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1. Variants of uncertain significance (VUS) in cancer predisposing genes: What are we learning from multigene panels?

Author

Lucci-Cordisco, E., Amenta, S., Panfili, A., Del Valle, J., Capellá, G., Pineda, M., Genuardi, M., Lucci-Cordisco E., Amenta S., Panfili A., Del Valle J., Capellá G., Pineda M., Genuardi M. (ORCID:0000-0002-7410-8351), Lucci-Cordisco, E., Amenta, S., Panfili, A., Del Valle, J., Capellá, G., Pineda, M., Genuardi, M., Lucci-Cordisco E., Amenta S., Panfili A., Del Valle J., Capellá G., Pineda M., and Genuardi M. (ORCID:0000-0002-7410-8351)

Abstract

One of the main factors influencing the clinical utility of genetic tests for cancer predisposition is the ability to provide actionable classifications (ie pathogenic or benign). However, a large fraction of the variants identified in cancer predisposing genes (CPGs) are of uncertain significance (VUS), and cannot be used for clinical purposes either to identify individuals at risk or to drive treatment. Here we analyze the current status of VUS identification in a subset of 24 CPGs included by the American College of Medical Genetics/Association for Molecular Pathology in the list of genes that should be considered for the return of incidental findings. To this purpose we retrieved published literature using different search strings according to the frequency of the condition and we extracted corresponding data from ClinVar. The total number of VUS has not decreased with time, due to widespread multigene panel testing, and the relative yield of VUS compared to pathogenic variants is higher in more recent studies, which tend to involve series not selected for the presence of specific high risk criteria. In addition, only few studies adopt gene specific interpretation criteria when these are available. Despite the large yield of VUS associated with multigene testing, the data obtained from such studies can be very useful for variant classification, especially for those variants that are more likely to be benign, since these are expected to be detected more frequently in a population that does not show gene specific manifestations. In addition, wider use of gene specific interpretation criteria should be promoted in order to optimize the interpretation process.

Published
2022

2. 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

3. Performance of BOADICEA and BRCAPRO genetic models and of empirical criteria based on cancer family history for predicting BRCA mutation carrier probabilities: A retrospective study in a sample of Italian cancer genetics clinics

Author

Varesco, L., Viassolo, V., Viel, A., Gismondi, V., Radice, P., Montagna, M., Alducci, E., Della Puppa, L., Oliani, C., Tommasi, S., Caligo, M.A., Vivanet, C., Zuradelli, M., Mandich, P., Tibiletti, M.G., Cavalli, P., Lucci Cordisco, E., Turchetti, D., Boggiani, D., Bracci, R., Bruzzi, P., and Bonelli, L.

Published
2013
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4. 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

5. 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, E., De Matteis, E., Cucinotto, I., Ronzino, G., Santonocito, C., Tornesello, A., De Giorgio, M. R., Lucci Cordisco, E., Minucci, A., Genuardi, M., 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, E., De Matteis, E., Cucinotto, I., Ronzino, G., Santonocito, C., Tornesello, A., De Giorgio, M. R., Lucci Cordisco, E., Minucci, A., Genuardi, M., 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
2020

6. Double pituitary adenomas

Author

Iacovazzo, D., Bianchi, A., Lugli, F., Milardi, D., Giampietro, A., Lucci-Cordisco, E., Doglietto, F., Lauriola, L., and De Marinis, L.

Published
2013
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7. 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

11. 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

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

Author

Feroce I., 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., Harris M., 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 P., 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., 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., 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 E., 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., Feroce I., 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., Harris M., 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 P., 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., 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., 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 E., 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., and Schmidt G.

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.Copyright © 2019 Wiley Periodicals, Inc.

