125 results on '"Gismondi, V."'
Search Results
2. Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2
- Author
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O'Mahony, DG, Ramus, SJ, Southey, MC, Meagher, NS, Hadjisavvas, A, John, EM, Hamann, U, Imyanitov, EN, Andrulis, IL, Sharma, P, Daly, MB, Hake, CR, Weitzel, JN, Jakubowska, A, Godwin, AK, Arason, A, Bane, A, Simard, J, Soucy, P, Caligo, MA, Mai, PL, Claes, KBM, Teixeira, MR, Chung, WK, Lazaro, C, Hulick, PJ, Toland, AE, Pedersen, IS, Neuhausen, SL, Vega, A, de la Hoya, M, Nevanlinna, H, Dhawan, M, Zampiga, V, Danesi, R, Varesco, L, Gismondi, V, Vellone, VG, James, PA, Janavicius, R, Nikitina-Zake, L, Nielsen, FC, van Overeem Hansen, T, Pejovic, T, Borg, A, Rantala, J, Offit, K, Montagna, M, Nathanson, KL, Domchek, SM, Osorio, A, Garcia, MJ, Karlan, BY, De Fazio, A, Bowtell, D, McGuffog, L, Leslie, G, Parsons, MT, Doerk, T, Speith, L-M, dos Santos, ES, da Costa, AABA, Radice, P, Peterlongo, P, Papi, L, Engel, C, Hahnen, E, Schmutzler, RK, Wappenschmidt, B, Easton, DF, Tischkowitz, M, Singer, CF, Tan, YY, Whittemore, AS, Sieh, W, Brenton, JD, Yannoukakos, D, Fostira, F, Konstantopoulou, I, Soukupova, J, Vocka, M, Chenevix-Trench, G, Pharoah, PDP, Antoniou, AC, Goldgar, DE, Spurdle, AB, Michailidou, K, Mourits, MJE, Lesueur, F, O'Mahony, DG, Ramus, SJ, Southey, MC, Meagher, NS, Hadjisavvas, A, John, EM, Hamann, U, Imyanitov, EN, Andrulis, IL, Sharma, P, Daly, MB, Hake, CR, Weitzel, JN, Jakubowska, A, Godwin, AK, Arason, A, Bane, A, Simard, J, Soucy, P, Caligo, MA, Mai, PL, Claes, KBM, Teixeira, MR, Chung, WK, Lazaro, C, Hulick, PJ, Toland, AE, Pedersen, IS, Neuhausen, SL, Vega, A, de la Hoya, M, Nevanlinna, H, Dhawan, M, Zampiga, V, Danesi, R, Varesco, L, Gismondi, V, Vellone, VG, James, PA, Janavicius, R, Nikitina-Zake, L, Nielsen, FC, van Overeem Hansen, T, Pejovic, T, Borg, A, Rantala, J, Offit, K, Montagna, M, Nathanson, KL, Domchek, SM, Osorio, A, Garcia, MJ, Karlan, BY, De Fazio, A, Bowtell, D, McGuffog, L, Leslie, G, Parsons, MT, Doerk, T, Speith, L-M, dos Santos, ES, da Costa, AABA, Radice, P, Peterlongo, P, Papi, L, Engel, C, Hahnen, E, Schmutzler, RK, Wappenschmidt, B, Easton, DF, Tischkowitz, M, Singer, CF, Tan, YY, Whittemore, AS, Sieh, W, Brenton, JD, Yannoukakos, D, Fostira, F, Konstantopoulou, I, Soukupova, J, Vocka, M, Chenevix-Trench, G, Pharoah, PDP, Antoniou, AC, Goldgar, DE, Spurdle, AB, Michailidou, K, Mourits, MJE, and Lesueur, F
- Abstract
BACKGROUND: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. METHODS: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). RESULTS: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. CONCLUSIONS: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.
