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2. Definition and management of colorectal polyposis not associated with APC/MUTYH germline pathogenic variants: AIFEG consensus statement

Author

Adami, Francesca, Alducci, Elisa, Amadori, Lucia, Arcangeli, Valentina, Balestrino, Luisa, Bao, Quoc Riccardo, Barana, Daniela, Bertario, Lucio, Bonanni, Bernardo, Boni, Stefania, Bullian, Pierluigi, Carbonardi, Fiorella, Carnevali, Ileana, Castelli, Paola, Celotto, Francesco, Cini, Giulia, Crivellari, Gino, Libera, Duilio Della, Dell'elice, Anastasia, Digennaro, Maria, D'urso, Alessandra, Fabretto, Antonella, Fanale, Daniele, Feroce, Irene, Furlan, Daniela, Ghiorzo, Paola, Giacché, Mara, Gusella, Milena, Liserre, Barbara, Lucci Cordisco, Emanuela, Mammi, Isabella, Martayan, Aline, Massuras, Stefania, Mazzà, Daniela, Mollica, Eleonora, Morabito, Alberto, Nardo, Giorgia, Oliani, Cristina, Palermo, Flavia, Panizza, Elena, Patruno, Margherita, Pedroni, Monica, Pensotti, Valeria Grazia Maria, Piozzi, Guglielmo Niccolo, Ponz de Leon, Maurizio, Pozzi, Simonetta, Presi, Silvia, Pucciarelli, Salvatore, Puzzono, Marta, Ranzani, Guglielmina Nadia, Ravegnani, Mila, Remo, Andrea, Ricci, Maria Teresa, Roncucci, Luca, Rossi, Giovanni Battsita, Sala, Elena Maria, Mete, Lupe Sanchez, Sandonà, Daniele, Sciallero, Stefania, Serrano, Davide, Signoroni, Stefano, Spina, Francesca, Stigliano, Vittoria, Taborelli, Monica, Tedaldi, Gianluca, Tibiletti, Maria Grazia, Tognazzo, Silvia, Tolva, Gianluca, Trovato, Cristina Maria Concetta, Turchetti, Daniela, Urso, Emanuele Damiano Luca, Varvara, Dora, Viel, Alessandra, Vitellaro, Marco, Vivanet, Caterina, Zovato, Stefania, Zuppardo, Raffaella Alessia, and Piozzi, Guglielmo Niccolò

Published
2021
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5. Ovarian cancer onset across different BRCA mutation types: a view to a more tailored approach for BRCA mutated patients

Author

Marchetti, Claudia, Ataseven, Beyhan, Cassani, Chiara, Sassu, Carolina Maria, Congedo, Luigi, D'Indinosante, Marco, Cappuccio, Serena, Rhiem, Kerstin, Hahnen, Eric, Lucci Cordisco, Emanuela, Arbustini, Eloisa, Harter, Philipp, Minucci, Angelo, Scambia, Giovanni, Fagotti, Anna, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Scambia, Giovanni (ORCID:0000-0003-2758-1063), Fagotti, Anna (ORCID:0000-0001-5579-335X), Marchetti, Claudia, Ataseven, Beyhan, Cassani, Chiara, Sassu, Carolina Maria, Congedo, Luigi, D'Indinosante, Marco, Cappuccio, Serena, Rhiem, Kerstin, Hahnen, Eric, Lucci Cordisco, Emanuela, Arbustini, Eloisa, Harter, Philipp, Minucci, Angelo, Scambia, Giovanni, Fagotti, Anna, Marchetti, Claudia (ORCID:0000-0001-7098-8956), Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Scambia, Giovanni (ORCID:0000-0003-2758-1063), and Fagotti, Anna (ORCID:0000-0001-5579-335X)

Abstract

ObjectiveTo evaluate the role of different specific types of germline breast cancer susceptibility BRCA mutations on the age of onset of high grade serous ovarian cancer. MethodsThis was a multicenter, international, retrospective cohort of 474 patients diagnosed with recurrent or newly diagnosed high grade serous ovarian cancer, with known germline mutations in BRCA1/2 genes, treated between January 2011 and December 2020 in three academic centers in Europe. Patients were classified into four groups related to the type of BRCA1/2 genes mutation: frameshift, missense, nonsense, and splicing. Data from patients with splicing mutations were removed from the analysis because of the small numbers. The other three groups were compared. ResultsExcluding the 29 patients with a splicing mutation, 474 patients were enrolled: 309 (65.2%) with frameshift mutations, 102 (21.5%) with nonsense mutations, and 63 (13.3%) with missense mutations. The BRCA1 gene was affected in 324 (68.4%) cases, while BRCA2 was involved in 150 (31.6%) women (p=0.06). We found a difference of more than 5 years in the age of onset of high grade serous ovarian cancer between BRCA1 and BRCA2 patients (mean 53.3 years vs 58.4 years; p=0.001), with a mean age of 55.1 years. Patients with nonsense germline mutations had the youngest age of onset, while women with frameshift mutations had the oldest age of onset of high grade serous ovarian cancer (mean 52.2 years vs mean 55.9 years), both in the BRCA1 and BRCA2 subgroups. There was no statistically significant difference in age of onset between early and advanced groups (mean 55.8 years vs 55.0 years; p=0.55). ConclusionDifferent types of germline BRCA mutations could determine different ages for onset of high grade serous ovarian cancer. If confirmed in larger series, this finding might have a clinical impact, potentially leading to a more tailored approach for risk reducing surgery for the prevention of high grade serous ovarian cancer.

Published
2023

7. Lynch Syndrome and Gynecologic Tumors: Incidence, Prophylaxis, and Management of Patients with Cancer

Author

Capasso, Ilaria, Santoro, Angela, Lucci Cordisco, Emanuela, Perrone, E., Tronconi, F., Catena, Ursula, Zannoni, Gian Franco, Scambia, Giovanni, Fanfani, Francesco, Lorusso, Domenica, Duranti, S., Capasso I., Santoro A. (ORCID:0000-0002-6964-5152), Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Catena U., Zannoni G. F. (ORCID:0000-0003-1809-129X), Scambia G. (ORCID:0000-0003-2758-1063), Fanfani F. (ORCID:0000-0003-1991-7284), Lorusso D., Capasso, Ilaria, Santoro, Angela, Lucci Cordisco, Emanuela, Perrone, E., Tronconi, F., Catena, Ursula, Zannoni, Gian Franco, Scambia, Giovanni, Fanfani, Francesco, Lorusso, Domenica, Duranti, S., Capasso I., Santoro A. (ORCID:0000-0002-6964-5152), Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Catena U., Zannoni G. F. (ORCID:0000-0003-1809-129X), Scambia G. (ORCID:0000-0003-2758-1063), Fanfani F. (ORCID:0000-0003-1991-7284), and Lorusso D.

Abstract

This review provides a comprehensive update on recent evidence regarding gynecologic tumors associated with Lynch Syndrome (LS). Endometrial cancer (EC) and ovarian cancer (OC) are the first and second most common gynecologic malignancies in developed countries, respectively, and LS is estimated to be the hereditary cause in 3% of both EC and OC. Despite the increasing evidence on LS-related tumors, few studies have analyzed the outcomes of LS-related EC and OC stratified by mutational variant. This review aims to provide a comprehensive overview of the literature and comparison between updated international guidelines, to help outline a shared pathway for the diagnosis, prevention, and management of LS. Through the widespread adoption of the immunohistochemistry-based Universal Screening, LS diagnosis and identification of mutational variants could be standardized and recognized by international guidelines as a feasible, reproducible, and cost-effective method. Furthermore, the development of a better understanding of LS and its mutational variants will support our ability to better tailor EC and OC management in terms of prophylactic surgery and systemic treatment in the light of the promising results shown by immunotherapy.

Published
2023

8. Lynch Syndrome and Gynecologic Tumors: Incidence, Prophylaxis, and Management of Patients with Cancer

Author

Capasso, Ilaria, primary, Santoro, Angela, additional, Lucci Cordisco, Emanuela, additional, Perrone, Emanuele, additional, Tronconi, Francesca, additional, Catena, Ursula, additional, Zannoni, Gian Franco, additional, Scambia, Giovanni, additional, Fanfani, Francesco, additional, Lorusso, Domenica, additional, and Duranti, Simona, additional

Published
2023
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10. Ovarian cancer onset across differentBRCAmutation types: a view to a more tailored approach forBRCAmutated patients

Author

Marchetti, Claudia, primary, Ataseven, Beyhan, additional, Cassani, Chiara, additional, Sassu, Carolina Maria, additional, Congedo, Luigi, additional, D'Indinosante, Marco, additional, Cappuccio, Serena, additional, Rhiem, Kerstin, additional, Hahnen, Eric, additional, Lucci Cordisco, Emanuela, additional, Arbustini, Eloisa, additional, Harter, Philipp, additional, Minucci, Angelo, additional, Scambia, Giovanni, additional, and Fagotti, Anna, additional

Published
2022
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11. Surgical management of BRCA pathogenic variant carriers with breast cancer: a recent literature review and current state of the art

Author

Terribile, Daniela Andreina, Mason, Elena Jane, Murando, Federica, Di Leone, Alba, Sanchez, Alejandro M, Scardina, Lorenzo, Magno, Stefano, Franco, Antonio, D'Archi, Sabatino, Natale, Maria, Lucci Cordisco, Emanuela, Masetti, Riccardo, Franceschini, Gianluca, Terribile, Daniela A (ORCID:0000-0002-3511-0010), Mason, Elena J, DI Leone, Alba, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Masetti, Riccardo (ORCID:0000-0002-7520-9111), Franceschini, Gianluca (ORCID:0000-0002-2950-3395), Terribile, Daniela Andreina, Mason, Elena Jane, Murando, Federica, Di Leone, Alba, Sanchez, Alejandro M, Scardina, Lorenzo, Magno, Stefano, Franco, Antonio, D'Archi, Sabatino, Natale, Maria, Lucci Cordisco, Emanuela, Masetti, Riccardo, Franceschini, Gianluca, Terribile, Daniela A (ORCID:0000-0002-3511-0010), Mason, Elena J, DI Leone, Alba, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Masetti, Riccardo (ORCID:0000-0002-7520-9111), and Franceschini, Gianluca (ORCID:0000-0002-2950-3395)