Published
2019

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

Author

Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, Spurdle, AB, Parsons, MT, Tudini, E, Li, H, Hahnen, E, Wappenschmidt, B, Feliubadalo, L, Aalfs, CM, Agata, S, Aittomaki, K, Alducci, E, Concepcion Alonso-Cerezo, M, Arnold, N, Auber, B, Austin, R, Azzollini, J, Balmana, J, Barbieri, E, Bartram, CR, Blanco, A, Bluemcke, B, Bonache, S, Bonanni, B, Borg, A, Bortesi, B, Brunet, J, Bruzzone, C, Bucksch, K, Cagnoli, G, Caldes, T, Caliebe, A, Caligo, MA, Calvello, M, Capone, GL, Caputo, SM, Carnevali, I, Carrasco, E, Caux-Moncoutier, V, Cavalli, P, Cini, G, Clarke, EM, Concolino, P, Cops, EJ, Cortesi, L, Couch, FJ, Darder, E, de la Hoya, M, Dean, M, Debatin, I, Del Valle, J, Delnatte, C, Derive, N, Diez, O, Ditsch, N, Domchek, SM, Dutrannoy, V, Eccles, DM, Ehrencrona, H, Enders, U, Evans, DG, Farra, C, Faust, U, Felbor, U, Feroce, I, Fine, M, Foulkes, WD, Galvao, HC, Gambino, G, Gehrig, A, Gensini, F, Gerdes, A-M, Germani, A, Giesecke, J, Gismondi, V, Gomez, C, Garcia, EBG, Gonzalez, S, Grau, E, Grill, S, Gross, E, Guerrieri-Gonzaga, A, Guillaud-Bataille, M, Gutierrez-Enriquez, S, Haaf, T, Hackmann, K, Hansen, TV, Harris, M, Hauke, J, Heinrich, T, Hellebrand, H, Herold, KN, Honisch, E, Horvath, J, Houdayer, C, Huebbel, V, Iglesias, S, Izquierdo, A, James, PA, Janssen, LA, Jeschke, U, Kaulfuss, S, Keupp, K, Kiechle, M, Koelbl, A, Krieger, S, Kruse, TA, Kvist, A, Lalloo, F, Larsen, M, Lattimore, VL, Lautrup, C, Ledig, S, Leinert, E, Lewis, AL, Lim, J, Loeffler, M, Lopez-Fernandez, A, Lucci-Cordisco, E, Maass, N, Manoukian, S, Marabelli, M, Matricardi, L, Meindl, A, Michelli, RD, Moghadasi, S, Moles-Fernandez, A, Montagna, M, Montalban, G, Monteiro, AN, Montes, E, Mori, L, Moserle, L, Mueller, CR, Mundhenke, C, Naldi, N, Nathanson, KL, Navarro, M, Nevanlinna, H, Nichols, CB, Niederacher, D, Nielsen, HR, Ong, K-R, Pachter, N, Palmero, E, Papi, L, Pedersen, IS, Peissel, B, Perez-Segura, P, Pfeifer, K, Pineda, M, Pohl-Rescigno, E, Poplawski, NK, Porfirio, B, Quante, AS, Ramser, J, Reis, RM, Revillion, F, Rhiem, K, Riboli, B, Ritter, J, Rivera, D, Rofes, P, Rump, A, Salinas, M, Sanchez de Abajo, AM, Schmidt, G, Schoenwiese, U, Seggewiss, J, Solanes, A, Steinemann, D, Stiller, M, Stoppa-Lyonnet, D, Sullivan, KJ, Susman, R, Sutter, C, Tavtigian, S, Teo, SH, Teule, A, Thomassen, M, Tibiletti, MG, Tischkowitz, M, Tognazzo, S, Toland, AE, Tornero, E, Torngren, T, Torres-Esquius, S, Toss, A, Trainer, AH, Tucker, KM, van Asperen, CJ, van Mackelenbergh, MT, Varesco, L, Vargas-Parra, G, Varon, R, Vega, A, Velasco, A, Vesper, A-S, Viel, A, Vreeswijk, MPG, Wagner, SA, Waha, A, Walker, LC, Walters, RJ, Wang-Gohrke, S, Weber, BHF, Weichert, W, Wieland, K, Wiesmueller, L, Witzel, I, Woeckel, A, Woodward, ER, Zachariae, S, Zampiga, V, Zeder-Goss, C, Lazaro, C, De Nicolo, A, Radice, P, Engel, C, Schmutzler, RK, Goldgar, DE, and Spurdle, AB

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

18. Lynch syndrome with exclusive skin involvement: time to consider a molecular definition?

Author

Vaisfeld, Alessandro, Calicchia, Martina, Pomponi, M. G., Lucci Cordisco, Emanuela, Reggiani-Bonetti, L., Genuardi, Maurizio, Vaisfeld A., Calicchia M., Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Genuardi M. (ORCID:0000-0002-7410-8351), Vaisfeld, Alessandro, Calicchia, Martina, Pomponi, M. G., Lucci Cordisco, Emanuela, Reggiani-Bonetti, L., Genuardi, Maurizio, Vaisfeld A., Calicchia M., Lucci Cordisco E. (ORCID:0000-0002-6279-7604), and Genuardi M. (ORCID:0000-0002-7410-8351)

Abstract

Muir–Torre syndrome (MTS) is clinically characterized by the occurrence of skin, usually sebaceous, and visceral tumors in the same individual. The most common underlying mechanism is a constitutional defect of the mismatch repair (MMR) genes that cause Lynch syndrome (LS). Herewithin we report on a 76 years-old male patient heterozygous for a pathogenic MSH2 missense substitution who presented with a striking cutaneous phenotype in the absence of typical LS visceral tumors. The patient developed 20 skin tumors, including sebaceous adenomas/carcinomas and keratoacanthomas. Two skin tumors showed immunohistochemical loss of MSH2 and MSH6 expression. There was no apparent family history of neoplasia. Based on the variable involvement of the skin and internal organs, we suggest that the definition of tumor associations that are often observed as variants of inherited tumor syndromes, such as MTS, should be guided by the underlying molecular bases. In addition, the presence of multiple sebaceous tumors, especially if showing MMR deficiency, appears to be a very strong indicator of a constitutional MMR gene defect. The reasons underlying the high phenotypic variability of cutaneous phenotypes associated with constitutional MMR defects are yet to be determined.

Published
2019

19. 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

21. Performance of BOADICEA and BRCAPRO genetic models and of empirical criteria based on cancer family history for predicting BRCA mutation carrier probabilities: a retrospective study in a sample of Italian cancer genetics clinics

Author

Varesco, L, Viassolo, V, Viel, A, Gismondi, V, Radice, P, Montagna, M, Alducci, E, Della Puppa, L, Oliani, C, Tommasi, S, Caligo, Ma, Vivanet, C, Zuradelli, M, Mandich, P, Tibiletti, Mg, Cavalli, P, Lucci Cordisco, E, Turchetti, D, Boggiani, D, Bracci, R, Bruzzi, P, Bonelli, L, Lucci Cordisco, E (ORCID:0000-0002-6279-7604), Varesco, L, Viassolo, V, Viel, A, Gismondi, V, Radice, P, Montagna, M, Alducci, E, Della Puppa, L, Oliani, C, Tommasi, S, Caligo, Ma, Vivanet, C, Zuradelli, M, Mandich, P, Tibiletti, Mg, Cavalli, P, Lucci Cordisco, E, Turchetti, D, Boggiani, D, Bracci, R, Bruzzi, P, Bonelli, L, and Lucci Cordisco, E (ORCID:0000-0002-6279-7604)

Abstract

To evaluate in current practice the performance of BOADICEA and BRCAPRO risk models and empirical criteria based on cancer family history for the selection of individuals for BRCA genetic testing.