- Published
- 2023
3. 597P Endometrial carcinoma and mismatch repair deficiency: Clinical association and universal screening for Lynch syndrome
- Author
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Puglisi, S., primary, Ponzano, M., additional, Perachino, M., additional, Pirrone, C., additional, Damassi, A., additional, Bregni, G., additional, Puccini, A., additional, Grassi, M., additional, Trevisan, L., additional, Gismondi, V., additional, Dono, M., additional, Lastraioli, S., additional, Fedele, P., additional, Cremante, M., additional, Gandini, A., additional, Giannelli, F., additional, Mammoliti, S., additional, Vellone, V.G., additional, Sciallero, M.S., additional, and Iaia, M.L., additional
- Published
- 2022
- Full Text
- View/download PDF
4. 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
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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
- Full Text
- View/download PDF
5. Evaluation of BRCA1 promoter hypermethylation (B1PHM) in ovarian carcinomas (OC)
- Author
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Paudice, M, Rivera, D, Banelli, B, Mammoliti, S, Centurioni, Mg, Caroti, C, Anselmi, G, Gismondi, V, Vellone, Vg, and Varesco, L
- Published
- 2021
6. P-205 Streamlining the diagnostic pathway for Lynch syndrome in colorectal cancer patients: A ten-year experience in a single Italian center
- Author
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Puccini, A., Nardin, S., Trevisan, L., Lastraioli, S., Ricciotti, I., Damiani, A., Bregni, G., Pastorino, A., Martelli, V., Murialdo, R., Gismondi, V., Battistuzzi, L., Varesco, L., Dono, M., Grillo, F., and Sciallero, S.
- Published
- 2023
- Full Text
- View/download PDF
7. BRCA And Ovarian Cancer: Implementing Routine Genetic Testing. The Genoa Experience
- Author
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Paudice, M, Rivera, D, Anselmi, G, Delle Piane, C, Centurioni, Mg, Mammoliti, S, Gismondi, V, Varesco, L, and Vellone, Vg
- Published
- 2019
8. Mutation in a splice-donor site of the APC gene in a family with polyposis and late age of colonic cancer death
- Author
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Varesco, L., Gismondi, V., Presciuttini, S., Groden, J., Spirio, L., Sala, P., Rossetti, C., De Benedetti, L., Bafico, A., Heouaine, A., Grammatico, P., Del Porto, G., White, R., Bertario, L., and Ferrara, G. B.
- Published
- 1994
- Full Text
- View/download PDF
9. Attenuated familial adenomatous polyposis and Muir–Torre syndrome linked to compound biallelic constitutional MYH gene mutations
- Author
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Ponti, G, de Leon, M Ponz, Maffei, S, Pedroni, M, Losi, L, Di Gregorio, C, Gismondi, V, Scarselli, A, Benatti, P, Roncari, B, Seidenari, S, Pellacani, G, Varotti, C, Prete, E, Varesco, L, and Roncucci, L
- Published
- 2005
10. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.
- Author
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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
11. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification
- Author
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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
12. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification
- Author
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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
13. Mutational analysis of BRCA1 and BRCA2 genes in high grade serous ovarian carcinoma with Next Generation Sequencing (NGS); correlation between somatic and germline mutations
- Author
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Paudice, M, Garuti, Anna, Gismondi, V, Varesco, Liliana, Fulcheri, Ezio, Ferrero, Simone, Zoppoli, Gabriele, and Vellone, VALERIO GAETANO
- Published
- 2016
14. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer
- Author
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Rebbeck, TR, Mitra, N, Wan, F, Sinilnikova, OM, Healey, S, McGuffog, L, Chenevix-Trench, G, Easton, DF, Antoniou, AC, Nathanson, KL, Laitman, Y, Kushnir, A, Paluch-Shimon, S, Berger, R, Zidan, J, Friedman, E, Ehrencrona, H, Stenmark-Askmalm, M, Einbeigi, Z, Loman, N, Harbst, K, Rantala, J, Melin, B, Huo, D, Olopade, OI, Seldon, J, Ganz, PA, Nussbaum, RL, Chan, SB, Odunsi, K, Gayther, SA, Domchek, SM, Arun, BK, Lu, KH, Mitchell, G, Karlan, BY, Walsh, C, Lester, J, Godwin, AK, Pathak, H, Ross, E, Daly, MB, Whittemore, AS, John, EM, Miron, A, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavičius, R, Tihomirova, L, Tung, N, Dorfling, CM, Van Rensburg, EJ, Steele, L, Neuhausen, SL, Ding, YC, Ejlertsen, B, Gerdes, AM, Hansen, TVO, Ramon Y Cajal, T, Osorio, A, Benitez, J, Godino, J, Tejada, MI, Duran, M, Weitzel, JN, Bobolis, KA, Sand, SR, Fontaine, A, Savarese, A, Pasini, B, Peissel, B, Bonanni, B, Zaffaroni, D, Vignolo-Lutati, F, Scuvera, G, Giannini, G, Bernard, L, Genuardi, M, Radice, P, Dolcetti, R, Manoukian, S, Pensotti, V, Gismondi, V, Yannoukakos, D, Fostira, F, Garber, J, Torres, D, and Rashid, MU
- Subjects
endocrine system diseases ,skin and connective tissue diseases - Abstract
Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2. Design, Setting, and Participants: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Exposures: Mutations of BRCA1 or BRCA2. Main Outcomes and Measures: Breast and ovarian cancer risks. Results: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. Conclusions and Relevance: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
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- 2015
15. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer
- Author
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Rebbeck, T.R., Mitra, N., Wan, F., Sinilnikova, O.M., Healey, S., McGuffog, L., Mazoyer, S., Chenevix-Trench, G., Easton, D.F., Antoniou, A.C., Nathanson, K.L., Laitman, Y., Kushnir, A., Paluch-Shimon, S., Berger, R., Zidan, J., Friedman, E., Ehrencrona, H., Stenmark-Askmalm, M., Einbeigi, Z., Loman, N., Harbst, K., Rantala, J., Melin, B., Huo, D., Olopade, O.I., Seldon, J., Ganz, P.A., Nussbaum, R.L., Chan, S.B., Odunsi, K., Gayther, S.A., Domchek, S.M., Arun, B.K., Lu, K.H., Mitchell, G., Karlan, B.Y., Walsh, C., Lester, J., Godwin, A.K., Pathak, H., Ross, E., Daly, M.B., Whittemore, A.S., John, E.M., Miron, A., Terry, M.B., Chung, W.K., Goldgar, D.E., Buys, S.S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C.M., Rensburg, E.J. van, Steele, L., Neuhausen, S.L., Ding, Y.C., Ejlertsen, B., Gerdes, A.M., Hansen, T., Ramon