, Johann S, Demichelis, Francesca, Nelson, Peter S, Rubin, Mark A., Chinnaiyan, Arul M, and Sawyers, Charles L
- Subjects
610 Medicine & health ,3. Good health - Abstract
Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associated with shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations.
173. Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity
- Author
-
Cyrta, Joanna, Augspach, Anke, De Filippo, Maria Rosaria, Prandi, Davide, Thienger, Phillip, Benelli, Matteo, Cooley, Victoria, Bareja, Rohan, Wilkes, David, Chae, Sung-Suk, Cavaliere, Paola, Dephoure, Noah, Uldry, Anne-Christine, Braga Lagache, Sophie, Roma, Luca, Cohen, Sandra, Jaquet, Muriel, Brandt, Laura P., Alshalalfa, Mohammed, Puca, Loredana, Sboner, Andrea, Feng, Felix, Wang, Shangqian, Beltran, Himisha, Lotan, Tamara, Spahn, Martin, Kruithof-De Julio, Marianna, Chen, Yu, Ballman, Karla V, Demichelis, Francesca, Piscuoglio, Salvatore, and Rubin, Mark A.
- Subjects
enzymes and coenzymes (carbohydrates) ,cells ,genetic processes ,macromolecular substances ,biological phenomena, cell phenomena, and immunity ,610 Medicine & health ,3. Good health - Abstract
Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10-20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors.
174. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer
- Author
-
Mu, Ping, Zhang, Zeda, Benelli, Matteo, Karthaus, Wouter R, Hoover, Elizabeth, Chen, Chi-Chao, Wongvipat, John, Ku, Sheng-Yu, Gao, Dong, Cao, Zhen, Shah, Neel, Adams, Elizabeth J, Abida, Wassim, Watson, Philip A, Prandi, Davide, Huang, Chun-Hao, De Stanchina, Elisa, Lowe, Scott W, Ellis, Leigh, Beltran, Himisha, Rubin, Mark Andrew, Goodrich, David W, Demichelis, Francesca, and Sawyers, Charles L
- Subjects
570 Life sciences ,biology ,500 Science ,3. Good health - Abstract
Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)-dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.
175. Mutational Analysis of Circulating Tumor DNA in Patients With Estrogen Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer Receiving Palbociclib: Results From the TREnd Trial.
- Author
-
Migliaccio, Ilenia, Romagnoli, Dario, Galardi, Francesca, De Luca, Francesca, Biagioni, Chiara, Curigliano, Giuseppe, Criscitiello, Carmen, Minisini, Alessandro Marco, Moretti, Erica, Risi, Emanuela, Guarducci, Cristina, Nardone, Agostina, Biganzoli, Laura, Benelli, Matteo, and Malorni, Luca
- Subjects
- *
EPIDERMAL growth factor receptors , *CIRCULATING tumor DNA , *SOMATIC mutation , *HORMONE receptor positive breast cancer , *BREAST cancer - Abstract
PURPOSE: To identify prognostic circulating biomarkers to cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), we performed a mutational analysis on circulating tumor DNA (ctDNA) samples from patients included in the TREnd trial, which randomly assigned patients to receive the CDK4/6i palbociclib alone or with the endocrine treatment (ET) to which they had progressed. METHODS: Forty-six patients were enrolled in this substudy. Plasma was collected before treatment (T0), after the first cycle of therapy (T1), and at the time of progression (T2). ctDNA hybridization and capture were performed using the Illumina TruSight Tumor 170 Kit. Acquired mutations were confirmed by digital polymerase chain reaction. Progression-free survival analysis was estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: The most frequently mutated genes at T0 were ESR1 (23%), PIK3CA (17%), AR , FGFR2, and TP53 (10%). Mutations in ESR1 at T0 conferred higher risk of progression in the entire population (P =.02) and in patients treated with palbociclib + ET (P =.04). ESR1 mutation effect remained significant after correction for clinical variables (P =.03). PIK3CA mutations at T0 were not prognostic, but higher risk of progression was observed when a broader analysis of PI3K pathway was performed (P =.04). At T2, we observed the emergence of nine new mutations in seven genes. CONCLUSION: Mutations in ESR1 and in PI3K pathway genes at T0 were associated with worse prognosis in palbociclib-treated patients. We describe the emergence of newly acquired mutations in palbociclib-treated patients, which might potentially affect subsequent treatment. ctDNA analysis of palbociclib-treated patients revealed an independent prognostic role of ESR1 mutations. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
176. Serum thymidine kinase activity in patients with HR-positive/HER2-negative advanced breast cancer treated with ribociclib plus letrozole: Results from the prospective BioItaLEE trial.
- Author
-
Malorni, Luca, Bianchini, Giampaolo, Caputo, Roberta, Zambelli, Alberto, Puglisi, Fabio, Bianchi, Giulia V., Del Mastro, Lucia, Paris, Ida, Montemurro, Filippo, Allegrini, Giacomo, Colleoni, Marco, Tamberi, Stefano, Zamagni, Claudio, Cazzaniga, Marina E., Orditura, Michele, Guarneri, Valentina, Castelletti, Daniela, Benelli, Matteo, Di Marino, Mariacristina, and Arpino, Grazia
- Subjects
- *
LETROZOLE , *CONFIDENCE intervals , *ANTINEOPLASTIC agents , *TRANSFERASES , *CELL proliferation , *POSTMENOPAUSE , *DESCRIPTIVE statistics , *TUMOR markers , *PROGRESSION-free survival , *BREAST tumors , *HORMONE receptor positive breast cancer , *PROPORTIONAL hazards models , *LONGITUDINAL method ,BODY fluid examination - Abstract
Thymidine kinase 1 (TK1) is an enzyme downstream of the CDK4/6 pathway, with a critical role in DNA synthesis; serum TK1 activity (sTKa) is a novel liquid biopsy biomarker of tumour cell proliferation. The phase IIIb, BioItaLEE trial (NCT03439046) collected sera from postmenopausal patients with hormone receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC) treated with first-line ribociclib plus letrozole at baseline, day 15 of cycle 1 (C1D15), day 1 of cycle 2 (C2D1), and at first imaging. Associations between sTKa assessed at different time points or sTKa dynamic patterns, and progression-free survival (PFS) were evaluated using multivariate Cox models. Overall, 287 patients were enroled. Median follow-up was 26.9 months. High sTKa (>median) at baseline was associated with higher risk of progression (hazard ratio [HR], 2.21; 95% confidence interval [95% CI], 1.45, 3.37; P = 0.0002); similar results were observed for patients with high sTKa levels at C1D15 and C2D1. Early sTKa dynamic patterns were strongly predictive of PFS. The pattern with high sTKa levels at C2D1 following initial decrease at C1D15 was associated with higher risk of progression versus the pattern with low sTKa levels at both time points (HR, 2.89; 95% CI, 1.57, 5.31; P = 0.0006), while the pattern with high sTKa levels at C1D15 was associated with the shortest PFS (HR, 5.65; CI: 2.84, 11.2; P < 0.0001). Baseline and dynamic sTKa changes provided independent information. sTKa appears to be a new promising prognostic and pharmacodynamic biomarker in patients with HR+/HER2– ABC treated with ribociclib plus letrozole as first-line therapy. • sTKa is a biomarker of outcome in ribociclib plus letrozole-treated HR+, HER2– ABC. • sTKa levels are strongly prognostic of mPFS at different time points. • sTKa early dynamic changes predict mPFS independently of prognosis by baseline sTKa. • sTKa early dynamic changes may be associated with inherent underlying tumour biology. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
177. MIMESIS: minimal DNA-methylation signatures to quantify and classify tumor signals in tissue and cell-free DNA samples.