Published
2013

22. Efficacy of Lanreotide Autogel in MEN1-Related Gastrinoma: A Case Series

Author

Iacovazzo D., Lugli F., Bianchi A., Capoluongo E., Lucci-Cordisco E., Persiani R., Doglietto G. B., Pontecorvi A., Rindi G., De Marinis L., Iacovazzo, D., Lugli, F., Bianchi, A., Capoluongo, E., Lucci-Cordisco, E., Persiani, R., Doglietto, G. B., Pontecorvi, A., Rindi, G., and De Marinis, L.

Published
2014

23. 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

24. Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients

Author

Russo, A, Sala, P, Alberici, P, Gazzoli, I, Radice, P, Montefusco, C, Torrini, M, Mareni, C, Fornasarig, M, Santarosa, M, Viel, A, Benatti, P, Pedroni, M, De Leon, M, Lucci Cordisco, E, Genuardi, Maurizio, Messerini, L, Stigliano, V, Cama, A, Curia, M, De Lellis, L, Signoroni, S, Pierotti, M, Bertario, L., Lucci Cordisco, E (ORCID:0000-0002-6279-7604), Genuardi, Maurizio (ORCID:0000-0002-7410-8351), Russo, A, Sala, P, Alberici, P, Gazzoli, I, Radice, P, Montefusco, C, Torrini, M, Mareni, C, Fornasarig, M, Santarosa, M, Viel, A, Benatti, P, Pedroni, M, De Leon, M, Lucci Cordisco, E, Genuardi, Maurizio, Messerini, L, Stigliano, V, Cama, A, Curia, M, De Lellis, L, Signoroni, S, Pierotti, M, Bertario, L., Lucci Cordisco, E (ORCID:0000-0002-6279-7604), and Genuardi, Maurizio (ORCID:0000-0002-7410-8351)

Abstract

Aims and background. Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. Methods. A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLITH-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. Results. Five-year survival rates were 0.73 (95% Cl, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% Cl, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P= 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% Cl, 0.51-0.981 for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). Conclusions. Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal, AIMS AND BACKGROUND: Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. METHODS: A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. RESULTS: Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). CONCLUSIONS: Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related co

Published
2009

25. La Genomica in Sanità Pubblica. Sintesi delle evidenze e delle conoscenze disponibili sull’utilizzo della genomica ai fini della prevenzione

Author

Boccia, S., Simone, B., Gualano, M., Agodi, A., Coviello, D., Dagna Bricarelli, F., Dallapiccola, B., Di Maria, E., Genuardi, M., Ricciardi, W., Baroncini, A., Calzolari, E., Capoluongo, E., Carrera, P., Compagni, A., Covolo, L., De Vito, C., Di Pietro, M., Federici, A., Ferrari, M., Gurrieri, F., Ianuale, C., Lucci Cordisco, E., Mazzucco, W., Miani, A., Migliore, L., Piccione, M., Sangiorgi, L., Sbrogiò, L., Torricelli, F., Varesco, L., Villari, P., Vitale, F., Boccia, S., Simone, B., Gualano, M., Agodi, A., Coviello, D., Dagna Bricarelli, F., Dallapiccola, B., Di Maria, E., Genuardi, M., Ricciardi, W., Baroncini, A., Calzolari, E., Capoluongo, E., Carrera, P., Compagni, A., Covolo, L., De Vito, C., Di Pietro, M., Federici, A., Ferrari, M., Gurrieri, F., Ianuale, C., Lucci Cordisco, E., Mazzucco, W., Miani, A., Migliore, L., Piccione, M., Sangiorgi, L., Sbrogiò, L., Torricelli, F., Varesco, L., Villari, P., and Vitale, F.

Subjects
Genomica di Sanità Pubblica, test genetici, test genomici, prevenzione, Public Health, Settore MED/42 - Igiene Generale E Applicata
Published
2012

27. High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints.

Author

Gervasini, C., Castronovo, P., Bentivegna, A., Mottadelli, F., Faravelli, F., Giovanucci Uzielli, M. L., Pessagno, A., Lucci Cordisco, E., Pinto, Anna Maria, Salviati, L., Selicorni, A., Tenconi, R., Neri, Giovanni, Larizza, L., Lucci Cordisco, E. (ORCID:0000-0002-6279-7604), Gervasini, C., Castronovo, P., Bentivegna, A., Mottadelli, F., Faravelli, F., Giovanucci Uzielli, M. L., Pessagno, A., Lucci Cordisco, E., Pinto, Anna Maria, Salviati, L., Selicorni, A., Tenconi, R., Neri, Giovanni, Larizza, L., and Lucci Cordisco, E. (ORCID:0000-0002-6279-7604)

Abstract

N/A

Published
2007

28. Erratum: Prognostic relevance of MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer patients (Tumori (2009) 95:6 (731-738))

Author

Russo, A., De Leon, M. P., Lucci-Cordisco, E., Genuardi, M., Messerini, L., Stigliano, V., Cama, A., Curia, M. C., De Lellis, L., Signoroni, S., Pierotti, M. A., Pedroni, M., Benatti, P., Sala, P., Alberici, P., Gazzoli, I., Radice, P., Montefusco, C., Torrini, M., Mareni, C., Fornasarig, M., Santarosa, M., Viel, A., and Bertario, L.