Y Cajal, T., Osorio, A., Benitez, J., Godino, J., Tejada, M.I., Duran, M., Weitzel, J.N., Bobolis, K.A., Sand, S.R., Fontaine, A., Savarese, A., Pasini, B., Peissel, B., Bonanni, B., Zaffaroni, D., Vignolo-Lutati, F., Scuvera, G., Giannini, G., Bernard, L., Genuardi, M., Radice, P., Dolcetti, R., Manoukian, S., Pensotti, V., Gismondi, V., Yannoukakos, D., Fostira, F., Garber, J., Torres, D., Rashid, M.U., Hamann, U., Peock, S., Frost, D., Platte, R., Evans, D.G., Eeles, R., Davidson, R., Eccles, D., Cole, T., Kets, M., Mensenkamp, A.R., et al., Rebbeck, T.R., Mitra, N., Wan, F., Sinilnikova, O.M., Healey, S., McGuffog, L., Mazoyer, S., Chenevix-Trench, G., Easton, D.F., Antoniou, A.C., Nathanson, K.L., Laitman, Y., Kushnir, A., Paluch-Shimon, S., Berger, R., Zidan, J., Friedman, E., Ehrencrona, H., Stenmark-Askmalm, M., Einbeigi, Z., Loman, N., Harbst, K., Rantala, J., Melin, B., Huo, D., Olopade, O.I., Seldon, J., Ganz, P.A., Nussbaum, R.L., Chan, S.B., Odunsi, K., Gayther, S.A., Domchek, S.M., Arun, B.K., Lu, K.H., Mitchell, G., Karlan, B.Y., Walsh, C., Lester, J., Godwin, A.K., Pathak, H., Ross, E., Daly, M.B., Whittemore, A.S., John, E.M., Miron, A., Terry, M.B., Chung, W.K., Goldgar, D.E., Buys, S.S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C.M., Rensburg, E.J. van, Steele, L., Neuhausen, S.L., Ding, Y.C., Ejlertsen, B., Gerdes, A.M., Hansen, T., Ramon Y Cajal, T., Osorio, A., Benitez, J., Godino, J., Tejada, M.I., Duran, M., Weitzel, J.N., Bobolis, K.A., Sand, S.R., Fontaine, A., Savarese, A., Pasini, B., Peissel, B., Bonanni, B., Zaffaroni, D., Vignolo-Lutati, F., Scuvera, G., Giannini, G., Bernard, L., Genuardi, M., Radice, P., Dolcetti, R., Manoukian, S., Pensotti, V., Gismondi, V., Yannoukakos, D., Fostira, F., Garber, J., Torres, D., Rashid, M.U., Hamann, U., Peock, S., Frost, D., Platte, R., Evans, D.G., Eeles, R., Davidson, R., Eccles, D., Cole, T., Kets, M., Mensenkamp, A.R., and et al.
- Abstract
Item does not contain fulltext, IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES: Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 x 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 x 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 x 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.73
- Published
- 2015
16. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer
- Author
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Rebbeck, R. (Timothy), Mitra, N. (Nandita), Wan, F. (Fei), Sinilnikova, O. (Olga), Healey, S. (Sue), McGuffog, L. (Lesley), Chenevix-Trench, G. (Georgia), Easton, D.F. (Douglas), Antoniou, A.C. (Antonis), Nathanson, K.L. (Katherine), Laitman, Y. (Yael), Kushnir, A. (Anya), Paluch-Shimon, S. (Shani), Berger, R. (Raanan), Zidan, J. (Jamal), Friedman, E. (Eitan), Ehrencrona, H. (Hans), Stenmark-Askmalm, M. (Marie), Einbeigi, Z. (Zakaria), Loman, N. (Niklas), Harbst, K. (Katja), Rantala, J. (Johanna), Melin, B. (Beatrice), Huo, D. (Dezheng), Olopade, O.I. (Olofunmilayo), Seldon, J.L. (Joyce), Ganz, P.A. (Patricia), Nussbaum, R.L. (Robert