Abstract

Surgical management of breast cancer patients carrying pathogenic variants (PV) on breast cancer genes (BRCA) 1 and 2 has changed throughout the last decade due to growing availability of genetic testing, and has shifted towards the diffusion of bilateral mastectomy. Today's scenario however is in further evolution because of emerging data that suggest a personalized modulation of treatment. In this work we aimed to gather recent evidence supporting a prophylactic or conservative surgical approach in order to define the state of the art in today's treatment of BRCA carriers with breast cancer. We reviewed the literature to identify studies providing evidence on surgical treatment in breast cancer patients with BRCA 1 and 2 PVs. We included articles comparing outcomes between patients undergoing breast conserving surgery (BCS) and mastectomy, and articles investigating contralateral risk-reducing mastectomy (CRRM), with a particular focus on recent literature. International guidelines were also reviewed. Optimal surgical management of BRCA PV carriers with breast cancer remains controversial. While the introduction of routine genetic testing has initially led surgeons to favor more radical treatments, recent literature provides evidence that a conservative approach is safe and feasible in selected cases. Guidelines are heterogeneous and provide guidance without constraining the surgeon. Patients should undergo adequate genetic and surgical counseling in order to receive the best tailored surgical treatment. Because guidelines vary in different countries and provide no definite protocol, they highlight the importance of accurate surgical planning. Clinical, familial and psychosocial factors should be taken into account when approaching a BRCA PV carrier with breast cancer, in order to guarantee the best evidence-based patient care in an era of personalized treatment.

Published
2021

12. Fertility-sparing treatment for endometrial cancer and atypical endometrial hyperplasia in patients with Lynch Syndrome: Molecular diagnosis after immunohistochemistry of MMR proteins

Author

Catena, Ursula, primary, Della Corte, Luigi, additional, Raffone, Antonio, additional, Travaglino, Antonio, additional, Lucci Cordisco, Emanuela, additional, Teodorico, Elena, additional, Masciullo, Valeria, additional, Bifulco, Giuseppe, additional, Di Spiezio Sardo, Attilio, additional, Scambia, Giovanni, additional, and Fanfani, Francesco, additional

Published
2022
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13. Cancer risk associated with STK11/LKB1 germline mutations in Peutz–Jeghers syndrome patients: Results of an Italian multicenter study

Author

Resta, Nicoletta, Pierannunzio, Daniela, Lenato, Gennaro Mariano, Stella, Alessandro, Capocaccia, Riccardo, Bagnulo, Rosanna, Lastella, Patrizia, Susca, Francesco Claudio, Bozzao, Cristina, Loconte, Daria Carmela, Sabbà, Carlo, Urso, Emanuele, Sala, Paola, Fornasarig, Mara, Grammatico, Paola, Piepoli, Ada, Host, Cristina, Turchetti, Daniela, Viel, Alessandra, Memo, Luigi, Giunti, Laura, Stigliano, Vittoria, Varesco, Liliana, Bertario, Lucio, Genuardi, Maurizio, Lucci Cordisco, Emanuela, Tibiletti, Maria Grazia, Di Gregorio, Carmela, Andriulli, Angelo, and Ponz de Leon, Maurizio

Published
2013
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14. Distribution of Cerebrovascular Phenotypes According to Variants of the ENG and ACVRL1 Genes in Subjects with Hereditary Hemorrhagic Telangiectasia

Author

Gaetani, Eleonora, primary, Peppucci, Elisabetta, additional, Agostini, Fabiana, additional, Di Martino, Luigi, additional, Lucci Cordisco, Emanuela, additional, Sturiale, Carmelo L., additional, Puca, Alfredo, additional, Porfidia, Angelo, additional, Alexandre, Andrea, additional, Pedicelli, Alessandro, additional, and Pola, Roberto, additional

Published
2022
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15. Distribution of Cerebrovascular Phenotypes According to Variants of the ENG and ACVRL1 Genes in Subjects with Hereditary Hemorrhagic Telangiectasia

Author

Gaetani, Eleonora, Peppucci, Elisabetta, Agostini, Fabiana, Di Martino, Luigi, Lucci Cordisco, Emanuela, Sturiale, Carmelo Lucio, Puca, Alfredo, Porfidia, Angelo, Alexandre, Andrea, Pedicelli, Alessandro, Pola, Roberto, Eleonora Gaetani (ORCID:0000-0002-7808-1491), Luigi Di Martino, Emanuela Lucci Cordisco (ORCID:0000-0002-6279-7604), Carmelo L. Sturiale (ORCID:0000-0002-4080-2492), Alfredo Puca (ORCID:0000-0001-6096-1776), Angelo Porfidia (ORCID:0000-0003-4915-2892), Andrea Alexandre, Alessandro Pedicelli (ORCID:0000-0002-2558-8838), Roberto Pola (ORCID:0000-0001-5224-2931), Gaetani, Eleonora, Peppucci, Elisabetta, Agostini, Fabiana, Di Martino, Luigi, Lucci Cordisco, Emanuela, Sturiale, Carmelo Lucio, Puca, Alfredo, Porfidia, Angelo, Alexandre, Andrea, Pedicelli, Alessandro, Pola, Roberto, Eleonora Gaetani (ORCID:0000-0002-7808-1491), Luigi Di Martino, Emanuela Lucci Cordisco (ORCID:0000-0002-6279-7604), Carmelo L. Sturiale (ORCID:0000-0002-4080-2492), Alfredo Puca (ORCID:0000-0001-6096-1776), Angelo Porfidia (ORCID:0000-0003-4915-2892), Andrea Alexandre, Alessandro Pedicelli (ORCID:0000-0002-2558-8838), and Roberto Pola (ORCID:0000-0001-5224-2931)

Abstract

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder caused, in more than 80% of cases, by mutations of either the endoglin (ENG) or the activin A receptorlike type 1 (ACVRL1) gene. Several hundred variants have been identified in these HHT-causing genes, including deletions, missense and nonsense mutations, splice defects, duplications, and insertions. In this study, we have analyzed retrospectively collected images of magnetic resonance angiographies (MRA) of the brain of HHT patients, followed at the HHT Center of our University Hospital, and looked for the distribution of cerebrovascular phenotypes according to specific gene variants. We found that cerebrovascular malformations were heterogeneous among HHT patients, with phenotypes that ranged from classical arteriovenous malformations (AVM) to intracranial aneurysms (IA), developmental venous anomalies (DVA), and cavernous angiomas (CA). There was also wide heterogeneity among the variants of the ENG and ACVRL1 genes, which included known pathogenic variants, variants of unknown significance, variants pending classification, and variants which had not been previously reported. The percentage of patients with cerebrovascular malformations was significantly higher among subjects with ENG variants than ACVRL1 variants (25.0% vs. 13.1%, p < 0.05). The prevalence of neurovascular anomalies was different among subjects with different gene variants, with an incidence that ranged from 3.3% among subjects with the c.1231C > T, c.200G > A, or c.1120C > T missense mutations of the ACVRL1 gene, to 75.0% among subjects with the c.1435C > T missense mutation of the ACVRL1 gene. Further studies and larger sample sizes are required to confirm these findings.

Published
2022

16. Fertility-sparing treatment for endometrial cancer and atypical endometrial hyperplasia in patients with Lynch Syndrome: Molecular diagnosis after immunohistochemistry of MMR proteins

Author

Catena, Ursula, Della Corte, L., Raffone, A., Travaglino, A., Lucci Cordisco, Emanuela, Teodorico, E., Masciullo, Valeria, Bifulco, G., Di Spiezio Sardo, A., Scambia, Giovanni, Fanfani, Francesco, Catena U., Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Masciullo V., Scambia G. (ORCID:0000-0003-2758-1063), Fanfani F. (ORCID:0000-0003-1991-7284), Catena, Ursula, Della Corte, L., Raffone, A., Travaglino, A., Lucci Cordisco, Emanuela, Teodorico, E., Masciullo, Valeria, Bifulco, G., Di Spiezio Sardo, A., Scambia, Giovanni, Fanfani, Francesco, Catena U., Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Masciullo V., Scambia G. (ORCID:0000-0003-2758-1063), and Fanfani F. (ORCID:0000-0003-1991-7284)

Abstract

Introduction: Lynch Syndrome (LS) represents the hereditary condition that is most frequently associated with endometrial cancer (EC). The aim of this study is to assess the presence of Lynch Syndrome (LS) in young women with mismatch repair (MMR)-deficient atypical endometrial hyperplasia (AEH) and non-myoinvasive FIGO G1 endometrioid EC and its possible impact on the outcome of conservative treatment. Methods: Six MMR-deficient cases identified from a previous cohort of 69 conservatively treated patients were selected to be screened for germline mutations in MMR genes. In each patient, the outcomes of conservative treatment for AEH and EEC, including response, relapse, progression, and pregnancy, were assessed. Results: Five out of 6 patients underwent genetic test for LS. Three out of these 5 patients showed a positive genetic test. Patient 1 showed the c.942 + 2 T>A heterozygous variant of MSH2 mutation; after 12 months of complete response, she had relapse and progression of disease. Patient 4 showed the c.2459-1G>C variant of MSH2 mutation; after complete response, she failed to achieve pregnancy; she had relapse after 24 months and underwent hysterectomy. Patient 6 showed the c.803 + 1 heterozygous variant of PMS2 mutation; she had relapse of disease after 18 months from the first complete response and then underwent hysterectomy. Conclusions: In this series, 3 out of 6 women with MMR-deficiency had LS. None of the patients achieved pregnancy, and those who responded to treatment had subsequent relapse of disease. Patients undergoing fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer should perform MMR immunohistochemical analysis in order to screen LS.