Published
2010

33. High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints

Author

Gervasini, C, Castronovo, P, Bentivegna, A, Mottadelli, F, Faravelli, F, Giovannucci Uzielli, M, Pessagno, A, Lucci Cordisco, E, Pinto, A, Salviati, L, Selicorni, A, Tenconi, R, Neri, G, Larizza, L, Giovannucci Uzielli, ML, Pinto, AM, Larizza, L., BENTIVEGNA, ANGELA, Gervasini, C, Castronovo, P, Bentivegna, A, Mottadelli, F, Faravelli, F, Giovannucci Uzielli, M, Pessagno, A, Lucci Cordisco, E, Pinto, A, Salviati, L, Selicorni, A, Tenconi, R, Neri, G, Larizza, L, Giovannucci Uzielli, ML, Pinto, AM, Larizza, L., and BENTIVEGNA, ANGELA

Abstract

Rubinstein-Taybi syndrome (RSTS) is a rare malformation disorder caused by mutations in the closely related CREBBP and EP300 genes, accounting respectively for up to 60 and 3% of cases. About 10% of CREBBP mutations are whole gene deletions often extending into flanking regions. Using FISH and microsatellite analyses as a first step in the CREBBP mutation screening of 42 Italian RSTS patients, we identified six deletions, three of which were in a mosaic condition that has not been previously reported in RSTS. The use of region-specific BAC clones and small CREBBP probes allowed us to assess the extent of all of the deletions by mapping their endpoints to genomic intervals of 5-10 kb. Four of our five intragenic breakpoints cluster at the 5' end of CREBBP, where there is a peak of breakpoints underlying rearrangements in RSTS patients and tumors. The search for genomic motifs did not reveal any low-copy repeats (LCRs) or any greater density of repetitive sequences. In contrast, the percentage of interspersed repetitive elements (mainly Alu and LINEs in the CREBBP exon 2 region) is significantly higher than that in the entire gene or the average in the genome, thus suggesting that this characteristic may be involved in the region's vulnerability to breaking and nonhomologous pairing. The FISH analysis extended to the EP300 genomic region did not reveal any deletions. The clinical presentation was typical in all cases, but more severe in the three patients carrying constitutional deletions, raising a question about the possible underdiagnosis of a few cases of mild RSTS

Published
2007

34. Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer

Author

de Leon, M, Benatti, P, Di Gregorio, C, Pedroni, M, Losi, L, Genuardi, M, Viel, A, Fornasarig, M, Lucci-Cordisco, E, Anti, M, Ponti, G, Borghi, F, Lamberti, I, Roncucci, L, Genuardi, M (ORCID:0000-0002-7410-8351), de Leon, M, Benatti, P, Di Gregorio, C, Pedroni, M, Losi, L, Genuardi, M, Viel, A, Fornasarig, M, Lucci-Cordisco, E, Anti, M, Ponti, G, Borghi, F, Lamberti, I, Roncucci, L, and Genuardi, M (ORCID:0000-0002-7410-8351)

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected - that is, with HNPCC-related cancer diagnosis - and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (P<0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we

Published
2004

36. BRCA1-related malignancies in a family presenting with von Recklinghausen's disease

Author

Ceccaroni, Marcello, Genuardi, Maurizio, Legge, F, Lucci-Cordisco, E, Carrara, S, D'Amico, F, Greggi, S, Scambia, Giovanni, Ceccaroni, M, Genuardi, M (ORCID:0000-0002-7410-8351), Scambia, G (ORCID:0000-0003-2758-1063), Ceccaroni, Marcello, Genuardi, Maurizio, Legge, F, Lucci-Cordisco, E, Carrara, S, D'Amico, F, Greggi, S, Scambia, Giovanni, Ceccaroni, M, Genuardi, M (ORCID:0000-0002-7410-8351), and Scambia, G (ORCID:0000-0003-2758-1063)

Abstract

Background. The association between neurofibromatosis and gynecologic malignancies is rarely reported in the literature. Both BRCA1 and NF1 genes are located on the long arm of chromosome 17. Case. We have observed a pedigree showing several individuals affected by both type 1 neurofibromatosis (NF1) and breast or coelomatic cancers. The number of individuals affected, their degree of relationship, and the early age at onset were suggestive of an hereditary breast/ovarian cancer syndrome. Linkage analysis was performed in order to establish whether markers in the chromosome 17 region containing the BRCA1 and NF1 loci were shared by affected individuals. Screening for BRCA1 mutations was performed by PTT and SSCP. Analysis of chromosome 17 DNA markers in the five family members tested show that three individuals affected by both NF1 and carcinomas share a common haplotype including the NF1 and BRCA1 loci on chromosome 17. Mutation analysis showed the presence of a nonsense mutation within BRCA1 exon 12 in two individuals, mother and daughter, affected by breast and peritoneal cancer, respectively, as well as in the son, who had rectal cancer at the early age of 27 years. All three subjects also had NF1. Conclusion. The concurrence of NF1 and hereditary breast ovarian cancer in this family is likely due to the presence of two linked mutations at the NF1 and BRCA1 loci. (C) 2002 Elsevier Science (USA).

Published
2002

37. Different molecular mechanisms underlie genomic deletions in the MLH1 gene

Author

Viel, A, Petronzelli, F, Della Puppa, L, Lucci-Cordisco, E, Fornasarig, M, Pucciarelli, S, Rovella, V, Quaia, M, de Leon, M, Boiocchi, M, Genuardi, Maurizio, Genuardi, M (ORCID:0000-0002-7410-8351), Viel, A, Petronzelli, F, Della Puppa, L, Lucci-Cordisco, E, Fornasarig, M, Pucciarelli, S, Rovella, V, Quaia, M, de Leon, M, Boiocchi, M, Genuardi, Maurizio, and Genuardi, M (ORCID:0000-0002-7410-8351)

Abstract

In this study we examined a series of 52 patients belonging to hereditary nonpolyposis colorectal cancer (HNPCC) or HNPCC-related families, all who had previously tested negative for mismatch repair (MMR) gene point mutations. Southern blot mutational screening of MLH1 and MSH2 genes was carried out with the aim of detecting large genomic rearrangements and of identifying the molecular mechanisms underlying the inactivation of the MMR genes. Three patients had abnormal restriction patterns and were found to carry distinct MLH1 internal deletions. Long-range PCRs identified the loss of DNA tracts spanning exon 6 (about 2.4 kb in proband A-AV20 and 0.8 kb in proband A-PD5) and exon 3 (about 2.5 kb in proband R-RM2). In A-AV20 the breakpoints occurred into identical 33-bp regions in introns 5 and 6 and a mechanism of classical Alu-mediated homologous recombination was evident. Also, in patient A-PD5 the breakpoints were located in these introns, but without direct involvement of repetitive sequences. In patient R-RM2 the breakpoints were located within repetitive L1 elements with poor homology in intron 2 and 3 and the rearranged allele was characterized by a complex insertion deletion (delCCinsACATAGTA), giving rise to a palindromic CTTAACATAGTATGTTAAG sequence in proximity of the fusion site. This study confirms that genomic rearrangements are an important component of the spectrum of MMR mutations. Although Alu repeats are likely to be implicated in the majority of cases, different molecular mechanisms may also be responsible for the observed MLH1 intragenic deletions. In particular, HNPCC resulting from L1-mediated recombination has been identified as a novel mechanism for MMR inactivating mutation.