L.), Chan, S. (Salina), Odunsi, K. (Kunle), Gayther, S.A. (Simon), Domchek, S.M. (Susan), Arun, B.K. (Banu), Lu, K.H. (Karen), Mitchell, G. (Gillian), Karlan, B.Y. (Beth), Walsh, C.S. (Christine), Lester, K.J. (Kathryn), Godwin, A.K. (Andrew), Pathak, S.S., Ross, E.B. (Eric), Daly, M.J. (Mark), Whittemore, A.S. (Alice), John, E.M. (Esther), Miron, A. (Alexander), Terry, M.B. (Mary Beth), Chung, W.K. (Wendy K.), Goldgar, D. (David), Buys, S.S. (Saundra), Janavicius, R. (Ramunas), Tihomirova, L. (Laima), Tung, N. (Nadine), Dorfling, C.M. (Cecilia), Rensburg, E.J. (Elizabeth) van, Steele, L. (Linda), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), Ejlertsen, B. (Bent), Gerdes, A-M. (Anne-Marie), Hansen, T.V.O. (Thomas), Ramon Y Cajal, T., Osorio, A. (Ana), Benítez, J. (Javier), Godino, J. (Javier), Tejada, M.I., Duran, M. (Mercedes), Weitzel, J.N. (Jeffrey), Bobolis, K.A. (Kristie A.), Sand, S.R. (Sharon), Fontaine, A. (Annette), Savarese, A. (Antonella), Pasini, B. (Barbara), Peissel, B. (Bernard), Bonnani, B. (Bernardo), Zaffaroni, D. (Daniela), Vignolo-Lutati, F. (Francesca), Scuvera, G. (Giulietta), Giannini, G. (Giuseppe), Bernard, L. (Loris), Genuardi, M. (Maurizio), Radice, P. (Paolo), Dolcetti, R. (Riccardo), Manoukian, S. (Siranoush), Pensotti, V. (Valeria), Gismondi, V. (Viviana), Yannoukakos, D. (Drakoulis), Fostira, F. (Florentia), Garber, J. (Judy), Torres, D. (Diana), Rashid, M.U. (Muhammad), Hamann, U. (Ute), Peock, S. (Susan), Frost, D. (Debra), Platte, R. (Radka), Evans, D.G. (Gareth), Eeles, R. (Rosalind), Davidson, R. (Rosemarie), Eccles, D. (Diana), Cole, T. (Trevor), Cook, J. (Jackie), Brewer, C. (Carole), Hodgson, S. (Shirley), Morrison, P.J. (Patrick), Walker, L.J. (Lisa), Porteous, M.E. (Mary), Kennedy, M.J. (John), Izatt, L. (Louise), Adlard, L., Donaldson, A. (Alan), Ellis, S.D. (Steve), Sharma, P. (Priyanka), Schmutzler, R.K. (Rita), Wapenschmidt, B. (Barbara), Becker, A. (Alexandra), Rhiem, K. (Kerstin), Hahnen, E. (Eric), Engel, C. (Christoph), Meindl, A. (Alfons), Engert, S. (Stefanie), Ditsch, N. (Nina), Arnold, N. (Norbert), Plendl, H. (Hansjoerg), Mundhenke, C. (Christoph), Niederacher, D. (Dieter), Fleisch, M.C. (Markus), Sutter, C. (Christian), Bartram, C.R. (Claus), Dikow, N. (Nicola), Wang-Gohrke, S. (Shan), Gadzicki, D. (Dorothea), Steinemann, D. (Doris), Kast, K. (Karin), Beer, M. (Marit), Varon-Mateeva, R. (Raymonda), Gehrig, P.A. (Paola A.), Weber, B.H.F. (Bernhard), Stoppa-Lyonnet, D. (Dominique), Belotti, M. (Muriel), Gauthier-Villars, M. (Marion), Damiola, F. (Francesca), Boutry-Kryza, N. (N.), Lasset, C. (Christine), Sobol, H. (Hagay), Peyrat, J.-P., Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Collonge-Rame, M.-A., Mortemousque, I. (Isabelle), Nogues, C. (Catherine), Rouleau, E. (Etienne), Isaacs, C. (Claudine), Paepe, A. (Anne) de, Poppe, B. (Bruce), Claes, K. (Kathleen), De Leeneer, K. (Kim), Piedmonte, M. (Marion), Rodriguez, G. (Gustavo), Wakely, K. (Katie), Boggess, J.F. (John), Blank, S.V. (Stephanie), Basil, J. (Jack), Azodi, M. (Masoud), Phillips, K.