- Author
-
Romagnoli, Dario, Nardone, Agostina, Galardi, Francesca, Paoli, Marta, Luca, Francesca De, Biagioni, Chiara, Franceschini, Gian Marco, Pestrin, Marta, Sanna, Giuseppina, Moretti, Erica, Demichelis, Francesca, Migliaccio, Ilenia, Biganzoli, Laura, Malorni, Luca, and Benelli, Matteo
- Subjects
- *
CELL-free DNA , *CIRCULATING tumor DNA , *METASTATIC breast cancer , *MIMESIS , *TUMOR classification , *SIGNAL detection , *DNA - Abstract
DNA-methylation alterations are common in cancer and display unique characteristics that make them ideal markers for tumor quantification and classification. Here we present MIMESIS, a computational framework exploiting minimal DNA-methylation signatures composed by a few dozen informative DNA-methylation sites to quantify and classify tumor signals in tissue and cell-free DNA samples. Extensive analyses of multiple independent and heterogenous datasets including >7200 samples demonstrate the capability of MIMESIS to provide precise estimations of tumor content and to enable accurate classification of tumor type and molecular subtype. To assess our framework for clinical applications, we designed a MIMESIS-informed assay incorporating the minimal signatures for breast cancer. Using both artificial samples and clinical serial cell-free DNA samples from patients with metastatic breast cancer, we show that our approach provides accurate estimations of tumor content, sensitive detection of tumor signal and the ability to capture clinically relevant molecular subtype in patients' circulation. This study provides evidence that our extremely parsimonious approach can be used to develop cost-effective and highly scalable DNA-methylation assays that could support and facilitate the implementation of precision oncology in clinical practice. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
178. Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer.
- Author
-
Beltran, Himisha, Romanel, Alessandro, Conteduca, Vincenza, Casiraghi, Nicola, Sigouros, Michael, Franceschini, Gian Marco, Orlando, Francesco, Fedrizzi, Tarcisio, Sheng-Yu Ku, Dann, Emma, Alonso, Alicia, Miguel Mosquera, Juan, Sboner, Andrea, Jenny Xiang, Elemento, Olivier, Nanus, David M., Tagawa, Scott T., Benelli, Matteo, Demichelis, Francesca, and Ku, Sheng-Yu
- Subjects
- *
PROTEINS , *ADENOCARCINOMA , *RESEARCH , *RESEARCH methodology , *EVALUATION research , *MEDICAL cooperation , *DNA methylation , *COMPARATIVE studies , *NEUROENDOCRINE tumors , *GENES , *GENE expression profiling , *RESEARCH funding , *PROSTATE tumors , *LONGITUDINAL method - Abstract
Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%-20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and sometimes challenging to diagnose due to morphologic heterogeneity. By studying whole-exome sequencing and whole-genome bisulfite sequencing of cell free DNA (cfDNA) and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-NE, we identified CRPC-NE features detectable in the circulation. Overall, there was markedly higher concordance between cfDNA and biopsy tissue genomic alterations in patients with CRPC-NE compared with castration-resistant adenocarcinoma, supporting greater intraindividual genomic consistency across metastases. Allele-specific copy number and serial sampling analyses allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was indicative of circulating tumor content fraction, reflective of methylation patterns observed in biopsy tissues, and was capable of detecting CRPC-NE-associated epigenetic changes (e.g., hypermethylation of ASXL3 and SPDEF; hypomethylation of INSM1 and CDH2). A targeted set combining genomic (TP53, RB1, CYLD, AR) and epigenomic (hypo- and hypermethylation of 20 differential sites) alterations applied to ctDNA was capable of identifying patients with CRPC-NE. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
179. Genome-wide plasma DNA methylation features of metastatic prostate cancer.
- Author
-
Anjui Wu, Cremaschi, Paolo, Wetterskog, Daniel, Conteduca, Vincenza, Franceschini, Gian Marco, Kleftogiannis, Dimitrios, Jayaram, Anuradha, Sandhu, Shahneen, Wong, Stephen Q., Benelli, Matteo, Salvi, Samanta, Gurioli, Giorgia, Feber, Andrew, Buongermino Pereira, Mariana, Wingate, Anna Maria, Gonzalez-Billalebeitia, Enrique, De Giorgi, Ugo, Demichelis, Francesca, Lise, Stefano, and Attard, Gerhardt
- Subjects
- *
RESEARCH , *SEQUENCE analysis , *RESEARCH methodology , *METASTASIS , *EVALUATION research , *MEDICAL cooperation , *DNA methylation , *COMPARATIVE studies , *GENES , *RESEARCH funding , *PROSTATE tumors - Abstract
Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and without bisulfite treatment from mCRPC patients receiving either abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically determined tumor fraction (r = -0.96; P < 10-8) and characterized by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the PC1 top-correlated segments revealed that these segments are comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual's cancer, we then focused on an orthogonal methylation signature, which revealed enrichment for androgen receptor binding sequences and hypomethylation of these segments associated with AR copy number gain. Individuals harboring this methylation pattern had a more aggressive clinical course. Plasma methylome analysis can accurately quantitate tumor fraction and identify distinct biologically relevant mCRPC phenotypes. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