Published
2022

17. Surgical management of BRCA pathogenic variant carriers with breast cancer: a recent literature review and current state of the art

Author

TERRIBILE, Daniela A., primary, MASON, Elena J., additional, MURANDO, Federica, additional, DI LEONE, Alba, additional, SANCHEZ, Alejandro M., additional, SCARDINA, Lorenzo, additional, MAGNO, Stefano, additional, FRANCO, Antonio, additional, D’ARCHI, Sabatino, additional, NATALE, Maria, additional, LUCCI CORDISCO, Emanuela, additional, MASETTI, Riccardo, additional, and FRANCESCHINI, Gianluca, additional

Published
2021
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18. Hereditary Nonpolyposis Colorectal Cancer : An Approach to the Selection of Candidates to Genetic Testing Based on Clinical and Molecular Characteristics

Author

Viel, Alessandra, Genuardi, Maurizio, Lucci-Cordisco, Emanuela, Capozzi, Eugenia, Rovella, Valentina, Fornasarig, Mara, de Leòn, Maurizio Ponz, Anti, Marcello, Pedroni, Monica, Bellacosa, Alfonso, Percesepe, Antonio, Covino, Marcello, Benatti, Piero, Del Tin, Laura, Roncucci, Luca, Valentini, Maurizio, Boiocchi, Mauro, and Neri, Giovanni

Published
1998

19. A new founder BRCA1 haplotype identified in the Puglia region is associated with a specific age-related cancer onset in three unrelated families

Author

Capoluongo, Ettore Domenico, De Matteis, Elisabetta, Cucinotto, I, Ronzino, G, Santonocito, Concetta, Tornesello, Assunta, De Giorgio, Mr, Lucci Cordisco, Emanuela, Minucci, Angelo, Genuardi, Maurizio, Capoluongo E (ORCID:0000-0001-9872-0572), De Matteis E, Santonocito C (ORCID:0000-0003-3624-1386), Tornesello A (ORCID:0000-0002-7485-7440), Lucci Cordisco E (ORCID:0000-0002-6279-7604), Minucci A, Genuardi M. (ORCID:0000-0002-7410-8351), Capoluongo, Ettore Domenico, De Matteis, Elisabetta, Cucinotto, I, Ronzino, G, Santonocito, Concetta, Tornesello, Assunta, De Giorgio, Mr, Lucci Cordisco, Emanuela, Minucci, Angelo, Genuardi, Maurizio, Capoluongo E (ORCID:0000-0001-9872-0572), De Matteis E, Santonocito C (ORCID:0000-0003-3624-1386), Tornesello A (ORCID:0000-0002-7485-7440), Lucci Cordisco E (ORCID:0000-0002-6279-7604), Minucci A, and Genuardi M. (ORCID:0000-0002-7410-8351)

Abstract

No abstract available

Published
2021

21. Definition and management of colorectal polyposis not associated with APC/MUTYH germline pathogenic variants: AIFEG consensus statement

Author

Urso, Emanuele Damiano Luca, primary, Ponz de Leon, Maurizio, additional, Vitellaro, Marco, additional, Piozzi, Guglielmo Niccolò, additional, Bao, Quoc Riccardo, additional, Martayan, Aline, additional, Remo, Andrea, additional, Stigliano, Vittoria, additional, Oliani, Cristina, additional, Lucci Cordisco, Emanuela, additional, Pucciarelli, Salvatore, additional, Ranzani, Guglielmina Nadia, additional, Viel, Alessandra, additional, Adami, Francesca, additional, Alducci, Elisa, additional, Amadori, Lucia, additional, Arcangeli, Valentina, additional, Balestrino, Luisa, additional, Barana, Daniela, additional, Bertario, Lucio, additional, Bonanni, Bernardo, additional, Boni, Stefania, additional, Bullian, Pierluigi, additional, Carbonardi, Fiorella, additional, Carnevali, Ileana, additional, Castelli, Paola, additional, Celotto, Francesco, additional, Cini, Giulia, additional, Crivellari, Gino, additional, Libera, Duilio Della, additional, Dell'elice, Anastasia, additional, Digennaro, Maria, additional, D'urso, Alessandra, additional, Fabretto, Antonella, additional, Fanale, Daniele, additional, Feroce, Irene, additional, Furlan, Daniela, additional, Ghiorzo, Paola, additional, Giacché, Mara, additional, Gusella, Milena, additional, Liserre, Barbara, additional, Mammi, Isabella, additional, Massuras, Stefania, additional, Mazzà, Daniela, additional, Mollica, Eleonora, additional, Morabito, Alberto, additional, Nardo, Giorgia, additional, Palermo, Flavia, additional, Panizza, Elena, additional, Patruno, Margherita, additional, Pedroni, Monica, additional, Pensotti, Valeria Grazia Maria, additional, Piozzi, Guglielmo Niccolo, additional, Pozzi, Simonetta, additional, Presi, Silvia, additional, Puzzono, Marta, additional, Ravegnani, Mila, additional, Ricci, Maria Teresa, additional, Roncucci, Luca, additional, Rossi, Giovanni Battsita, additional, Sala, Elena Maria, additional, Mete, Lupe Sanchez, additional, Sandonà, Daniele, additional, Sciallero, Stefania, additional, Serrano, Davide, additional, Signoroni, Stefano, additional, Spina, Francesca, additional, Taborelli, Monica, additional, Tedaldi, Gianluca, additional, Tibiletti, Maria Grazia, additional, Tognazzo, Silvia, additional, Tolva, Gianluca, additional, Trovato, Cristina Maria Concetta, additional, Turchetti, Daniela, additional, Urso, Emanuele Damiano Luca, additional, Varvara, Dora, additional, Vivanet, Caterina, additional, Zovato, Stefania, additional, and Zuppardo, Raffaella Alessia, additional

Published
2021
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26. Correction: Intrafamilial communication of hereditary breast and ovarian cancer genetic information in Italian women: towards a personalised approach

Author

Di Pietro, Maria Luisa, primary, Zaçe, Drieda, additional, Orfino, Alessia, additional, Di Raimo, Francesca Romana, additional, Poscia, Andrea, additional, de Matteis, Elisabetta, additional, Turchetti, Daniela, additional, Godino, Lea, additional, Bertonazzi, Benedetta, additional, Franiuk, Marzena, additional, Bruzzone, Carla, additional, Varesco, Liliana, additional, Lucci-Cordisco, Emanuela, additional, and Genuardi, Maurizio, additional

Published
2020
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27. Intrafamilial communication of hereditary breast and ovarian cancer genetic information in Italian women: towards a personalised approach

Author

Di Pietro, Maria Luisa, primary, Zaçe, Drieda, additional, Orfino, Alessia, additional, Di Raimo, Francesca Romana, additional, Poscia, Andrea, additional, de Matteis, Elisabetta, additional, Turchetti, Daniela, additional, Godino, Lea, additional, Bertonazzi, Benedetta, additional, Franiuk, Marzena, additional, Bruzzone, Carla, additional, Varesco, Liliana, additional, Lucci-Cordisco, Emanuela, additional, and Genuardi, Maurizio, additional

Published
2020
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28. Cost-effectiveness analysis of genetic diagnostic strategies for Lynch syndrome in Italy

Author

Pastorino, Roberta, primary, Basile, Michele, additional, Tognetto, Alessia, additional, Di Marco, Marco, additional, Grossi, Adriano, additional, Lucci-Cordisco, Emanuela, additional, Scaldaferri, Franco, additional, De Censi, Andrea, additional, Federici, Antonio, additional, Villari, Paolo, additional, Genuardi, Maurizio, additional, Ricciardi, Walter, additional, and Boccia, Stefania, additional

Published
2020
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29. A new founder BRCA1 haplotype identified in the Puglia region is associated with a specific age-related cancer onset in three unrelated families

Author

Capoluongo, Ettore, primary, De Matteis, Elisabetta, additional, Cucinotto, Iole, additional, Ronzino, Graziana, additional, Santonocito, Concetta, additional, Tornesello, Assunta, additional, De Giorgio, Maria Rita, additional, Lucci Cordisco, Emanuela, additional, Minucci, Angelo, additional, and Genuardi, Maurizio, additional

Published
2020
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30. Orbital Desmoid-Type Fibromatosis: A Case Report and Literature Review

Author

Moro, Alessandro, De Angelis, Paolo, Gasparini, Giulio, Pelo, Sandro, Petrone, Gianluigi, Lucci Cordisco, Emanuela, Garagiola, Umberto, D'Amato, Giuseppe, Saponaro, Gianmarco, Moro, Alessandro (ORCID:0000-0002-6708-171X), Gasparini, Giulio (ORCID:0000-0001-5091-5178), Pelo, Sandro (ORCID:0000-0002-7141-0395), Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Moro, Alessandro, De Angelis, Paolo, Gasparini, Giulio, Pelo, Sandro, Petrone, Gianluigi, Lucci Cordisco, Emanuela, Garagiola, Umberto, D'Amato, Giuseppe, Saponaro, Gianmarco, Moro, Alessandro (ORCID:0000-0002-6708-171X), Gasparini, Giulio (ORCID:0000-0001-5091-5178), Pelo, Sandro (ORCID:0000-0002-7141-0395), and Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604)

Abstract

Purpose: Desmoid-type fibromatosis is a benign fibrous neoplasia originating from connective tissue, fascial planes, and musculoaponeurotic structures of the muscles. Currently, there is no evidence-based treatment approach available for desmoid fibromatosis. In this article, a case of a patient in the pediatric age affected by desmoid fibromatosis localized in the orbit is presented. The aim of the article is to describe this unusual and rare location for the desmoid fibromatosis and outline the principle phases in the decision-making process and the therapeutic alternatives for a patient affected by desmoid fibromatosis. Methods: The protocol of this review included study objectives, search strategy, and selection criteria. The primary end point of this study was to analyze the head and neck desmoid fibromatosis. The secondary end point was to identify the available therapies and assess their specific indications. Results: The mean age of patients was 18.9 years ranging from 0 to 66, and 52% were female. A bimodal age distribution was observed, and two age peaks were identified: 0-14 years (57%) and 28-42 years (18%). The most common involved areas were the mandible (25%) followed by the neck (21%). In 86% of the cases, the treatment was the surgical resection of the disease, and only in 5% of the cases, the surgical resection was followed by adjuvant radiotherapy. Conclusion: The orbital location is extremely rare, especially in the pediatric population. The management of desmoid fibromatosis is based on the function preservation and the maintenance of a good quality of life, but in case of symptomatic patients or aggressive course of the disease or risk of functional damages, the surgical approach may be considered. Therapeutic alternatives to surgical resection are radiotherapy and systemic therapy.