Published
2002

39. Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer

Author

Ponz de Leon, M, primary, Benatti, P, additional, Di Gregorio, C, additional, Pedroni, M, additional, Losi, L, additional, Genuardi, M, additional, Viel, A, additional, Fornasarig, M, additional, Lucci-Cordisco, E, additional, Anti, M, additional, Ponti, G, additional, Borghi, F, additional, Lamberti, I, additional, and Roncucci, L, additional

Published
2004
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40. A novel microdeletion syndrome with loss of theMSH2locus and hereditary non-polyposis colorectal cancer.

Author

Lucci-Cordisco, E., Zollino, M., Baglioni, S., Mancuso, I., Lecce, R., Gurrieri, F., Crucitti, A., Papi, L., Neri, G., and Genuardi, M.

Subjects
*GENETIC disorders, *CHROMOSOMES, *PHENOTYPES, *CANCER, *COLON cancer, *INTELLECTUAL disabilities
Abstract

Lucci-Cordisco E, Zollino M, Baglioni S, Mancuso I, Lecce R, Gurrieri F, Crucitti A, Papi L, Neri G, Genuardi M. A novel microdeletion syndrome with loss of theMSH2locus and hereditary non-polyposis colorectal cancer.Constitutional chromosome deletions can predispose to the development of cancer with the phenotypic characteristics of inherited cancer syndromes, when the deleted region encompasses a tumour suppressor gene. Examples of such conditions are represented by the cytogenetic deletions associated with retinoblastoma, Wilms tumour and familial adenomatous polyposis. So far, no constitutional deletions involving the genes implicated in hereditary non-polyposis colorectal cancer (HNPCC) have been identified. This may be at least partially because of the lack of distinctive phenotypic manifestations in HNPCC. We describe the first case of a constitutional microdeletion associated with HNPCC. Suspicion of a microdeletion was prompted by the association of mental retardation, postnatal growth deficiency, minor congenital anomalies and early onset (37 years) sporadic colon cancer. The patient was found to harbour a microdeletion within chromosome 2p16-p21, including theMSH2gene. Since there are very few reports of deletions of the 2p16-p21 region, our observation sets the grounds for the definition of a novel multiple congenital anomaly/mental retardation/cancer microdeletion syndrome. [ABSTRACT FROM AUTHOR]

Published
2005
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41. Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer.

Author

de Leon, M. Ponz, Benatti, P., di Gregorio, C., Pedroni, M., Losi, L., Genuardi, M., Viel, A., Fornasarig, M., Lucci-Cordisco, E., Anti, M., Ponti, G., Borghi, F., Lamberti, I., and Roncucci, L.

Subjects
HUMAN chromosome abnormality diagnosis, COLON cancer, MICROSATELLITE repeats, DNA repair, GENES, GENETIC mutation
Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected - that is, with HNPCC-related cancer diagnosis - and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or ‘fatalistic’ attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (P<0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families.British Journal of Cancer (2004) 90, 882-887. doi:10.1038/sj.bjc.6601529 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Published
2004
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42. Mutations of the 'minor' mismatch repair gene MSH6 in typical and atypical hereditary nonpolyposis colorectal cancer

Author

Lucci-Cordisco, E., Rovella, V., Carrara, S., Percesepe, A., Monica Pedroni, Bellacosa, A., Caluseriu, O., Forasarig, M., Anti, M., Neri, G., Leon, M. P., Viel, A., and Genuardi, M.

Subjects
Adult, Male, DNA Repair, Base Pair Mismatch, DNA Mutational Analysis, Molecular Sequence Data, Settore MED/09, Polymerase Chain Reaction, Settore MED/06, Stomach Neoplasms, Humans, Genetic Testing, Frameshift Mutation, Base Sequence, Rectal Neoplasms, DNA, DNA, Neoplasm, Middle Aged, Colorectal Neoplasms, Hereditary Nonpolyposis, Hereditary Nonpolyposis, DNA-Binding Proteins, Phenotype, Settore MED/03, Tandem Repeat Sequences, Neoplasm, Female, Colorectal Neoplasms
Abstract

Mutations of the mismatch repair (MMR) genes MLH1 and MSH2 are associated with hereditary nonpolyposis colorectal cancer (HNPCC), a highly penetrant autosomal dominant condition characterized by hypermutability of short tandemly repeated sequences in tumor DNA. Mutations of another MMR gene, MSH6, seem to be less common than MLH1 and MSH2 defects, and have been mostly observed in atypical HNPCC families, characterized by a weaker tumor family history, higher age at disease onset, and low degrees of microsatellite instability (MSI), predominantly involving mononucleotide runs. We have investigated the MSH6 gene sequence in the peripheral blood of 4 HNPCC and 20 atypical HNPCC probands. Two frameshift mutations within exon 4 were detected in 2 patients. One mutation was found in a proband from a typical HNPCC family, who had developed a colorectal cancer (CRC), a gastric cancer and a rectal adenoma. The CRC and the adenoma showed mild MSI limited to mononucleotide tracts, while the gastric carcinoma was microsatellite stable. The other mutation was detected in an atypical HNPCC proband, whose CRC showed widespread MSI involving both mono- and dinucleotide repeats. The phenotypic variability associated with MSH6 constitutional mutations represents a complicating factor for the optimization of strategies aimed at identifying candidates to MSH6 genetic testing.