180. Genomic correlates of clinical outcome in advanced prostate cancer.
- Author
-
Abida, Wassim, Cyrta, Joanna, Heller, Glenn, Prandi, Davide, Armenia, Joshua, Coleman, Ilsa, Cieslik, Marcin, Benelli, Matteo, Robinson, Dan, Van Allen, Eliezer M., Sboner, Andrea, Fedrizzi, Tarcisio, Mosquera, Juan Miguel, Robinson, Brian D., De Sarkar, Navonil, Kunju, Lakshmi P., Tomlins, Scott, YiMi Wu, Rodrigues, Daniel Nava, and Massimo Loda
- Subjects
- *
CASTRATION-resistant prostate cancer , *TRANSCRIPTOMES , *PROSTATE cancer & genetics , *ANDROGEN receptors , *EXOMES - Abstract
Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate cancer (mCRPC) linked with longitudinal clinical outcomes, integrating findings from whole-exome, transcriptome, and histologic analysis. For 128 patients treated with a first-line next-generation androgen receptor signaling inhibitor (ARSI; abiraterone or enzalutamide), we examined the association of 18 recurrent DNA- and RNA-based genomic alterations, including androgen receptor (AR) variant expression, AR transcriptional output, and neuroendocrine expression signatures, with clinical outcomes. Of these, only RB1 alteration was significantly associated with poor survival, whereas alterations in RB1, AR, and TP53 were associatedwith shorter time on treatment with an ARSI. This large analysis integrating mCRPC genomics with histology and clinical outcomes identifies RB1 genomic alteration as a potent predictor of poor outcome, and is a community resource for further interrogation of clinical and molecular associations. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
181. ddSeeker: a tool for processing Bio-Rad ddSEQ single cell RNA-seq data.
- Author
-
Romagnoli, Dario, Boccalini, Giulia, Bonechi, Martina, Biagioni, Chiara, Fassan, Paola, Bertorelli, Roberto, Sanctis, Veronica De, Leo, Angelo Di, Migliaccio, Ilenia, Malorni, Luca, and Benelli, Matteo
- Subjects
- *
RNA sequencing , *TRANSCRIPTOMES , *BIOINFORMATICS , *MICROFLUIDICS , *SOURCE code - Abstract
Background: New single-cell isolation technologies are facilitating studies on the transcriptomics of individual cells. Bio-Rad ddSEQ is a droplet-based microfluidic system that, when coupled with downstream Illumina library preparation and sequencing, enables the monitoring of thousands of genes per cell. Sequenced reads show unique features that do not permit the use of freely available tools to perform single cell demultiplexing. Results: We present ddSeeker, a tool to perform initial processing and quality metrics of reads generated through Bio-Rad ddSEQ/Illumina experiments. Its application to the Illumina test dataset demonstrates that ddSeeker performs better than Illumina BaseSpace software, enabling a higher recovery of valid reads. We also show its utility in the analysis of an in-house dataset including two read sets characterized by low and high sequencing quality. ddSeeker and its source code are available at https://github.com/cgplab/ddSeeker. Conclusions: ddSeeker is a freely available tool to perform initial processing and quality metrics of reads generated through Bio-Rad ddSEQ/Illumina single cell transcriptomic experiments. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
182. Differential impact of RB status on E2F1 reprogramming in human cancer.
- Author
-
McNair, Christopher, Kexin Xu, Mandigo, Amy C., Benelli, Matteo, Leiby, Benjamin, Rodrigues, Daniel, Lindberg, Johan, Gronberg, Henrik, Crespo, Mateus, De Laere, Bram, Dirix, Luc, Visakorpi, Tapio, Fugen Li, Feng, Felix Y., de Bono, Johann, Demichelis, Francesca, Rubin, Mark A., Brown, Myles, Knudsen, Karen E., and Xu, Kexin
- Subjects
- *
RETINOBLASTOMA , *TRANSCRIPTION factors , *PROSTATE cancer patients , *HUMAN cell cycle , *DNA , *PROTEIN metabolism , *CELL differentiation , *PROSTATE tumors , *PROTEINS , *RESEARCH funding - Abstract
The tumor suppressor protein retinoblastoma (RB) is mechanistically linked to suppression of transcription factor E2F1-mediated cell cycle regulation. For multiple tumor types, loss of RB function is associated with poor clinical outcome. RB action is abrogated either by direct depletion or through inactivation of RB function; however, the basis for this selectivity is unknown. Here, analysis of tumor samples and cell-free DNA from patients with advanced prostate cancer showed that direct RB loss was the preferred pathway of disruption in human disease. While RB loss was associated with lethal disease, RB-deficient tumors had no proliferative advantage and exhibited downstream effects distinct from cell cycle control. Mechanistically, RB loss led to E2F1 cistrome expansion and different binding specificity, alterations distinct from those observed after functional RB inactivation. Additionally, identification of protumorigenic transcriptional networks specific to RB loss that were validated in clinical samples demonstrated the ability of RB loss to differentially reprogram E2F1 in human cancers. Together, these findings not only identify tumor-suppressive functions of RB that are distinct from cell cycle control, but also demonstrate that the molecular consequence of RB loss is distinct from RB inactivation. Thus, these studies provide insight into how RB loss promotes disease progression, and identify new nodes for therapeutic intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
183. Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer
- Author
-
Ilenia Migliaccio, Angelo Di Leo, Luca Malorni, Dario Romagnoli, Giulia Boccalini, Matteo Benelli, C. Kent Osborne, Carmine De Angelis, Martina Bonechi, Rachel Schiff, Roberto Verardo, Chiara Biagioni, Cristina Guarducci, Guarducci, Cristina, Bonechi, Martina, Benelli, Matteo, Biagioni, Chiara, Boccalini, Giulia, Romagnoli, Dario, Verardo, Roberto, Schiff, Rachel, Osborne, C Kent, De Angelis, Carmine, Di Leo, Angelo, Malorni, Luca, and Migliaccio, Ilenia
- Subjects
0301 basic medicine ,Cell ,Cancer ,Palbociclib ,Biology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,lcsh:RC254-282 ,Article ,3. Good health ,03 medical and health sciences ,Cyclin E1 ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Breast cancer ,Oncology ,Hormone receptor ,030220 oncology & carcinogenesis ,Gene expression ,medicine ,Cancer research ,Biomarker (medicine) ,Pharmacology (medical) ,Radiology, Nuclear Medicine and imaging - Abstract
CDK4/6 inhibitors represent a new treatment standard for hormone receptor-positive (HR+), HER2-negative advanced breast cancer (BC) patients. Although efficacious, resistance to these agents is universal. Here, we profiled a large panel of HR+ BC cell lines with conditioned resistance to the CDK4/6 inhibitor palbociclib, and analyzed cell cycle-related markers by gene expression profiles (GEP) and western blot (WB). GEP showed high molecular heterogeneity among the models, with E2F targets being significantly enriched both during treatment and at the time of resistance. By both WB and GEP, a common molecular feature at the time of palbociclib resistance was the concomitant overexpression of cyclin E1 and down-regulation of Rb. CCNE1 was the only significantly up-regulated gene among E2F targets at resistance with CCNE1 genomic amplification being observed in two resistant models. Rb was downregulated in all resistant models; a reduction of RB1 copy number was observed in three resistant cell lines. In silico analyses showed that CCNE1/RB1 ratio correlated with palbociclib IC50 in different datasets of both breast and non-breast cancer cell lines, performing better than CCNE1 or RB1 taken separately. Finally, the CCNE1/RB1 ratio was shown to be an adverse prognostic factor in patients with ER+ BC and to be able to discriminate palbociclib-sensitive versus resistant among patients enrolled in the NeoPalAna trial, a neoadjuvant trial testing palbociclib, performing better than CCNE1 or RB1 alone. Our data suggest that the CCNE1/RB1 ratio may be a viable biomarker of palbociclib resistance, warranting further clinical validation., Biomarkers: Prognostic indicator for resistance to cell cycle–targeted drug The expression levels of two genes involved in controlling the cell cycle offers a promising predictive indicator of whether women with hormone receptor–positive breast cancer are likely to develop resistance to the drug palbociclib. A team led by Luca Malorni and Ilenia Migliaccio from the Hospital of Prato, Italy, analyzed gene and protein profiles in a panel of breast cancer cell lines with differential sensitivity to palbociclib. The researchers found that, compared to palbociclib-sensitive cell lines, those that were drug-resistant tended to have elevated expression of one cell-cycle–related gene, called CCNE1, and reduced expression of another, called Rb. The ratio of CCNE1:Rb expression proved to be an accurate prognostic factor among patients enrolled in a clinical trial of palbociclib, performing better than either CCNE1 or Rb levels on their own.