Published
2018

31. Safety of antithrombotic therapy in subjects with hereditary hemorrhagic telangiectasia: prospective data from a multidisciplinary working group

Author

Gaetani, Eleonora, Agostini, Fabiana, Porfidia, Angelo, Giarretta, Igor, Feliciani, Daniela, Di Martino, Luigi, Tortora, Annalisa, Gasbarrini, Antonio, Pola, Roberto, Passali, Giulio Cesare, Riccioni, Maria Elena, Puca, Alfredo, Sturiale, Carmelo Lucio, Riccardi, L, Di Stasi, Carmine, Contegiacomo, Andrea, Del Ciello AE, Ferraro, Pietro Manuel, Cavaliere, Af, Lucci Cordisco, Emanuela, Zampino, Giuseppe, Giorgio, Valentina, Ojetti, Veronica, Marrone, G, Spoletini, G, Locorotondo, G, Lanza, Gaetano Antonio, De Candia, Erica, Peppucci, Elisabetta, Corina, Luigi, and Lombardi, Mt.

Subjects
Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Blood transfusion, medicine.medical_treatment, Interdisciplinary Research, Settore MED/27 - NEUROCHIRURGIA, lcsh:Medicine, antithrombotic therapy, 030105 genetics & heredity, Hemoglobins, 03 medical and health sciences, 0302 clinical medicine, Fibrinolytic Agents, Antithrombotic, medicine, Humans, Pharmacology (medical), Prospective Studies, Prospective cohort study, Telangiectasia, Letter to the Editor, Genetics (clinical), Aged, Hereditary Hemorrhagic Teleangectasia, antithrombotic therapy, business.industry, lcsh:R, Settore MED/09 - MEDICINA INTERNA, Autosomal dominant trait, General Medicine, Middle Aged, Hereditary Hemorrhagic Teleangectasia, Interim analysis, medicine.disease, Thrombosis, Discontinuation, Female, Telangiectasia, Hereditary Hemorrhagic, Settore MED/31 - OTORINOLARINGOIATRIA, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Subjects with the rare autosomal dominant disease Hereditary Hemorrhagic Telangiectasia (HHT) may develop medical conditions that require antithrombotic therapy (AT). However, safety of AT is uncertain in these patients and the only data currently available derive from retrospective analyses of registries and/or databases. At the HHT Centre of the ‘Fondazione Policlinico Universitario A. Gemelli IRCCS’ (Rome, Italy), a prospective study is currently ongoing to evaluate the safety of AT in subjects affected by HHT. The study is enrolling subjects with a definite diagnosis of HHT who receive an AT prescription by one of the physicians of the HHT Centre. The primary outcome is the number of hemorrhagic events, distinguished in major, clinically relevant non-major (CRNM), and minor bleedings, according to the criteria of the International Society on Thrombosis and Hemostasis (ISTH). Another primary outcome is worsening of epistaxis upon initiation of AT, assessed using the internationally accepted Epistaxis Severity Score (ESS). Additional outcomes are changes in hemoglobin levels and changes in the need of blood transfusion after initiation of AT. Here, we present the results of an interim analysis, conducted on the 12 HHT subjects that have been enrolled so far. After a mean follow-up of 6.5 ± 0.8 months, no major bleedings, no CRNM bleedings, and no minor bleedings different from epistaxis were recorded. Worsening of epistaxis upon initiation of AT was documented only in one patient, but did not require discontinuation of AT. There were no significant changes in the mean ESS measured before and after initiation of AT. There were no significant changes in hemoglobin levels and need for blood transfusion after initiation of AT. Although preliminary, these are the first prospective data on the safety of AT in HHT patients. Our interim analysis suggests that, when prescribed by experienced physicians in a multidisciplinary setting, AT is well tolerated by HHT patients. More patients and a longer follow-up are needed to confirm these findings.

Published
2019
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32. The Spectrum of WRN Mutations in Werner Syndrome Patients

Author

Huang, Shurong, Lee, Lin, Hanson, Nancy B., Lenaerts, Catherine, Hoehn, Holger, Poot, Martin, Rubin, Craig D., Chen, Da-Fu, Yang, Chih-Chao, Juch, Heike, Dorn, Thomas, Spiegel, Roland, Oral, Elif Arioglu, Abid, Mohammed, Battisti, Carla, Lucci-Cordisco, Emanuela, Neri, Giovanni, Steed, Erin H., Kidd, Alexa, Isley, William, Showalter, David, Vittone, Janet L., Konstantinow, Alexander, Ring, Johannes, Meyer, Peter, Wenger, Sharon L., von Herbay, Axel, Wollina, Uwe, Schuelke, Markus, Huizenga, Carin R., Leistritz, Dru F., Martin, George M., Mian, Saira I., and Oshima, Junko

Published
2006
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33. Cost-effectiveness analysis of genetic diagnostic strategies for Lynch syndrome in Italy

Author

Pastorino, Roberta, Basile, Mattia, Tognetto, A., Di Marco, M., Grossi, A., Lucci Cordisco, Emanuela, Scaldaferri, Franco, de Censi, A., Federici, Anna, Villari, Paolo, Genuardi, Maurizio, Ricciardi, Walter, Boccia, Stefania, Pastorino R. (ORCID:0000-0001-5013-0733), Basile M., Lucci-Cordisco E. (ORCID:0000-0002-6279-7604), Scaldaferri F. (ORCID:0000-0001-8334-7541), Federici A., Villari P., Genuardi M. (ORCID:0000-0002-7410-8351), Ricciardi W. (ORCID:0000-0002-5655-688X), Boccia S. (ORCID:0000-0002-1864-749X), Pastorino, Roberta, Basile, Mattia, Tognetto, A., Di Marco, M., Grossi, A., Lucci Cordisco, Emanuela, Scaldaferri, Franco, de Censi, A., Federici, Anna, Villari, Paolo, Genuardi, Maurizio, Ricciardi, Walter, Boccia, Stefania, Pastorino R. (ORCID:0000-0001-5013-0733), Basile M., Lucci-Cordisco E. (ORCID:0000-0002-6279-7604), Scaldaferri F. (ORCID:0000-0001-8334-7541), Federici A., Villari P., Genuardi M. (ORCID:0000-0002-7410-8351), Ricciardi W. (ORCID:0000-0002-5655-688X), and Boccia S. (ORCID:0000-0002-1864-749X)

Abstract

Lynch syndrome (LS) is an autosomal dominant condition caused by pathogenic variants in mismatch repair (MMR) genes that predispose individuals to different malignancies, such as colorectal cancer (CRC) and endometrial cancer. Current guidelines recommended testing for LS in individuals with newly diagnosed CRC to reduce cancer morbidity and mortality in relatives. Economic evaluations in support of such approach, however, are not available in Italy. We developed a decision-analytic model to analyze the cost-effectiveness of LS screening from the perspective of the Italian National Health System. Three testing strategies: the sequencing of all MMR genes without prior tumor analysis (Strategy 1), a sequential IHC and MS-MLPA analysis (Strategy 2), and an age-targeted strategy with a revised Bethesda criteria assessment before IHC and methylation-specific MLPA for patients ≥ than 70 years old (Strategy 3) were analyzed and compared to the “no testing” strategy. Quality Adjusted Life Years (QALYs) in relatives after colonoscopy, aspirin prophylaxis and an intensive gynecological surveillance were estimated through a Markov model. Assuming a CRC incidence rate of 0.09% and a share of patients affected by LS equal to 2.81%, the number of detected pathogenic variants among CRC cases ranges, in a given year, between 910 and 1167 depending on the testing strategy employed. The testing strategies investigated, provided one-time to the entire eligible population (CRC patients), were associated with an overall cost ranging between €1,753,059.93-€10,388,000.00. The incremental cost-effectiveness ratios of the Markov model ranged from €941.24 /QALY to €1,681.93 /QALY, thus supporting that “universal testing” versus “no testing” is cost-effective, but not necessarily in comparison with age-targeted strategies. This is the first economic evaluation on different testing strategies for LS in Italy. The results might support the introduction of cost-effective recommendations for LS s

Published
2020

34. Intrafamilial communication of hereditary breast and ovarian cancer genetic information in Italian women: towards a personalised approach