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

Author

Ursula Catena, Luigi Della Corte, Antonio Raffone, Antonio Travaglino, Emanuela Lucci Cordisco, Elena Teodorico, Valeria Masciullo, Giuseppe Bifulco, Attilio Di Spiezio Sardo, Giovanni Scambia, Francesco Fanfani, Catena, U., Della Corte, L., Raffone, A., Travaglino, A., Lucci Cordisco, E., Teodorico, E., Masciullo, V., Bifulco, G., Di Spiezio Sardo, A., Scambia, G., and Fanfani, F.

Subjects
mismatch repair, Lynch Syndrome, endometrial cancer, immunohistochemistry, fertility-sparing treatment, General Medicine, genetic testing
Abstract

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

Author

Maurizio Genuardi, Concetta Santonocito, G. Ronzino, Ettore Capoluongo, Iole Cucinotto, Emanuela Lucci Cordisco, Assunta Tornesello, Maria Rita De Giorgio, Elisabetta De Matteis, Angelo Minucci, Capoluongo, E., De Matteis, E., Cucinotto, I., Ronzino, G., Santonocito, C., Tornesello, A., De Giorgio, M. R., Lucci Cordisco, E., Minucci, A., and Genuardi, M.

Subjects
Genetics, business.industry, HBOC, Biochemistry (medical), Clinical Biochemistry, Haplotype, MEDLINE, Cancer, General Medicine, BRCA1, Settore MED/03 - GENETICA MEDICA, medicine.disease, BRCA1/2, Age related, Medicine, founder mutation, business, Founder mutation, novel mutations
Published
2021

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

Author

Emanuele Damiano Luca Urso, Maurizio Ponz de Leon, Marco Vitellaro, Guglielmo Niccolò Piozzi, Quoc Riccardo Bao, Aline Martayan, Andrea Remo, Vittoria Stigliano, Cristina Oliani, Emanuela Lucci Cordisco, Salvatore Pucciarelli, Guglielmina Nadia Ranzani, Alessandra Viel, Francesca Adami, Elisa Alducci, Lucia Amadori, Valentina Arcangeli, Luisa Balestrino, Daniela Barana, Lucio Bertario, Bernardo Bonanni, Stefania Boni, Pierluigi Bullian, Fiorella Carbonardi, Ileana Carnevali, Paola Castelli, Francesco Celotto, Giulia Cini, Gino Crivellari, Duilio Della Libera, Anastasia Dell'elice, Maria Digennaro, Alessandra D'urso, Antonella Fabretto, Daniele Fanale, Irene Feroce, Daniela Furlan, Paola Ghiorzo, Mara Giacché, Milena Gusella, Barbara Liserre, Isabella Mammi, Stefania Massuras, Daniela Mazzà, Eleonora Mollica, Alberto Morabito, Giorgia Nardo, Flavia Palermo, Elena Panizza, Margherita Patruno, Monica Pedroni, Valeria Grazia Maria Pensotti, Guglielmo Niccolo Piozzi, Simonetta Pozzi, Silvia Presi, Marta Puzzono, Mila Ravegnani, Maria Teresa Ricci, Luca Roncucci, Giovanni Battsita Rossi, Elena Maria Sala, Lupe Sanchez Mete, Daniele Sandonà, Stefania Sciallero, Davide Serrano, Stefano Signoroni, Francesca Spina, Monica Taborelli, Gianluca Tedaldi, Maria Grazia Tibiletti, Silvia Tognazzo, Gianluca Tolva, Cristina Maria Concetta Trovato, Daniela Turchetti, Dora Varvara, Caterina Vivanet, Stefania Zovato, Raffaella Alessia Zuppardo, Urso E.D.L., Ponz de Leon M., Vitellaro M., Piozzi G.N., Bao Q.R., Martayan A., Remo A., Stigliano V., Oliani C., Lucci Cordisco E., Pucciarelli S., Ranzani G.N., Viel A., Adami F., Alducci E., Amadori L., Arcangeli V., Balestrino L., Barana D., Bertario L., Bonanni B., Boni S., Bullian P., Carbonardi F., Carnevali I., Castelli P., Celotto F., Cini G., Crivellari G., Libera D.D., Dell'elice A., Digennaro M., D'urso A., Fabretto A., Fanale D., Feroce I., Furlan D., Ghiorzo P., Giacche M., Gusella M., Liserre B., Mammi I., Massuras S., Mazza D., Mollica E., Morabito A., Nardo G., Palermo F., Panizza E., Patruno M., Pedroni M., Pensotti V.G.M., Pozzi S., Presi S., Puzzono M., Ravegnani M., Ricci M.T., Roncucci L., Rossi G.B., Sala E.M., Mete L.S., Sandona D., Sciallero S., Serrano D., Signoroni S., Spina F., Taborelli M., Tedaldi G., Tibiletti M.G., Tognazzo S., Tolva G., Trovato C.M.C., Turchetti D., Varvara D., Vivanet C., Zovato S., and Zuppardo R.A.

Subjects
Oncology, medicine.medical_specialty, Gastrointestinal tumors, Colorectal cancer, Surgical Management, Colorectal polyposis, Germline, 03 medical and health sciences, Cancer Genetic, 0302 clinical medicine, MUTYH, Internal medicine, medicine, Cancer Genetics, Polyposis coli, Hepatology, Pathogenic mutation, business.industry, Colorectal polyposis not associated with APC/MUTYH mutation, Polyposis management guideline, Gastroenterology, Expert consensus, Endoscopic surveillance, medicine.disease, Consensus development conference, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, business
Abstract

An expert consensus panel convened by the Italian Association for Inherited and Familial Gastrointestinal Tumors (Associazione Italiana per lo Studio della Familiarita ed Ereditarieta dei Tumori Gastrointestinali, AIFEG) reviewed the literature and agreed on a number of position statements regarding the definition and management of polyposis coli without an identified pathogenic mutation on the APC or MUTYH genes, defined in the document as NAMP (non-APC/MUTYH polyposis).