- Published
- 2018
184. Contemporary genetic testing in inherited cardiac disease: Tools, ethical issues, and clinical applications
- Author
-
Kalliope Pilichou, Iacopo Olivotto, Cristina Basso, Cristina Mazzaccara, Benedetta Tomberli, Matteo Benelli, Giulia Frisso, Giuseppe Limongelli, Eloisa Arbustini, Lia Crotti, Ruggiero Mango, Francesca Girolami, Maria Iascone, Girolami, Francesca, Frisso, Giulia, Benelli, Matteo, Crotti, Lia, Iascone, Maria, Mango, Ruggiero, Mazzaccara, Cristina, Pilichou, Kalliope, Arbustini, Eloisa, Tomberli, Benedetta, Limongelli, Giuseppe, Basso, Cristina, Olivotto, Iacopo, Girolami, F, Frisso, G, Benelli, M, Crotti, L, Iascone, M, Mango, R, Mazzaccara, C, Pilichou, K, Arbustini, E, Tomberli, B, Limongelli, G, Basso, C, and Olivotto, I
- Subjects
cardiomyopathies ,0301 basic medicine ,medicine.medical_specialty ,Pathology ,MED/03 - GENETICA MEDICA ,arrhythmias ,genetic counselling ,genetic testing ,massive sequencing ,Death, Sudden, Cardiac ,Europe ,Genetic Predisposition to Disease ,Genetic Testing ,Heart Diseases ,Humans ,Phenotype ,Practice Guidelines as Topic ,Societies, Medical ,Genetic counseling ,Population ,Disease ,030204 cardiovascular system & hematology ,arrhythmia ,Sudden cardiac death ,Cardiology and Cardiovascular Medicine ,03 medical and health sciences ,0302 clinical medicine ,Molecular genetics ,Epidemiology ,medicine ,Intensive care medicine ,education ,arrhythmias, cardiomyopathies, genetic counselling, genetic testing, massive sequencing ,Genetic testing ,education.field_of_study ,cardiomyopathie ,medicine.diagnostic_test ,Clinical Guidelines and Scientific Statements ,business.industry ,MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE ,General Medicine ,medicine.disease ,030104 developmental biology ,Differential diagnosis ,business - Abstract
Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype-phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, 'real-world' experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines.
- Published
- 2018
185. A novel founder MYO15A frameshift duplication is the major cause of genetic hearing loss in Oman
- Author
-
Guido Alberto Gnecchi Ruscone, Mohammed Nasser Al Kindi, Marco Seri, Tania Giangregorio, Andrea Angius, Tommaso Pippucci, Paolo Gasparini, Manuela Oppo, Giorgia Girotto, Marco Sazzini, Flavia Palombo, Nadia Al-Wardy, Mazin Al Khabori, Khalsa Al Lamki, Matteo Benelli, Francesco Cucca, Alberto Magi, Giovanni Romeo, Palombo, Flavia, Al Wardy, Nadia, Ruscone, Guido Alberto Gnecchi, Oppo, Manuela, Kindi, Mohammed Nasser Al, Angius, Andrea, Al Lamki, Khalsa, Girotto, Giorgia, Giangregorio, Tania, Benelli, Matteo, Magi, Alberto, Seri, Marco, Gasparini, Paolo, Cucca, Francesco, Sazzini, Marco, Al Khabori, Mazin, Pippucci, Tommaso, Romeo, Giovanni, Al-Wardy, Nadia, and Gnecchi Ruscone, Guido Alberto
- Subjects
0301 basic medicine ,Proband ,Adult ,MYO15A ,Genetics ,Genetics (clinical) ,Adolescent ,Oman ,GHL ,Population ,Locus (genetics) ,H3M2 ,Consanguinity ,Biology ,Deafness ,Myosins ,Frameshift mutation ,03 medical and health sciences ,Young Adult ,Genetic ,Gene Duplication ,Exome Sequencing ,Gene duplication ,Humans ,Exome ,Deafne ,education ,Frameshift Mutation ,education.field_of_study ,Base Sequence ,Haplotype ,Sequence Analysis, DNA ,Middle Aged ,Founder Effect ,030104 developmental biology ,Evolutionary biology - Abstract
The increased risk for autosomal recessive disorders is one of the most well-known medical implications of consanguinity. In the Sultanate of Oman, a country characterized by one of the highest rates of consanguineous marriages worldwide, prevalence of genetic hearing loss (GHL) is estimated to be 6/10 000. Families of GHL patients have higher consanguinity rates than the general Omani population, indicating a major role for recessive forms. Mutations in GJB2, the most commonly mutated GHL gene, have been sporadically described. We collected 97 DNA samples of GHL probands, affected/unaffected siblings and parents from 26 Omani consanguineous families. Analyzing a first family by whole-exome sequencing, we identified a novel homozygous frameshift duplication (c.1171_1177dupGCCATCT) in MYO15A, the gene linked to the deafness locus DFNB3. This duplication was then found in a total of 8/26 (28%) families, within a 849 kb founder haplotype. Reconstruction of haplotype structure at MYO15A surrounding genomic regions indicated that the founder haplotype branched out in the past two to three centuries from a haplotype present worldwide. The MYO15A duplication emerges as the major cause of GHL in Oman. These findings have major implications for the design of GHL diagnosis and prevention policies in Oman.
- Published
- 2016
186. Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation.