Author

Di Pietro, Maria Luisa, Zace, Drieda, Orfino, Alessia, Romana Di Raimo, Francesca, Poscia, Andrea, De Matteis, Elisabetta, Turchetti, Daniela, Godino, Lea, Bertonazzi, Benedetta, Franiuk, Marzena, Bruzzone, Carla, Varesco, Liliana, Lucci Cordisco, Emanuela, Genuardi, Maurizio, Maria Luisa Di Pietro (ORCID:0000-0002-3893-8788), Drieda Zace, Andrea Poscia (ORCID:0000-0002-7616-3389), Elisabetta de Matteis, Emanuela Lucci-Cordisco (ORCID:0000-0002-6279-7604), Maurizio Genuardi (ORCID:0000-0002-7410-8351), Di Pietro, Maria Luisa, Zace, Drieda, Orfino, Alessia, Romana Di Raimo, Francesca, Poscia, Andrea, De Matteis, Elisabetta, Turchetti, Daniela, Godino, Lea, Bertonazzi, Benedetta, Franiuk, Marzena, Bruzzone, Carla, Varesco, Liliana, Lucci Cordisco, Emanuela, Genuardi, Maurizio, Maria Luisa Di Pietro (ORCID:0000-0002-3893-8788), Drieda Zace, Andrea Poscia (ORCID:0000-0002-7616-3389), Elisabetta de Matteis, Emanuela Lucci-Cordisco (ORCID:0000-0002-6279-7604), and Maurizio Genuardi (ORCID:0000-0002-7410-8351)

Abstract

Genomic testing expansion is accompanied by an increasing need for genetic counselling and intrafamilial communication. Genetic counselling can play an important role in facilitating intrafamilial communication and relationships. We conducted a cross-sectional, multicenter study including 252 Italian women, using a questionnaire divided in two sections, the first one to be filled after the pre-test counselling and the second after receiving BRCA test results. We assessed the factors influencing intrafamilial disclosure of genetic information for hereditary breast and ovarian cancer, family members with whom probands are more prone to share genetic information, and the perceived understanding of information received by counselees during genetic counselling. Women were accompanied to the counselling more often by their husband/partner. Among those with a positive BRCA test result, 49% intended to communicate it to their offspring and 27% to their husband/ partner. Younger women, those living with their husband/partner, and those who described family communication as open/ profound and spontaneous/sincere had a higher probability of being accompanied during genetic counselling and discuss about it with relatives. Spontaneous/sincere or open/profound family communication and joyful/happy familial relationships were associated with the decision to undergo genetic testing as a responsibility towards relatives. Women had a good understanding of counselling contents (mean score 9.27 in a scale 1–10). Genetic counselling providers should consider that genetic information disclosure does not depend only on the clarity of the information provided, but also on pre-existing intrafamilial communication and relationships, family structure and marital status, indicating the need for a personalised approach accounting for these factors.

Published
2020

36. Identification of Muir–Torre syndrome among patients with sebaceous tumors and keratoacanthomas: Role of clinical features, microsatellite instability, and immunohistochemistry

Author

Ponti, Giovanni, Losi, Lorena, Di Gregorio, Carmela, Roncucci, Luca, Pedroni, Monica, Scarselli, Alessandra, Benatti, Piero, Seidenari, Stefania, Pellacani, Giovanni, Lembo, Luigi, Rossi, Giuseppina, Marino, Massimiliano, Lucci-Cordisco, Emanuela, and de Leon, Maurizio Ponz

Published
2005
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37. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Parsons, Michael T., primary, Tudini, Emma, additional, Li, Hongyan, additional, Hahnen, Eric, additional, Wappenschmidt, Barbara, additional, Feliubadaló, Lidia, additional, Aalfs, Cora M., additional, Agata, Simona, additional, Aittomäki, Kristiina, additional, Alducci, Elisa, additional, Alonso‐Cerezo, María Concepción, additional, Arnold, Norbert, additional, Auber, Bernd, additional, Austin, Rachel, additional, Azzollini, Jacopo, additional, Balmaña, Judith, additional, Barbieri, Elena, additional, Bartram, Claus R., additional, Blanco, Ana, additional, Blümcke, Britta, additional, Bonache, Sandra, additional, Bonanni, Bernardo, additional, Borg, Åke, additional, Bortesi, Beatrice, additional, Brunet, Joan, additional, Bruzzone, Carla, additional, Bucksch, Karolin, additional, Cagnoli, Giulia, additional, Caldés, Trinidad, additional, Caliebe, Almuth, additional, Caligo, Maria A., additional, Calvello, Mariarosaria, additional, Capone, Gabriele L., additional, Caputo, Sandrine M., additional, Carnevali, Ileana, additional, Carrasco, Estela, additional, Caux‐Moncoutier, Virginie, additional, Cavalli, Pietro, additional, Cini, Giulia, additional, Clarke, Edward M., additional, Concolino, Paola, additional, Cops, Elisa J., additional, Cortesi, Laura, additional, Couch, Fergus J., additional, Darder, Esther, additional, Hoya, Miguel, additional, Dean, Michael, additional, Debatin, Irmgard, additional, Del Valle, Jesús, additional, Delnatte, Capucine, additional, Derive, Nicolas, additional, Diez, Orland, additional, Ditsch, Nina, additional, Domchek, Susan M., additional, Dutrannoy, Véronique, additional, Eccles, Diana M., additional, Ehrencrona, Hans, additional, Enders, Ute, additional, Evans, D. Gareth, additional, Farra, Chantal, additional, Faust, Ulrike, additional, Felbor, Ute, additional, Feroce, Irene, additional, Fine, Miriam, additional, Foulkes, William D., additional, Galvao, Henrique C.R., additional, Gambino, Gaetana, additional, Gehrig, Andrea, additional, Gensini, Francesca, additional, Gerdes, Anne‐Marie, additional, Germani, Aldo, additional, Giesecke, Jutta, additional, Gismondi, Viviana, additional, Gómez, Carolina, additional, Garcia, Encarna B., additional, González, Sara, additional, Grau, Elia, additional, Grill, Sabine, additional, Gross, Eva, additional, Guerrieri‐Gonzaga, Aliana, additional, Guillaud‐Bataille, Marine, additional, Gutiérrez‐Enríquez, Sara, additional, Haaf, Thomas, additional, Hackmann, Karl, additional, Hansen, Thomas V.O., additional, Harris, Marion, additional, Hauke, Jan, additional, Heinrich, Tilman, additional, Hellebrand, Heide, additional, Herold, Karen N., additional, Honisch, Ellen, additional, Horvath, Judit, additional, Houdayer, Claude, additional, Hübbel, Verena, additional, Iglesias, Silvia, additional, Izquierdo, Angel, additional, James, Paul A., additional, Janssen, Linda A.M., additional, Jeschke, Udo, additional, Kaulfuß, Silke, additional, Keupp, Katharina, additional, Kiechle, Marion, additional, Kölbl, Alexandra, additional, Krieger, Sophie, additional, Kruse, Torben A., additional, Kvist, Anders, additional, Lalloo, Fiona, additional, Larsen, Mirjam, additional, Lattimore, Vanessa L., additional, Lautrup, Charlotte, additional, Ledig, Susanne, additional, Leinert, Elena, additional, Lewis, Alexandra L., additional, Lim, Joanna, additional, Loeffler, Markus, additional, López‐Fernández, Adrià, additional, Lucci‐Cordisco, Emanuela, additional, Maass, Nicolai, additional, Manoukian, Siranoush, additional, Marabelli, Monica, additional, Matricardi, Laura, additional, Meindl, Alfons, additional, Michelli, Rodrigo D., additional, Moghadasi, Setareh, additional, Moles‐Fernández, Alejandro, additional, Montagna, Marco, additional, Montalban, Gemma, additional, Monteiro, Alvaro N., additional, Montes, Eva, additional, Mori, Luigi, additional, Moserle, Lidia, additional, Müller, Clemens R., additional, Mundhenke, Christoph, additional, Naldi, Nadia, additional, Nathanson, Katherine L., additional, Navarro, Matilde, additional, Nevanlinna, Heli, additional, Nichols, Cassandra B., additional, Niederacher, Dieter, additional, Nielsen, Henriette R., additional, Ong, Kai‐ren, additional, Pachter, Nicholas, additional, Palmero, Edenir I., additional, Papi, Laura, additional, Pedersen, Inge Sokilde, additional, Peissel, Bernard, additional, Perez‐Segura, Pedro, additional, Pfeifer, Katharina, additional, Pineda, Marta, additional, Pohl‐Rescigno, Esther, additional, Poplawski, Nicola K., additional, Porfirio, Berardino, additional, Quante, Anne S., additional, Ramser, Juliane, additional, Reis, Rui M., additional, Revillion, Françoise, additional, Rhiem, Kerstin, additional, Riboli, Barbara, additional, Ritter, Julia, additional, Rivera, Daniela, additional, Rofes, Paula, additional, Rump, Andreas, additional, Salinas, Monica, additional, Sánchez de Abajo, Ana María, additional, Schmidt, Gunnar, additional, Schoenwiese, Ulrike, additional, Seggewiß, Jochen, additional, Solanes, Ares, additional, Steinemann, Doris, additional, Stiller, Mathias, additional, Stoppa‐Lyonnet, Dominique, additional, Sullivan, Kelly J., additional, Susman, Rachel, additional, Sutter, Christian, additional, Tavtigian, Sean V., additional, Teo, Soo H., additional, Teulé, Alex, additional, Thomassen, Mads, additional, Tibiletti, Maria Grazia, additional, Tischkowitz, Marc, additional, Tognazzo, Silvia, additional, Toland, Amanda E., additional, Tornero, Eva, additional, Törngren, Therese, additional, Torres‐Esquius, Sara, additional, Toss, Angela, additional, Trainer, Alison H., additional, Tucker, Katherine M., additional, Asperen, Christi J., additional, Mackelenbergh, Marion T., additional, Varesco, Liliana, additional, Vargas‐Parra, Gardenia, additional, Varon, Raymonda, additional, Vega, Ana, additional, Velasco, Ángela, additional, Vesper, Anne‐Sophie, additional, Viel, Alessandra, additional, Vreeswijk, Maaike P. G., additional, Wagner, Sebastian A., additional, Waha, Anke, additional, Walker, Logan C., additional, Walters, Rhiannon J., additional, Wang‐Gohrke, Shan, additional, Weber, Bernhard H. F., additional, Weichert, Wilko, additional, Wieland, Kerstin, additional, Wiesmüller, Lisa, additional, Witzel, Isabell, additional, Wöckel, Achim, additional, Woodward, Emma R., additional, Zachariae, Silke, additional, Zampiga, Valentina, additional, Zeder‐Göß, Christine, additional, Investigators, KConFab, additional, Lázaro, Conxi, additional, Nicolo, Arcangela, additional, Radice, Paolo, additional, Engel, Christoph, additional, Schmutzler, Rita K., additional, Goldgar, David E., additional, and Spurdle, Amanda B., additional