Published
2021

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

Author

Maurizio Genuardi, Marzena Franiuk, Carla Bruzzone, Daniela Turchetti, Emanuela Lucci-Cordisco, Alessia Orfino, Elisabetta De Matteis, Lea Godino, Andrea Poscia, Francesca Romana Di Raimo, D Zace, Maria Luisa Di Pietro, Benedetta Bertonazzi, Liliana Varesco, Di Pietro M.L., Zace D., Orfino A., Di Raimo F.R., Poscia A., de Matteis E., Turchetti D., Godino L., Beronazzi B., Franiuk M., Bruzzone C., Varesco L., Lucci-Cordisco E., and Genuardi M.

Subjects
Proband, Adult, Genetic testing, Genetic counseling, Genes, BRCA2, MEDLINE, Genes, BRCA1, hereditary cancer, intrafamilial communication, personalised approach, Breast Neoplasms, Genetic Counseling, Disclosure, Settore MED/03 - GENETICA MEDICA, Article, law.invention, intrafamilial communication, 03 medical and health sciences, law, Surveys and Questionnaires, Genetics, medicine, Humans, Family, Genetic Predisposition to Disease, cancer risk communication, Genetics (clinical), Ovarian Neoplasms, Personalized genetic counseling, 0303 health sciences, medicine.diagnostic_test, business.industry, Communication, 030305 genetics & heredity, Correction, Middle Aged, BRCA1, BRCA2, Test (assessment), Cross-Sectional Studies, personalised approach, Italy, hereditary cancer, CLARITY, Marital status, Female, Personalized medicine, Psychology, business, Clinical psychology
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
2021

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

Author

Andrea Poscia, D Zace, Emanuela Lucci-Cordisco, Lea Godino, A Orfino, Maurizio Genuardi, F.R. Di Raimo, E. de Matteis, Carla Bruzzone, Daniela Turchetti, Benedetta Bertonazzi, Liliana Varesco, Marzena Franiuk, M.L. Di Pietro, Di Pietro M.L., Zace D., Orfino A., Di Raimo F.R., Poscia A., de Matteis E., Turchetti D., Godino L., Bertonazzi B., Franiuk M., Bruzzone C., Varesco L., Lucci-Cordisco E., and Genuardi M.

Subjects
Oncology, medicine.medical_specialty, business.industry, medicine.disease, Human genetics, Breast cancer, Internal medicine, Cancer genetics, Breast Cancer, Cancer Genetics, Genetics, medicine, business, Ovarian cancer, Genetics (clinical)
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
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48. High frequency of mosaic CREBBP deletions in Rubinstein–Taybi syndrome patients and mapping of somatic and germ-line breakpoints

Author

Angelo Selicorni, Anna Maria Pinto, Maria Luisa Giovannucci-Uzielli, Romano Tenconi, Cristina Gervasini, Francesca Faravelli, Lidia Larizza, Angela Bentivegna, Alice Pessagno, Emanuela Lucci-Cordisco, Paola Castronovo, Federica Mottadelli, Leonardo Salviati, Giovanni Neri, Gervasini, C, Castronovo, P, Bentivegna, A, Mottadelli, F, Faravelli, F, Giovannucci Uzielli, M, Pessagno, A, Lucci Cordisco, E, Pinto, A, Salviati, L, Selicorni, A, Tenconi, R, Neri, G, and Larizza, L

Subjects
Adult, Rubinstein–Taybi syndrome, MED/03 - GENETICA MEDICA, DELETIONS RUBINSTEIN-TAYBI SYNDROME, Biology, Settore MED/03 - GENETICA MEDICA, Genome, Germline, 03 medical and health sciences, Exon, medicine, Genetics, Humans, EP300, Gene, Sequence Deletion, 030304 developmental biology, Rubinstein-Taybi Syndrome, Breakpoint mapping, 0303 health sciences, Mosaicism, 030305 genetics & heredity, Breakpoint, Infant, Newborn, Chromosome Mapping, medicine.disease, CREB-Binding Protein, Germ Cells, CREBBP deletion, Microsatellite, Microdeletion, Female
Abstract

Rubinstein–Taybi syndrome (RSTS) is a rare malformation disorder caused by mutations in the closely related CREBBP and EP300 genes, accounting respectively for up to 60 and 3% of cases. About 10% of CREBBP mutations are whole gene deletions often extending into flanking regions. Using FISH and microsatellite analyses as a first step in the CREBBP mutation screening of 42 Italian RSTS patients, we identified six deletions, three of which were in a mosaic condition that has not been previously reported in RSTS. The use of region-specific BAC clones and small CREBBP probes allowed us to assess the extent of all of the deletions by mapping their endpoints to genomic intervals of 5–10 kb. Four of our five intragenic breakpoints cluster at the 5′ end of CREBBP, where there is a peak of breakpoints underlying rearrangements in RSTS patients and tumors. The search for genomic motifs did not reveal any low-copy repeats (LCRs) or any greater density of repetitive sequences. In contrast, the percentage of interspersed repetitive elements (mainly Alu and LINEs in the CREBBP exon 2 region) is significantly higher than that in the entire gene or the average in the genome, thus suggesting that this characteristic may be involved in the region’s vulnerability to breaking and nonhomologous pairing. The FISH analysis extended to the EP300 genomic region did not reveal any deletions. The clinical presentation was typical in all cases, but more severe in the three patients carrying constitutional deletions, raising a question about the possible underdiagnosis of a few cases of mild RSTS.