- Author
-
Franceschini GM, Quaini O, Mizuno K, Orlando F, Ciani Y, Ku SY, Sigouros M, Rothmann E, Alonso A, Benelli M, Nardella C, Auh J, Freeman D, Hanratty B, Adil M, Elemento O, Tagawa ST, Feng FY, Caffo O, Buttigliero C, Basso U, Nelson PS, Corey E, Haffner MC, Attard G, Aparicio A, Demichelis F, and Beltran H
- Subjects
- Male, Humans, DNA Methylation, Prospective Studies, Biopsy, Prostatic Neoplasms, Castration-Resistant diagnosis, Prostatic Neoplasms, Castration-Resistant genetics, Cell-Free Nucleic Acids genetics
- Abstract
Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy. We developed a targeted DNA methylation assay to detect CRPC-NE using plasma cell-free DNA (cfDNA). The assay quantifies tumor content and provides a phenotype evidence score that captures diverse CRPC phenotypes, leveraging regions to inform transcriptional state. We tested the design in independent clinical cohorts (n = 222 plasma samples) and qualified it achieving an AUC > 0.93 for detecting pathology-confirmed CRPC-NE (n = 136). Methylation-defined cfDNA tumor content was associated with clinical outcomes in two prospective phase II clinical trials geared towards aggressive variant CRPC and CRPC-NE. These data support the application of targeted DNA methylation for CRPC-NE detection and patient stratification., Significance: Neuroendocrine prostate cancer is an aggressive subtype of treatment-resistant prostate cancer. Early detection is important, but the diagnosis currently relies on metastatic biopsy. We describe the development and validation of a plasma cell-free DNA targeted methylation panel that can quantify tumor fraction and identify patients with neuroendocrine prostate cancer noninvasively. This article is featured in Selected Articles from This Issue, p. 384., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
- Full Text
- View/download PDF
187. Acetyl-CoA carboxylase 1 controls a lipid droplet-peroxisome axis and is a vulnerability of endocrine-resistant ER + breast cancer.
- Author
-
Bacci M, Lorito N, Smiriglia A, Subbiani A, Bonechi F, Comito G, Morriset L, El Botty R, Benelli M, López-Velazco JI, Caffarel MM, Urruticoechea A, Sflomos G, Malorni L, Corsini M, Ippolito L, Giannoni E, Meattini I, Matafora V, Havas K, Bachi A, Chiarugi P, Marangoni E, and Morandi A
- Subjects
- Humans, Female, Aromatase Inhibitors pharmacology, Aromatase Inhibitors therapeutic use, Peroxisomes metabolism, Peroxisomes pathology, Acetyl-CoA Carboxylase, Lipid Droplets metabolism, Lipid Droplets pathology, Cell Line, Tumor, Estrogens metabolism, Drug Resistance, Neoplasm, Breast Neoplasms pathology
- Abstract
Targeting aromatase deprives ER
+ breast cancers of estrogens and is an effective therapeutic approach for these tumors. However, drug resistance is an unmet clinical need. Lipidomic analysis of long-term estrogen-deprived (LTED) ER+ breast cancer cells, a model of aromatase inhibitor resistance, revealed enhanced intracellular lipid storage. Functional metabolic analysis showed that lipid droplets together with peroxisomes, which we showed to be enriched and active in the LTED cells, controlled redox homeostasis and conferred metabolic adaptability to the resistant tumors. This reprogramming was controlled by acetyl-CoA-carboxylase-1 (ACC1), whose targeting selectively impaired LTED survival. However, the addition of branched- and very long-chain fatty acids reverted ACC1 inhibition, a process that was mediated by peroxisome function and redox homeostasis. The therapeutic relevance of these findings was validated in aromatase inhibitor-treated patient-derived samples. Last, targeting ACC1 reduced tumor growth of resistant patient-derived xenografts, thus identifying a targetable hub to combat the acquisition of estrogen independence in ER+ breast cancers.- Published
- 2024
- Full Text
- View/download PDF
188. BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors.
- Author
-
Petrelli A, Rizzolio S, Pietrantonio F, Bellomo SE, Benelli M, De Cecco L, Romagnoli D, Berrino E, Orrù C, Ribisi S, Moya-Rull D, Migliore C, Conticelli D, Maina IM, Puliga E, Serra V, Pellegrino B, Llop-Guevara A, Musolino A, Siena S, Sartore-Bianchi A, Prisciandaro M, Morano F, Antista M, Fumagalli U, De Manzoni G, Degiuli M, Baiocchi GL, Amisano MF, Ferrero A, Marchiò C, Corso S, and Giordano S
- Subjects
- Humans, Female, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Germ-Line Mutation, Retrospective Studies, BRCA1 Protein genetics, BRCA2 Protein genetics, Stomach Neoplasms drug therapy, Stomach Neoplasms genetics, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Ovarian Neoplasms drug therapy
- Abstract
Despite negative results of clinical trials conducted on the overall population of patients with gastric cancer, PARP inhibitor (PARPi) therapeutic strategy still might represent a window of opportunity for a subpopulation of patients with gastric cancer. An estimated 7% to 12% of gastric cancers exhibit a mutational signature associated with homologous recombination (HR) failure, suggesting that these patients could potentially benefit from PARPis. To analyze responsiveness of gastric cancer to PARPi, we exploited a gastroesophageal adenocarcinoma (GEA) platform of patient-derived xenografts (PDX) and PDX-derived primary cells and selected 10 PDXs with loss-of-function mutations in HR pathway genes. Cell viability assays and preclinical trials showed that olaparib treatment was effective in PDXs harboring BRCA2 germline mutations and somatic inactivation of the second allele. Olaparib responsive tumors were sensitive to oxaliplatin as well. Evaluation of HR deficiency (HRD) and mutational signatures efficiently stratified responder and nonresponder PDXs. A retrospective analysis on 57 patients with GEA showed that BRCA2 inactivating variants were associated with longer progression-free survival upon platinum-based regimens. Five of 7 patients with BRCA2 germline mutations carried the p.K3326* variant, classified as "benign." However, familial history of cancer, the absence of RAD51 foci in tumor cells, and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer., Significance: PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