Published
2019
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38. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Parsons, Michael T., Tudini, Emma, Li, Hongyan, Hahnen, Eric, Wappenschmidt, Barbara, Feliubadalo, Lidia, Aalfs, Cora M., Agata, Simona, Aittomaki, Kristiina, Alducci, Elisa, Concepcion Alonso-Cerezo, Maria, Arnold, Norbert, Auber, Bernd, Austin, Rachel, Azzollini, Jacopo, Balmana, Judith, Barbieri, Elena, Bartram, Claus R., Blanco, Ana, Bluemcke, Britta, Bonache, Sandra, Bonanni, Bernardo, Borg, Ake, Bortesi, Beatrice, Brunet, Joan, Bruzzone, Carla, Bucksch, Karolin, Cagnoli, Giulia, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Calvello, Mariarosaria, Capone, Gabriele L., Caputo, Sandrine M., Carnevali, Ileana, Carrasco, Estela, Caux-Moncoutier, Virginie, Cavalli, Pietro, Cini, Giulia, Clarke, Edward M., Concolino, Paola, Cops, Elisa J., Cortesi, Laura, Couch, Fergus J., Darder, Esther, de la Hoya, Miguel, Dean, Michael, Debatin, Irmgard, Del Valle, Jesus, Delnatte, Capucine, Derive, Nicolas, Diez, Orland, Ditsch, Nina, Domchek, Susan M., Dutrannoy, Veronique, Eccles, Diana M., Ehrencrona, Hans, Enders, Ute, Evans, D. Gareth, Farra, Chantal, Faust, Ulrike, Felbor, Ute, Feroce, Irene, Fine, Miriam, Foulkes, William D., Galvao, Henrique Cr, Gambino, Gaetana, Gehrig, Andrea, Gensini, Francesca, Gerdes, Anne-Marie, Germani, Aldo, Giesecke, Jutta, Gismondi, Viviana, Gomez, Carolina, Garcia, Encarna B. Gomez, Gonzalez, Sara, Grau, Elia, Grill, Sabine, Gross, Eva, Guerrieri-Gonzaga, Aliana, Guillaud-Bataille, Marine, Gutierrez-Enriquez, Sara, Haaf, Thomas, Hackmann, Karl, Hansen, Thomas Vo, Harris, Marion, Hauke, Jan, Heinrich, Tilman, Hellebrand, Heide, Herold, Karen N., Honisch, Ellen, Horvath, Judit, Houdayer, Claude, Huebbel, Verena, Iglesias, Silvia, Izquierdo, Angel, James, Paul A., Janssen, Linda Am, Jeschke, Udo, Kaulfuss, Silke, Keupp, Katharina, Kiechle, Marion, Koelbl, Alexandra, Krieger, Sophie, Kruse, Torben A., Kvist, Anders, Lalloo, Fiona, Larsen, Mirjam, Lattimore, Vanessa L., Lautrup, Charlotte, Ledig, Susanne, Leinert, Elena, Lewis, Alexandra L., Lim, Joanna, Loeffler, Markus, Lopez-Fernandez, Adria, Lucci-Cordisco, Emanuela, Maass, Nicolai, Manoukian, Siranoush, Marabelli, Monica, Matricardi, Laura, Meindl, Alfons, Michelli, Rodrigo D., Moghadasi, Setareh, Moles-Fernandez, Alejandro, Montagna, Marco, Montalban, Gemma, Monteiro, Alvaro N., Montes, Eva, Mori, Luigi, Moserle, Lidia, Mueller, Clemens R., Mundhenke, Christoph, Naldi, Nadia, Nathanson, Katherine L., Navarro, Matilde, Nevanlinna, Heli, Nichols, Cassandra B., Niederacher, Dieter, Nielsen, Henriette R., Ong, Kai-ren, Pachter, Nicholas, Palmero, Edenir, I, Papi, Laura, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Pfeifer, Katharina, Pineda, Marta, Pohl-Rescigno, Esther, Poplawski, Nicola K., Porfirio, Berardino, Quante, Anne S., Ramser, Juliane, Reis, Rui M., Revillion, Francoise, Rhiem, Kerstin, Riboli, Barbara, Ritter, Julia, Rivera, Daniela, Rofes, Paula, Rump, Andreas, Salinas, Monica, Sanchez de Abajo, Ana Maria, Schmidt, Gunnar, Schoenwiese, Ulrike, Seggewiss, Jochen, Solanes, Ares, Steinemann, Doris, Stiller, Mathias, Stoppa-Lyonnet, Dominique, Sullivan, Kelly J., Susman, Rachel, Sutter, Christian, Tavtigian, Sean, V, Teo, Soo H., Teule, Alex, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Tornero, Eva, Torngren, Therese, Torres-Esquius, Sara, Toss, Angela, Trainer, Alison H., Tucker, Katherine M., van Asperen, Christi J., van Mackelenbergh, Marion T., Varesco, Liliana, Vargas-Parra, Gardenia, Varon, Raymonda, Vega, Ana, Velasco, Angela, Vesper, Anne-Sophie, Viel, Alessandra, Vreeswijk, Maaike P. G., Wagner, Sebastian A., Waha, Anke, Walker, Logan C., Walters, Rhiannon J., Wang-Gohrke, Shan, Weber, Bernhard H. F., Weichert, Wilko, Wieland, Kerstin, Wiesmueller, Lisa, Witzel, Isabell, Woeckel, Achim, Woodward, Emma R., Zachariae, Silke, Zampiga, Valentina, Zeder-Goss, Christine, Lazaro, Conxi, De Nicolo, Arcangela, Radice, Paolo, Engel, Christoph, Schmutzler, Rita K., Goldgar, David E., Spurdle, Amanda B., Parsons, Michael T., Tudini, Emma, Li, Hongyan, Hahnen, Eric, Wappenschmidt, Barbara, Feliubadalo, Lidia, Aalfs, Cora M., Agata, Simona, Aittomaki, Kristiina, Alducci, Elisa, Concepcion Alonso-Cerezo, Maria, Arnold, Norbert, Auber, Bernd, Austin, Rachel, Azzollini, Jacopo, Balmana, Judith, Barbieri, Elena, Bartram, Claus R., Blanco, Ana, Bluemcke, Britta, Bonache, Sandra, Bonanni, Bernardo, Borg, Ake, Bortesi, Beatrice, Brunet, Joan, Bruzzone, Carla, Bucksch, Karolin, Cagnoli, Giulia, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Calvello, Mariarosaria, Capone, Gabriele L., Caputo, Sandrine M., Carnevali, Ileana, Carrasco, Estela, Caux-Moncoutier, Virginie, Cavalli, Pietro, Cini, Giulia, Clarke, Edward M., Concolino, Paola, Cops, Elisa J., Cortesi, Laura, Couch, Fergus J., Darder, Esther, de la Hoya, Miguel, Dean, Michael, Debatin, Irmgard, Del Valle, Jesus, Delnatte, Capucine, Derive, Nicolas, Diez, Orland, Ditsch, Nina, Domchek, Susan M., Dutrannoy, Veronique, Eccles, Diana M., Ehrencrona, Hans, Enders, Ute, Evans, D. Gareth, Farra, Chantal, Faust, Ulrike, Felbor, Ute, Feroce, Irene, Fine, Miriam, Foulkes, William D., Galvao, Henrique Cr, Gambino, Gaetana, Gehrig, Andrea, Gensini, Francesca, Gerdes, Anne-Marie, Germani, Aldo, Giesecke, Jutta, Gismondi, Viviana, Gomez, Carolina, Garcia, Encarna B. Gomez, Gonzalez, Sara, Grau, Elia, Grill, Sabine, Gross, Eva, Guerrieri-Gonzaga, Aliana, Guillaud-Bataille, Marine, Gutierrez-Enriquez, Sara, Haaf, Thomas, Hackmann, Karl, Hansen, Thomas Vo, Harris, Marion, Hauke, Jan, Heinrich, Tilman, Hellebrand, Heide, Herold, Karen N., Honisch, Ellen, Horvath, Judit, Houdayer, Claude, Huebbel, Verena, Iglesias, Silvia, Izquierdo, Angel, James, Paul A., Janssen, Linda Am, Jeschke, Udo, Kaulfuss, Silke, Keupp, Katharina, Kiechle, Marion, Koelbl, Alexandra, Krieger, Sophie, Kruse, Torben A., Kvist, Anders, Lalloo, Fiona, Larsen, Mirjam, Lattimore, Vanessa L., Lautrup, Charlotte, Ledig, Susanne, Leinert, Elena, Lewis, Alexandra L., Lim, Joanna, Loeffler, Markus, Lopez-Fernandez, Adria, Lucci-Cordisco, Emanuela, Maass, Nicolai, Manoukian, Siranoush, Marabelli, Monica, Matricardi, Laura, Meindl, Alfons, Michelli, Rodrigo D., Moghadasi, Setareh, Moles-Fernandez, Alejandro, Montagna, Marco, Montalban, Gemma, Monteiro, Alvaro N., Montes, Eva, Mori, Luigi, Moserle, Lidia, Mueller, Clemens R., Mundhenke, Christoph, Naldi, Nadia, Nathanson, Katherine L., Navarro, Matilde, Nevanlinna, Heli, Nichols, Cassandra B., Niederacher, Dieter, Nielsen, Henriette R., Ong, Kai-ren, Pachter, Nicholas, Palmero, Edenir, I, Papi, Laura, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Pfeifer, Katharina, Pineda, Marta, Pohl-Rescigno, Esther, Poplawski, Nicola K., Porfirio, Berardino, Quante, Anne S., Ramser, Juliane, Reis, Rui M., Revillion, Francoise, Rhiem, Kerstin, Riboli, Barbara, Ritter, Julia, Rivera, Daniela, Rofes, Paula, Rump, Andreas, Salinas, Monica, Sanchez de Abajo, Ana Maria, Schmidt, Gunnar, Schoenwiese, Ulrike, Seggewiss, Jochen, Solanes, Ares, Steinemann, Doris, Stiller, Mathias, Stoppa-Lyonnet, Dominique, Sullivan, Kelly J., Susman, Rachel, Sutter, Christian, Tavtigian, Sean, V, Teo, Soo H., Teule, Alex, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Tornero, Eva, Torngren, Therese, Torres-Esquius, Sara, Toss, Angela, Trainer, Alison H., Tucker, Katherine M., van Asperen, Christi J., van Mackelenbergh, Marion T., Varesco, Liliana, Vargas-Parra, Gardenia, Varon, Raymonda, Vega, Ana, Velasco, Angela, Vesper, Anne-Sophie, Viel, Alessandra, Vreeswijk, Maaike P. G., Wagner, Sebastian A., Waha, Anke, Walker, Logan C., Walters, Rhiannon J., Wang-Gohrke, Shan, Weber, Bernhard H. F., Weichert, Wilko, Wieland, Kerstin, Wiesmueller, Lisa, Witzel, Isabell, Woeckel, Achim, Woodward, Emma R., Zachariae, Silke, Zampiga, Valentina, Zeder-Goss, Christine, Lazaro, Conxi, De Nicolo, Arcangela, Radice, Paolo, Engel, Christoph, Schmutzler, Rita K., Goldgar, David E., and Spurdle, Amanda B.