Published
2007
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49. Survival Outcomes with Regorafenib and/or Trifluridine/Tipiracil Sequencing to Rechallenge with Third-Line Regimens in Metastatic Colorectal Cancer: A Multicenter Retrospective Real-World Subgroup Comparison from the ReTrITA Study.

Author

Signorelli C, Calegari MA, Anghelone A, Passardi A, Frassineti GL, Bittoni A, Lucchetti J, Angotti L, Di Giacomo E, Zurlo IV, Morelli C, Dell'Aquila E, Artemi A, Gemma D, Corsi DC, Emiliani A, Ribelli M, Mazzuca F, Arrivi G, Zoratto F, Chilelli MG, Schirripa M, Morandi MG, Santamaria F, Dettori M, Cosimati A, Saltarelli R, Minelli A, Lucci-Cordisco E, and Basso M

Subjects
Humans, Male, Female, Retrospective Studies, Middle Aged, Aged, Neoplasm Metastasis, Aged, 80 and over, Drug Combinations, Adult, Treatment Outcome, Phenylurea Compounds therapeutic use, Colorectal Neoplasms drug therapy, Colorectal Neoplasms mortality, Colorectal Neoplasms pathology, Trifluridine therapeutic use, Pyridines therapeutic use, Thymine therapeutic use, Pyrrolidines therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use
Abstract

Background: There is ongoing discussion around the optimal course of treatment for metastatic colorectal cancer (mCRC) following the second line. Trifluridine/tipiracil (T) and regorafenib (R) have been the mainstay of therapy in this situation, as they both increased overall survival (OS) in comparison to a placebo. Despite the paucity of evidence, therapy rechallenge is also recognized as an option for practical use. In the third-line scenario of mCRC, we planned to investigate the survival outcomes using (T) and (R), both with and without prior rechallenge treatment., Materials and Methods: Between 2012 and 2023, we examined the medical records of 1156 patients with refractory mCRC who were enrolled in the multicenter retrospective ReTrITA study. We then separated the patients into two cohorts based on the rechallenge therapy that was given before regorafenib and/or trifluridine/tipiracil at 17 Italian centres., Results: A total of 981 patients underwent T and/or R therapy, while 175 patients had therapy rechallenge before T and/or R. The median overall survival (mOS) for patients treated with T/R and R/T sequences in the rechallenge therapy cohort was 14.5 months and 17.6 months, respectively ( p = 0.1955). A statistically significant survival benefit was observed in patients who received monotheraphy with R (mOS: 6 months) compared to the T group (mOS: 4.2 months) ( p = 0.0332). In the same cohort, a median progression-free survival (mPFS) benefit was demonstrated in favour of the R/T group (11.3 months) vs. 9 months of the reverse sequence ( p = 0.4004). In the no-rechallenge cohort, the mOS was statistically longer in the R/T sequence than in the T/R sequence (16.2 months vs. 12.3 months, respectively; p = 0.0014). In terms of the mPFS, we saw the same significant result for the adoption of R/T treatment (11.5 months vs. 8.4 months, respectively; p < 0.0001). The two monotherapy groups did not reveal any significant differences., Conclusions: This study suggests that rechallenge therapy may improve survival rates in the third-line treatment of mCRC, particularly if it is administered before sequential R/T treatment. This could allow for the extension of mCRC treatment choices until prospective studies are finished or randomised trials are performed.

Published
2024
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50. Assessing the efficacy of an innovative diagnostic method for identifying 5 % variants in somatic ctDNA.

Author

Mareso C, Crosta L, De Vita MG, Cristofoli F, Tanzi B, Benedetti S, Bonetti G, Donofrio CA, Cominetti M, Riccio L, Fioravanti A, Generali D, Lucci Cordisco E, Chiurazzi P, Gatta V, Stuppia L, Cecchin S, Bertelli M, and Marceddu G

Subjects
Humans, Liquid Biopsy methods, Biomarkers, Tumor genetics, Biomarkers, Tumor blood, Gene Frequency, Circulating Tumor DNA genetics, Circulating Tumor DNA blood, High-Throughput Nucleotide Sequencing methods, Neoplasms genetics, Neoplasms diagnosis, Neoplasms blood
Abstract

Background: Liquid biopsy is considered a complementary and recently also an alternative method to surgical biopsy. It allows for the acquisition of valuable information regarding the potential presence of tumors, particularly through the analysis of circulating tumor DNA (ctDNA). CtDNA is a fraction of circulating free DNA (cfDNA) that can be extracted from various tissues, with blood being the most readily available., Results: To maximize the yield of plasma separation, specific Streck tubes are recommended for blood collection. The MagPurix CFC DNA Extraction Kit can be used for cfDNA extraction, and the TWIST Library Preparation protocol can be optimized for further analysis. Next-generation sequencing (NGS) can be employed to compare somatic and germline lineages, enabling the identification of somatic variants with a Variant Allele Frequency (VAF) of 5 % or higher, which are absent in the germline lineage., Conclusion: This analysis helps in the assessment of recurrence, analysis, and monitoring of cancer tissue., Competing Interests: Declaration of competing interest The authors of this scientific article often publish together, being part of the same group and/or scientific society. The scientific journal designated to publish this article has a specific policy to ensure the optimal handling of these situations. The journal’s policy ensures that the peer review process is kept independent by selecting reviewers independent of the authors of the article. All affiliations of the authors with private companies have been declared to make clear the position regarding the interests of these companies. The authors are affiliated with private companies for which there could be a possible conflict of interest. The authors state that the research was conducted in the absence of any commercial relationship that could be construed as a possible direct conflict of interest avoiding mention of any products or services sold by private companies related to the authors. The authors of this article are reported to be patents inventors., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2024
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