- Full Text
- View/download PDF
189. CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing.
- Author
-
Kerschbamer E, Arnoldi M, Tripathi T, Pellegrini M, Maturi S, Erdin S, Salviato E, Di Leva F, Sebestyén E, Dassi E, Zarantonello G, Benelli M, Campos E, Basson MA, Gusella JF, Gustincich S, Piazza S, Demichelis F, Talkowski ME, Ferrari F, and Biagioli M
- Subjects
- Chromatin, Lysine metabolism, RNA metabolism, Humans, Induced Pluripotent Stem Cells, Neural Stem Cells, Autism Spectrum Disorder genetics, Alternative Splicing, Histones metabolism, Cadherins genetics
- Abstract
Disruptive mutations in the chromodomain helicase DNA-binding protein 8 gene (CHD8) have been recurrently associated with autism spectrum disorders (ASDs). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. CHD8 suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states. H3K36me3 reduction specifically affects highly expressed, CHD8-bound genes and correlates with altered alternative splicing patterns of 462 genes implicated in 'regulation of RNA splicing' and 'mRNA catabolic process'. Mass spectrometry analysis uncovered a novel interaction between CHD8 and the splicing regulator heterogeneous nuclear ribonucleoprotein L (hnRNPL), providing the first mechanistic insights to explain the CHD8 suppression-derived splicing phenotype, partly implicating SETD2, a H3K36me3 methyltransferase. In summary, our results point toward broad molecular consequences of CHD8 suppression, entailing altered histone deposition/maintenance and RNA processing regulation as important regulatory processes in ASD., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2022
- Full Text
- View/download PDF
190. PIK3CA co-occurring mutations and copy-number gain in hormone receptor positive and HER2 negative breast cancer.
- Author
-
Migliaccio I, Paoli M, Risi E, Biagioni C, Biganzoli L, Benelli M, and Malorni L
- Abstract
We aim to elucidate the prognostic value of PIK3CA mutations and copy number (CN) gain (PIK3CA-mut/gain) in hormone receptor-positive and HER2-negative (HR + /HER2-) breast cancer (BC). We analyzed primary HR + /HER2- BC from three publicly available datasets comprising over 2000 samples and assessed the associations with tumoral and clinical characteristics and outcome. Clinical benefit (CB) in alpelisib-treated patients from two studies including 46 patients was analyzed. About 8-10% of HR + /HER2- primary BC had PIK3CA-mut/gain. In two of the datasets analyzed, among patients with PIK3CA mutant tumors, those with mut/gain had significantly worse outcome compared to those with CN neutral (PIK3CA-mut/neut) and PIK3CA-mut/gain remained an independent prognostic factor. CB of alpelisib-treated patients with PIK3CA-mut/gain and PIK3CA-mut/neut tumors was comparable. PIK3CA CN might help clarifying the prognostic and predictive role of PIK3CA mutations. Further studies are warranted., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
191. Charting differentially methylated regions in cancer with Rocker-meth.
- Author
-
Benelli M, Franceschini GM, Magi A, Romagnoli D, Biagioni C, Migliaccio I, Malorni L, and Demichelis F
- Subjects
- Humans, Markov Chains, Computational Biology methods, DNA Methylation, Epigenesis, Genetic, Neoplasms genetics
- Abstract
Differentially DNA methylated regions (DMRs) inform on the role of epigenetic changes in cancer. We present Rocker-meth, a new computational method exploiting a heterogeneous hidden Markov model to detect DMRs across multiple experimental platforms. Through an extensive comparative study, we first demonstrate Rocker-meth excellent performance on synthetic data. Its application to more than 6,000 methylation profiles across 14 tumor types provides a comprehensive catalog of tumor type-specific and shared DMRs, and agnostically identifies cancer-related partially methylated domains (PMD). In depth integrative analysis including orthogonal omics shows the enhanced ability of Rocker-meth in recapitulating known associations, further uncovering the pan-cancer relationship between DNA hypermethylation and transcription factor deregulation depending on the baseline chromatin state. Finally, we demonstrate the utility of the catalog for the study of colorectal cancer single-cell DNA-methylation data., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
192. Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer.
- Author
-
De Angelis C, Fu X, Cataldo ML, Nardone A, Pereira R, Veeraraghavan J, Nanda S, Qin L, Sethunath V, Wang T, Hilsenbeck SG, Benelli M, Migliaccio I, Guarducci C, Malorni L, Litchfield LM, Liu J, Donaldson J, Selenica P, Brown DN, Weigelt B, Reis-Filho JS, Park BH, Hurvitz SA, Slamon DJ, Rimawi MF, Jansen VM, Jeselsohn R, Osborne CK, and Schiff R
- Subjects
- Breast Neoplasms chemistry, Female, Humans, Receptors, Estrogen analysis, Signal Transduction, Tumor Cells, Cultured, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Piperazines therapeutic use, Pyridines therapeutic use
- Abstract
Purpose: Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor-positive (ER
+ )/HER2- breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes., Experimental Design: Parental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes., Results: Parental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an "IFN-related palbociclib-resistance Signature" (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+ /HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis., Conclusions: Aberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i., (©2021 American Association for Cancer Research.)- Published
- 2021
- Full Text
- View/download PDF
193. On the dependence of quantitative diffusion-weighted imaging on scanner system characteristics and acquisition parameters: A large multicenter and multiparametric phantom study with unsupervised clustering analysis.
- Author
-
Fedeli L, Benelli M, Busoni S, Belli G, Ciccarone A, Coniglio A, Esposito M, Nocetti L, Sghedoni R, Tarducci R, Altabella L, Belligotti E, Bettarini S, Betti M, Caivano R, Carnì M, Chiappiniello A, Cimolai S, Cretti F, Fulcheri C, Gasperi C, Giacometti M, Levrero F, Lizio D, Maieron M, Marzi S, Mascaro L, Mazzocchi S, Meliadò G, Morzenti S, Niespolo A, Noferini L, Oberhofer N, Orsingher L, Quattrocchi M, Ricci A, Savini A, Taddeucci A, Testa C, Tortoli P, Gobbi G, Gori C, Bernardi L, Giannelli M, and Mazzoni LN
- Subjects
- Cluster Analysis, Diffusion, Phantoms, Imaging, Reproducibility of Results, Diffusion Magnetic Resonance Imaging
- Abstract
Purpose: The purpose of this multicenter phantom study was to exploit an innovative approach, based on an extensive acquisition protocol and unsupervised clustering analysis, in order to assess any potential bias in apparent diffusion coefficient (ADC) estimation due to different scanner characteristics. Moreover, we aimed at assessing, for the first time, any effect of acquisition plan/phase encoding direction on ADC estimation., Methods: Water phantom acquisitions were carried out on 39 scanners. DWI acquisitions (b-value = 0-200-400-600-800-1000 s/mm
2 ) with different acquisition plans (axial, coronal, sagittal) and phase encoding directions (anterior/posterior and right/left, for the axial acquisition plan), for 3 orthogonal diffusion weighting gradient directions, were performed. For each acquisition setup, ADC values were measured in-center and off-center (6 different positions), resulting in an entire dataset of 84 × 39 = 3276 ADC values. Spatial uniformity of ADC maps was assessed by means of the percentage difference between off-center and in-center ADC values (Δ)., Results: No significant dependence of in-center ADC values on acquisition plan/phase encoding direction was found. Ward unsupervised clustering analysis showed 3 distinct clusters of scanners and an association between Δ-values and manufacturer/model, whereas no association between Δ-values and maximum gradient strength, slew rate or static magnetic field strength was revealed. Several acquisition setups showed significant differences among groups, indicating the introduction of different biases in ADC estimation., Conclusions: Unsupervised clustering analysis of DWI data, obtained from several scanners using an extensive acquisition protocol, allows to reveal an association between measured ADC values and manufacturer/model of scanner, as well as to identify suboptimal DWI acquisition setups for accurate ADC estimation., (Copyright © 2021 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
194. Circulating tumor cells and palbociclib treatment in patients with ER-positive, HER2-negative advanced breast cancer: results from a translational sub-study of the TREnd trial.