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Published
2019

39. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., and Lucci Cordisco E. (ORCID:0000-0002-6279-7604)

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Published
2019

40. A new founder BRCA1 haplotype identified in the Puglia region is associated with a specific age-related cancer onset in three unrelated families.

Author

Capoluongo, Ettore, De Matteis, Elisabetta, Cucinotto, Iole, Ronzino, Graziana, Santonocito, Concetta, Tornesello, Assunta, De Giorgio, Maria Rita, Lucci Cordisco, Emanuela, Minucci, Angelo, and Genuardi, Maurizio

Subjects
BRCA genes, AGE factors in cancer, HAPLOTYPES, GENETIC databases, HEAD & neck cancer, FAMILIES, CANCER genes
Abstract

Keywords: BRCA1/2; founder mutation; HBOC; novel mutations EN BRCA1/2 founder mutation HBOC novel mutations e95 e98 4 02/06/21 20210301 NES 210301 To the Editor, Inherited pathogenic variants (PVs) in cancer susceptibility genes account for approximately 5%-10% of all breast (BC) and ovarian cancers (OvCa), with a large proportion of mutations found in families with several affected patients over multiple generations [[1]], [[2]], [[3]]. Graph: Figure 1: Family pedigree by cancer gene software BRCAPRO v6.The proband is indicated with an arrow. [Extracted from the article]

Published
2021
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41. Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis.

Author

Tricarico, Rossella, Cortellino, Salvatore, Riccio, Antonio, Jagmohan Changur, Shantie, Van Der Klift, Helen, Wijnen, Juul, Turner, David, Ventura, Andrea, Rovella, Valentina, Percesepe, Antonio, Lucci Cordisco, Emanuela, Radice, Paolo, Bertario, Lucio, Pedroni, Monica, Ponz De Leon, Maurizio, Mancuso, Pietro, Devarajan, Karthik, Cai, Kathy, Klein Szanto, Andrea, Neri, Giovanni, Moller, Pal, Viel, Alessandra, Genuardi, Maurizio, Fodde, Riccardo, Bellacosa, Alfonso, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Genuardi, Maurizio (ORCID:0000-0002-7410-8351), Tricarico, Rossella, Cortellino, Salvatore, Riccio, Antonio, Jagmohan Changur, Shantie, Van Der Klift, Helen, Wijnen, Juul, Turner, David, Ventura, Andrea, Rovella, Valentina, Percesepe, Antonio, Lucci Cordisco, Emanuela, Radice, Paolo, Bertario, Lucio, Pedroni, Monica, Ponz De Leon, Maurizio, Mancuso, Pietro, Devarajan, Karthik, Cai, Kathy, Klein Szanto, Andrea, Neri, Giovanni, Moller, Pal, Viel, Alessandra, Genuardi, Maurizio, Fodde, Riccardo, Bellacosa, Alfonso, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), and Genuardi, Maurizio (ORCID:0000-0002-7410-8351)

Abstract

The DNA glycosylase gene MBD4 safeguards genomic stability at CpG sites and is frequently mutated at coding poly-A tracks in mismatch repair (MMR)-defective colorectal tumors (CRC). Mbd4 biallelic inactivation in mice provided conflicting results as to its role in tumorigenesis. Thus, it is unclear whether MBD4 alterations are only secondary to MMR defects without functional consequences or can contribute to the mutator phenotype. We investigated MBD4 variants in a large series of hereditary/familial and sporadic CRC cases. Whereas MBD4 frameshifts were only detected in tumors, missense variants were found in both normal and tumor DNA. In CRC with double-MBD4/MMR and single-MBD4 variants, transition mutation frequency was increased, indicating that MBD4 defects may affect the mutational landscape independently of MMR defect. Mbd4-deficient mice showed reduced survival when combined with Mlh1-/- genotype. Taken together, these data suggest that MBD4 inactivation may contribute to tumorigenesis, acting as a modifier of MMR-deficient cancer phenotype.

Published
2015

43. The growing complexity of the intestinal polyposis syndromes.

Author

Lucci Cordisco, Emanuela, Risio, M, Venesio, T, Genuardi, Maurizio, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Genuardi, Maurizio (ORCID:0000-0002-7410-8351), Lucci Cordisco, Emanuela, Risio, M, Venesio, T, Genuardi, Maurizio, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), and Genuardi, Maurizio (ORCID:0000-0002-7410-8351)

Abstract

Familial adenomatous polyposis has been the first form of inherited intestinal polyposis to be recognized. For a long time it has been considered the main polyposis syndrome, associated with an easily recognizable phenotype, with a marginal role attributed to a few very rare hamartomatous conditions. More recently, it has been gradually demonstrated that the intestinal polyposes encompass a range of conditions within a wide spectrum of disease severity, polyp histology, and extraintestinal manifestations. A growing number of genes and phenotypes has been identified, and heterogeneity of somatic molecular pathways underlying epithelial transformation in different syndromes and associated tumors has been documented. Increasing knowledge on the molecular bases and more widespread use of genetic tests has shown phenotypic overlaps between conditions that were previously considered distinct, highlighting diagnostic difficulties. With the advent of next generation sequencing, the diagnosis and the classification of these syndromes will be progressively based more on genetic testing results. However, the phenotypic variability documented among patients with mutations in the same genes cannot be fully explained by different expressivity, indicating a role for as yet unknown modifying factors. Until the latter will be identified, the management of patients with polyposis syndromes should be guided by both clinical and genetic findings.

Published
2013

44. MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events

Author

Aretz, S, Tricarico, R, Papi, L, Spier, I, Pin, E, Horpaopan, S, Lucci Cordisco, Emanuela, Pedroni, M, Stienen, D, Gentile, A, Panza, A, Piepoli, A, De Leon, Mp, Friedl, W, Viel, A, Genuardi, Maurizio, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Genuardi, Maurizio (ORCID:0000-0002-7410-8351), Aretz, S, Tricarico, R, Papi, L, Spier, I, Pin, E, Horpaopan, S, Lucci Cordisco, Emanuela, Pedroni, M, Stienen, D, Gentile, A, Panza, A, Piepoli, A, De Leon, Mp, Friedl, W, Viel, A, Genuardi, Maurizio, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), and Genuardi, Maurizio (ORCID:0000-0002-7410-8351)

Abstract

MUTYH-associated polyposis (MAP) is an autosomal recessive adenomatous polyposis caused by biallelic germline mutations of the base-excision-repair gene MUTYH. In MAP patients of European origin, the combined allele frequency of the mutations p.Tyr179Cys and p.Gly396Asp ranges between 50 and 82%, while these mutations have not been identified in Far Eastern Asian populations, supporting the hypothesis that a founder effect has occurred at some point in European history. To investigate the natural history of the two common European MUTYH alleles, we genotyped six gene-flanking microsatellite markers in 80 unrelated Italian and German MAP patients segregating one or both mutations and calculated their age in generations (g) by using DMLE+2.2 software. Three distinct common haplotypes, one for p.Tyr179Cys and two for p.Gly396Asp, were identified. Estimated mutation ages were 305 g (95% CS: 271-418) for p.Tyr179Cys and 350 g (95% CS: 313-435) for p.Gly396Asp. These results provide evidence for strong founder effects and suggest that the p.Tyr179Cys and p.Gly396Asp mutations derive from ancestors who lived between 5-8 thousand years and 6-9 thousand years B.C., respectively.European Journal of Human Genetics advance online publication, 30 January 2013; doi:10.1038/ejhg.2012.309.