- Author
-
Galardi F, De Luca F, Biagioni C, Migliaccio I, Curigliano G, Minisini AM, Bonechi M, Moretti E, Risi E, McCartney A, Benelli M, Romagnoli D, Cappadona S, Gabellini S, Guarducci C, Conti V, Biganzoli L, Di Leo A, and Malorni L
- Subjects
- Biomarkers, Tumor blood, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Count, Disease Progression, Female, Humans, Neoplastic Cells, Circulating drug effects, Neoplastic Cells, Circulating metabolism, Progression-Free Survival, Receptor, ErbB-2 deficiency, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Retinoblastoma Binding Proteins metabolism, Treatment Outcome, Ubiquitin-Protein Ligases metabolism, Breast Neoplasms drug therapy, Neoplastic Cells, Circulating pathology, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyridines therapeutic use
- Abstract
Background: Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation., Methods: Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood samples were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. Samples with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR., Results: All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 (n = 26) had a worse PFS than those with 0 CTCs (n = 16) (p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, (p = 0.004). Finally, patients with ≥ 5 CTCs at T2 (n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF (p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels., Conclusions: CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied sample size.
- Published
- 2021
- Full Text
- View/download PDF
195. Genome-wide plasma DNA methylation features of metastatic prostate cancer.
- Author
-
Wu A, Cremaschi P, Wetterskog D, Conteduca V, Franceschini GM, Kleftogiannis D, Jayaram A, Sandhu S, Wong SQ, Benelli M, Salvi S, Gurioli G, Feber A, Pereira MB, Wingate AM, Gonzalez-Billalebeitia E, De Giorgi U, Demichelis F, Lise S, and Attard G
- Subjects
- Adult, Aged, Aged, 80 and over, Genome-Wide Association Study, Humans, Male, Middle Aged, Neoplasm Metastasis, Circulating Tumor DNA blood, Circulating Tumor DNA genetics, DNA Methylation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms blood, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and without bisulfite treatment from mCRPC patients receiving either abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically determined tumor fraction (r = -0.96; P < 10-8) and characterized by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the PC1 top-correlated segments revealed that these segments are comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual's cancer, we then focused on an orthogonal methylation signature, which revealed enrichment for androgen receptor binding sequences and hypomethylation of these segments associated with AR copy number gain. Individuals harboring this methylation pattern had a more aggressive clinical course. Plasma methylome analysis can accurately quantitate tumor fraction and identify distinct biologically relevant mCRPC phenotypes.
- Published
- 2020
- Full Text
- View/download PDF
196. Estimating the magnitude of clinical benefit from (neo)adjuvant chemotherapy in patients with ER-positive/HER2-negative breast cancer.
- Author
-
McCartney A, Benelli M, and Di Leo A
- Subjects
- Biomarkers, Tumor analysis, Breast Neoplasms metabolism, Chemotherapy, Adjuvant methods, Female, Humans, Prognosis, Prospective Studies, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Retrospective Studies, Breast Neoplasms drug therapy, Neoplasm Recurrence, Local etiology, Patient Selection, Risk Assessment methods
- Abstract
Gene-expression assays were originally validated retrospectively as tools of prognostication, with evidence emerging from more recent prospectively-conducted studies such as MINDACT and TAILORx supporting their clinical validity and utility as biomarkers in identifying patients with luminal breast cancer who might be spared chemotherapy. However, these assays still do not have the ability to identify all patients who may safely avoid chemotherapy, and may over-estimate the risk of relapse in some cases. Future studies should aim to prospectively integrate contemporary approaches that assume a theoretical risk of relapse (based on pathological and/or genomic evaluation of the primary tumour), with new tools that can detect signals of active micro-metastatic disease. Until current methods of estimating prognosis and predicting benefit from adjuvant chemotherapy are significantly refined, estimating and improving the true magnitude of benefit derived from chemotherapy remains a challenge for clinicians., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
197. Core Biopsies from Prostate Cancer Patients in Active Surveillance Protocols Harbor PTEN and MYC Alterations.
- Author
-
Gandellini P, Casiraghi N, Rancati T, Benelli M, Doldi V, Romanel A, Colecchia M, Marenghi C, Valdagni R, Demichelis F, and Zaffaroni N
- Subjects
- Aged, Biomarkers, Tumor genetics, Biopsy, Large-Core Needle, Exome genetics, Humans, Male, Middle Aged, Mutation, Neoplasm Grading, Prostatectomy, Prostatic Neoplasms surgery, Retrospective Studies, PTEN Phosphohydrolase genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Proto-Oncogene Proteins c-myc genetics, Watchful Waiting standards
- Abstract
Background: Genomic characterization of prostate cancer (PCa) biopsies may improve criteria for the selection of patients suitable for active surveillance (AS)., Objective: To identify somatic genomic aberrations associated with adverse outcome as AS protocol exclusion indicators., Design, Setting and Participants: Whole-exome sequencing profiles were generated for Gleason score (GS)=3+3 biopsies obtained from 54 PCa patients enrolled in two AS protocols. Patients were selected as representative of a nonindolent population, consisting of 27 patients who dropped out from AS due to upgrading (ie, finding of GS>3+3 at a follow-up biopsy) within 2 yr, and a potentially indolent population, consisting of 27 patients in AS for ≥4 yr without any evidence of reclassification., Outcome Measurements and Statistical Analysis: The genomic alteration landscape of core biopsies was analyzed using an integrated computational pipeline and correlated with patient reclassification due to upgrading., Results and Limitations: Of all the GS=3+3 biopsies of the study cohort, 34% showed clear evidence of somatic copy number aberrations along the genome. Of these, 39% came from the potentially indolent and 61% from the nonindolent population. Single-nucleotide variants demonstrated low allelic fractions and included a common F133C mutation in the SPOP gene. The minimally altered genomic landscape of the study cohort presented a distinct set of monoallelic deletions, including on 8p, 13q, 16q, and 21q, and rare amplifications of 8q, which were observed in both AS patient populations. Concerning lesions typically associated with adverse outcome, PTEN deletions and MYC amplification, though observed in a small number of cases, were detected exclusively or preferentially, respectively, in nonindolent patients. Such molecular findings were confirmed by immunohistochemistry on the same tissue blocks. The small sample size and the retrospective nature of the analysis represent the main study limitations., Conclusions: Genomic features enriched in aggressive tumors can be detected in GS=3+3 core biopsies of AS patients., Patient Summary: PTEN and MYC alterations at the time of diagnosis would deserve investigation in larger cohorts of AS patients to assess their potential as biomarkers for a more precise/earlier identification of patients at risk of reclassification., (Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
198. Benefit from anti-EGFRs in RAS and BRAF wild-type metastatic transverse colon cancer: a clinical and molecular proof of concept study.
- Author
-
Cremolini C, Benelli M, Fontana E, Pagani F, Rossini D, Fucà G, Busico A, Conca E, Di Donato S, Loupakis F, Schirripa M, Lonardi S, Borelli B, Ongaro E, Eason K, Morano F, Casagrande M, Fassan M, Sadanandam A, de Braud F, Falcone A, and Pietrantonio F
- Abstract
Objective: Primary tumour location is regarded as a reliable surrogate of colorectal cancer biology. Sensitivity to anti-EGFRs (Epidermal Growth Factor Receptor) of metastatic transverse colon cancers (mTCCs) has usually been assumed similar to right-sided tumours; however, evidence about the clinical behaviour of mTCC is limited. Thus, to verify sensitivity of mTCC to anti-EGFRs we conducted the present study., Methods: Patients with RAS/BRAF wild-type microsatellite stable (MSS) mTCC receiving anti-EGFR monotherapy, or in combination with irinotecan if clearly irinotecan-refractory, were included. Hypothesising an overall response rate (ORR) of 35%, 11 patients, of whom at least 3 were responders, were necessary to be able to reject the null hypothesis of an ORR of 5%, with α and β errors of 0.05 and 0.20. PRESSING panel and consensus molecular subtypes (CMS) were assessed on tumour samples, whereas in-silico data were obtained from TCGA dataset., Results: Among nine eligible patients, four and three achieved response and disease stabilisation (ORR 44%). At a median follow-up of 23.1 months, median progression-free survival and overall survival were 7.3 (95% CI 3.9 to NA) and 15.0 months (95% CI 10.0 to NA), respectively. A MET amplification and an ERBB4 S303F substitution were detected in patients with rapid disease progression, while others had PRESSING panel-negative tumours with CMS2 or CMS4 subtypes., Conclusions: RAS/BRAF wild-type MSS mTCCs may be sensitive to anti-EGFRs, as confirmed by molecular analyses., Competing Interests: Competing interests: None declared.
- Published
- 2019
- Full Text
- View/download PDF
199. Dependence of apparent diffusion coefficient measurement on diffusion gradient direction and spatial position - A quality assurance intercomparison study of forty-four scanners for quantitative diffusion-weighted imaging.
- Author
-
Fedeli L, Belli G, Ciccarone A, Coniglio A, Esposito M, Giannelli M, Mazzoni LN, Nocetti L, Sghedoni R, Tarducci R, Altabella L, Belligotti E, Benelli M, Betti M, Caivano R, Carni' M, Chiappiniello A, Cimolai S, Cretti F, Fulcheri C, Gasperi C, Giacometti M, Levrero F, Lizio D, Maieron M, Marzi S, Mascaro L, Mazzocchi S, Meliado' G, Morzenti S, Noferini L, Oberhofer N, Quattrocchi MG, Ricci A, Taddeucci A, Tenori L, Luchinat C, Gobbi G, Gori C, and Busoni S
- Subjects
- Diffusion, Phantoms, Imaging, Quality Control, Diffusion Magnetic Resonance Imaging instrumentation
- Abstract
Purpose: To propose an MRI quality assurance procedure that can be used for routine controls and multi-centre comparison of different MR-scanners for quantitative diffusion-weighted imaging (DWI)., Materials and Methods: 44 MR-scanners with different field strengths (1 T, 1.5 T and 3 T) were included in the study. DWI acquisitions (b-value range 0-1000 s/mm
2 ), with three different orthogonal diffusion gradient directions, were performed for each MR-scanner. All DWI acquisitions were performed by using a standard spherical plastic doped water phantom. Phantom solution ADC value and its dependence with temperature was measured using a DOSY sequence on a 600 MHz NMR spectrometer. Apparent diffusion coefficient (ADC) along each diffusion gradient direction and mean ADC were estimated, both at magnet isocentre and in six different position 50 mm away from isocentre, along positive and negative AP, RL and HF directions., Results: A good agreement was found between the nominal and measured mean ADC at isocentre: more than 90% of mean ADC measurements were within 5% from the nominal value, and the highest deviation was 11.3%. Away from isocentre, the effect of the diffusion gradient direction on ADC estimation was larger than 5% in 47% of included scanners and a spatial non uniformity larger than 5% was reported in 13% of centres., Conclusion: ADC accuracy and spatial uniformity can vary appreciably depending on MR scanner model, sequence implementation (i.e. gradient diffusion direction) and hardware characteristics. The DWI quality assurance protocol proposed in this study can be employed in order to assess the accuracy and spatial uniformity of estimated ADC values, in single- as well as multi-centre studies., (Copyright © 2018. Published by Elsevier Ltd.)- Published
- 2018
- Full Text
- View/download PDF
200. Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications.
- Author
-
Girolami F, Frisso G, Benelli M, Crotti L, Iascone M, Mango R, Mazzaccara C, Pilichou K, Arbustini E, Tomberli B, Limongelli G, Basso C, and Olivotto I
- Subjects
- Death, Sudden, Cardiac etiology, Europe, Genetic Predisposition to Disease, Humans, Phenotype, Practice Guidelines as Topic, Societies, Medical, Genetic Testing ethics, Genetic Testing methods, Heart Diseases diagnosis, Heart Diseases genetics
- Abstract
: Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. With a combined estimated prevalence of 3% in the general population, these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. In current practice, genetic testing can be used in a clinically affected patient to confirm diagnosis, or to formulate a differential diagnosis among overlapping phenotypes or between hereditary and acquired (nongenetic) forms of disease. Although genotype-phenotype correlations are generally unpredictable, a precise molecular diagnosis can help predict prognosis in specific patient subsets and may guide management. In clinically unaffected relatives, genetic cascade testing is recommended, after the initial identification of a pathogenic variation, with the aim of identifying asymptomatic relatives who might be at risk of disease-related complications, including unexpected sudden cardiac death. Future implications include the identification of novel therapeutic targets and development of tailored treatments including gene therapy. This document reflects the multidisciplinary, 'real-world' experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines.
- Published
- 2018
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.