Published
2013

45. Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: Results of an Italian multicenter study

Author

Resta, N, Pierannunzio, D, Lenato, Gm, Stella, A, Capocaccia, R, Bagnulo, R, Lastella, P, Susca, Fc, Bozzao, C, Loconte, Dc, Sabbà, C, Urso, E, Sala, P, Fornasarig, M, Grammatico, P, Piepoli, A, Host, C, Turchetti, D, Viel, A, Memo, L, Giunti, L, Stigliano, V, Varesco, L, Bertario, L, Genuardi, Maurizio, Lucci Cordisco, Emanuela, Tibiletti, Mg, Di Gregorio, C, Andriulli, A, Ponz De Leon, M., Genuardi, Maurizio (ORCID:0000-0002-7410-8351), Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Resta, N, Pierannunzio, D, Lenato, Gm, Stella, A, Capocaccia, R, Bagnulo, R, Lastella, P, Susca, Fc, Bozzao, C, Loconte, Dc, Sabbà, C, Urso, E, Sala, P, Fornasarig, M, Grammatico, P, Piepoli, A, Host, C, Turchetti, D, Viel, A, Memo, L, Giunti, L, Stigliano, V, Varesco, L, Bertario, L, Genuardi, Maurizio, Lucci Cordisco, Emanuela, Tibiletti, Mg, Di Gregorio, C, Andriulli, A, Ponz De Leon, M., Genuardi, Maurizio (ORCID:0000-0002-7410-8351), and Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604)

Abstract

BACKGROUND: Germline mutations in the STK11/LKB1 gene cause Peutz-Jeghers syndrome, an autosomal-dominantly inherited condition characterized by mucocutaneous pigmentation, hamartomatous gastrointestinal polyposis, and an increased risk for various malignancies. We here report the results of the first Italian collaborative study on Peutz-Jeghers syndrome. AIMS: To assess cancer risks in a large homogenous cohort of patients with Peutz-Jeghers syndrome, carrying, in large majority, an identified STK11/LKB1 mutation. METHODS: One-hundred and nineteen patients with Peutz-Jeghers syndrome, ascertained in sixteen different Italian centres, were enrolled in a retrospective cohort study. Relative and cumulative cancer risks and genotype-phenotype correlations were evaluated. RESULTS: 36 malignant tumours were found in 31/119 (29 STK11/LKB1 mutation carriers) patients. The mean age at first cancer diagnosis was 41 years. The relative overall cancer risk was 15.1 with a significantly higher risk (p<0.001) in females (22.0) than in males (8.6). Highly increased relative risks were present for gastrointestinal (126.2) and gynaecological cancers (27.7), in particular for pancreatic (139.7) and cervical cancer (55.6). The Kaplan-Meier estimates for overall cumulative cancer risks were 20%, 43%, 71%, and 89%, at age 40, 50, 60 and 65 years, respectively. CONCLUSION: Peutz-Jeghers syndrome entails markedly elevated cancer risks, mainly for pancreatic and cervical cancers. This study provides a helpful reference for improving current surveillance protocols.

Published
2013

46. Double pituitary adenomas

Author

Iacovazzo, Donato, Bianchi, Antonio, Lugli, Francesca, Milardi, Domenico, Giampietro, Antonella, Lucci Cordisco, Emanuela, Doglietto, Francesco, Lauriola, Libero, De Marinis Grasso, Laura, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Doglietto, Francesco (ORCID:0000-0002-7438-0734), Lauriola, Libero (ORCID:0000-0003-0481-5138), De Marinis, Laura (ORCID:0000-0001-9916-0669), Iacovazzo, Donato, Bianchi, Antonio, Lugli, Francesca, Milardi, Domenico, Giampietro, Antonella, Lucci Cordisco, Emanuela, Doglietto, Francesco, Lauriola, Libero, De Marinis Grasso, Laura, Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Doglietto, Francesco (ORCID:0000-0002-7438-0734), Lauriola, Libero (ORCID:0000-0003-0481-5138), and De Marinis, Laura (ORCID:0000-0001-9916-0669)

Abstract

Double pituitary adenomas represent up to 2.6 % of pituitary adenomas in large surgical series and up to 3.3 % of patients with Cushing's disease have been found to have double or multiple pituitary adenomas. We report the case of a 60-year-old male patient whose medical history began in 2002 with erectile dysfunction; hyperprolactinemia was found and MRI showed a 6-mm area of delayed enhancement in the lateral portion of the right pituitary lobe. Treatment with cabergoline was started with normalization of prolactin levels; the following MRI, performed in 2005 and 2008, showed shrinkage of the pituitary lesion. In 2005, the patient began to manifest weight gain, hypertension, and facial plethora, but no further evaluations were done. In January 2010, the patient came to our attention and underwent multiple tests that suggested Cushing's disease. A new MRI was negative. Bilateral inferior petrosal sinus sampling showed significant pituitary-to-peripheral ratio and, in May 2010, the patient underwent exploratory pituitary surgery with evidence of a 1-2-mm white-coloured midline area compatible with pituitary adenoma that was surgically removed. Post-operatively, the patient's clinical conditions improved with onset of secondary hypoadrenalism. The histologic examination confirmed a pituitary adenoma (immunostaining was found to be positive for ACTH and negative for prolactin). We report the case of an ACTH-producing microadenoma metachronous to a prolactin secreting microadenoma although not confirmed histologically, shrunk by medical treatment. A review of data in the literature regarding double or multiple pituitary adenomas has also been done.

Published
2013

47. A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer

Author

Viel, Alessandra, primary, Bruselles, Alessandro, additional, Meccia, Ettore, additional, Fornasarig, Mara, additional, Quaia, Michele, additional, Canzonieri, Vincenzo, additional, Policicchio, Eleonora, additional, Urso, Emanuele Damiano, additional, Agostini, Marco, additional, Genuardi, Maurizio, additional, Lucci-Cordisco, Emanuela, additional, Venesio, Tiziana, additional, Martayan, Aline, additional, Diodoro, Maria Grazia, additional, Sanchez-Mete, Lupe, additional, Stigliano, Vittoria, additional, Mazzei, Filomena, additional, Grasso, Francesca, additional, Giuliani, Alessandro, additional, Baiocchi, Marta, additional, Maestro, Roberta, additional, Giannini, Giuseppe, additional, Tartaglia, Marco, additional, Alexandrov, Ludmil B., additional, and Bignami, Margherita, additional

Published
2017
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48. Three unrelated patients with congenital anterior pituitary aplasia and a characteristic physical and neuropsychological phenotype: a new syndrome?

Author

Lucci Cordisco, Emanuela, Scommegna, S, Orteschi, Daniela, Galeazzi, D, Neri, Giovanni, Boscherini, B., Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Lucci Cordisco, Emanuela, Scommegna, S, Orteschi, Daniela, Galeazzi, D, Neri, Giovanni, Boscherini, B., and Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604)

Abstract

Anterior pituitary aplasia (APA) is a very rare cause of congenital-onset multiple pituitary hormone deficiency (CO-MPHD). We report on molecular analysis and clinical follow-up of three previously reported cases of APA [Scommegna et al., 2004], who share a characteristic physical and neuropsychological profile. Mutation analysis of genes encoding transcription factors involved in pituitary development (PROP1, POUF1, HESX1, LHX3, and LHX4) did not demonstrate a any mutation. In order to identify the genetic cause underlying the phenotypes we performed an array-based comparative genomic hybridization (array-CGH), which showed a cryptic interstitial deletion of 9p (200 kb), including the TEK and MOBKL2B, in one patient. Although an apparently identical deletion was carried by the clinically normal father, we assumed that the patient's phenotype might be due to a recessive mutation in the other allele. However, sequence analysis of exons and splice junctions of these genes did not detect pathogenic or predisposing variants in the three patients. We suggest that the constellation of clinical signs in these patients constitutes a previously undescribed syndrome, whose genetic cause has yet to be identified.

Published
2012

49. The Simpson-Golabi-Behmel syndrome: a clinical case and a detective story

Author

Gurrieri, Fiorella, Pomponi, Maria Grazia, Pietrobono, Roberta, Lucci Cordisco, Emanuela, Silvestri, Evelina, Storniello, G, Neri, Giovanni, Gurrieri, Fiorella (ORCID:0000-0002-6775-5972), Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604), Gurrieri, Fiorella, Pomponi, Maria Grazia, Pietrobono, Roberta, Lucci Cordisco, Emanuela, Silvestri, Evelina, Storniello, G, Neri, Giovanni, Gurrieri, Fiorella (ORCID:0000-0002-6775-5972), and Lucci Cordisco, Emanuela (ORCID:0000-0002-6279-7604)

Published
2011

50. A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer.

Author

Viel, A, Bruselles, A, Meccia, E, Fornasarig, M, Quaia, M, Canzonieri, V, Policicchio, E, Urso, Ed, Agostini, M, Genuardi, Maurizio, Lucci Cordisco, Emanuela, Venesio, T, Martayan, Aline, Diodoro, Mg, Sanchez-Mete, L, Stigliano, V, Mazzei, Francesca, Grasso, F, Giuliani, Alessandro, Baiocchi, M, Maestro, R, Giannini, G, Tartaglia, Marco, Alexandrov, Lb, Bignami, M., Genuardi M (ORCID:0000-0002-7410-8351), Lucci-Cordisco E (ORCID:0000-0002-6279-7604), Martayan A, Tartaglia M, Viel, A, Bruselles, A, Meccia, E, Fornasarig, M, Quaia, M, Canzonieri, V, Policicchio, E, Urso, Ed, Agostini, M, Genuardi, Maurizio, Lucci Cordisco, Emanuela, Venesio, T, Martayan, Aline, Diodoro, Mg, Sanchez-Mete, L, Stigliano, V, Mazzei, Francesca, Grasso, F, Giuliani, Alessandro, Baiocchi, M, Maestro, R, Giannini, G, Tartaglia, Marco, Alexandrov, Lb, Bignami, M., Genuardi M (ORCID:0000-0002-7410-8351), Lucci-Cordisco E (ORCID:0000-0002-6279-7604), Martayan A, and Tartaglia M

Abstract

8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C>T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.

Published
2017

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