-A. (Kelly-Anne), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Romero, A. (Atocha), Nevanlinna, H. (Heli), Aittomäki, K. (Kristiina), Hout, A.H. (Annemarie) van der, Hogervorst, F.B.L. (Frans), Verhoef, S., Collée, J.M. (Margriet), Seynaeve, C.M. (Caroline), Oosterwijk, J.C. (Jan), Gille, J.J. (Johan), Wijnen, J.T. (Juul), Gómez García, E.B. (Encarna), Kets, C.M. (Marleen), Ausems, M.G.E.M. (Margreet), Aalfs, C.M. (Cora), Devilee, P. (Peter), Mensenkamp, A.R. (Arjen), Kwong, A. (Ava), Olah, E., Papp, J. (Janos), Díez, O. (Orland), Lázaro, C. (Conxi), Darder, E. (Esther), Blanco, I. (Ignacio), Salinas, M., Jakubowska, A. (Anna), Lubinski, J. (Jan), Gronwald, J. (Jacek), Jaworska-Bieniek, K. (Katarzyna), Durda, K. (Katarzyna), Sukiennicki, G. (Grzegorz), Huzarski, T. (Tomasz), Byrski, T. (Tomasz), Cybulski, C. (Cezary), Toloczko-Grabarek, A. (Aleksandra), Złowocka-Perłowska, E. (Elzbieta), Menkiszak, J. (Janusz), Arason, A. (Adalgeir), Barkardottir, R.B. (Rosa), Simard, J. (Jacques), Laframboise, R. (Rachel), Montagna, M. (Marco), Agata, S. (Simona), Alducci, E. (Elisa), Peixoto, A. (Ana), Teixeira, P.J., Spurdle, A.B. (Amanda), Lee, M.H. (Min Hyuk), Park, S.K. (Sue), Kim, S.-W. (Sung-Won), Friebel, M.O.W. (Mark ), Couch, F.J. (Fergus), Lindor, N.M. (Noralane), Pankratz, V.S. (Shane), Guidugli, L. (Lucia), Wang, X. (Xianshu), Tischkowitz, M. (Marc), Foretova, L. (Lenka), Vijai, J. (Joseph), Offit, K. (Kenneth), Robson, M. (Mark), Rau-Murthy, R. (Rohini), Kauff, N. (Noah), Fink-Retter, A. (Anneliese), Singer, C.F. (Christian), Rappaport, C. (Christine), Gschwantler-Kaulich, D. (Daphne), Pfeiler, G. (Georg), Tea, M.-K., Berger, A. (Andreas), Greene, M.H. (Mark), Mai, P.L. (Phuong), Imyanitov, E.N. (Evgeny), Toland, A.E. (Amanda), Senter, L. (Leigha), Bojesen, A. (Anders), Pedersen, I.S. (Inge Sokilde), Skytte, A.-B. (Anne-Bine), Sunde, L. (Lone), Thomassen, M. (Mads), Moeller, S.T. (Sanne Traasdahl), Kruse, T.A. (Torben), Jensen, U.B., Caligo, M.A. (Maria), Aretini, P. (Paolo), Teo, S.-H. (Soo-Hwang), Selkirk, C.G. (Christina), Hulick, P.J. (Peter), Andrulis, I.L. (Irene), Rebbeck, R. (Timothy), Mitra, N. (Nandita), Wan, F. (Fei), Sinilnikova, O. (Olga), Healey, S. (Sue), McGuffog, L. (Lesley), Chenevix-Trench, G. (Georgia), Easton, D.F. (Douglas), Antoniou, A.C. (Antonis), Nathanson, K.L. (Katherine), Laitman, Y. (Yael), Kushnir, A. (Anya), Paluch-Shimon, S. (Shani), Berger, R. (Raanan), Zidan, J. (Jamal), Friedman, E. (Eitan), Ehrencrona, H. (Hans), Stenmark-Askmalm, M. (Marie), Einbeigi, Z. (Zakaria), Loman, N. (Niklas), Harbst, K. (Katja), Rantala, J. (Johanna), Melin, B. (Beatrice), Huo, D. (Dezheng), Olopade, O.I. (Olofunmilayo), Seldon, J.L. (Joyce), Ganz, P.A. (Patricia), Nussbaum, R.L. (Robert L.), Chan, S. (Salina), Odunsi, K. (Kunle), Gayther, S.A. (Simon), Domchek, S.M. (Susan), Arun, B.K. (Banu), Lu, K.H. (Karen), Mitchell, G. (Gillian), Karlan, B.Y. (Beth), Walsh, C.S. (Christine), Lester, K.J. (Kathryn), Godwin, A.K. (Andrew), Pathak, S.S., Ross, E.B. (Eric), Daly, M.J. (Mark), Whittemore, A.S. (Alice), John, E.M. (Esther), Miron, A. (Alexander), Terry, M.B. (Mary Beth), Chung, W.K. (Wendy K.), Goldgar, D. (David), Buys, S.S. (Saundra), Janavicius, R. (Ramunas), Tihomirova, L. (Laima), Tung, N. (Nadine), Dorfling, C.M. (Cecilia), Rensburg, E.J. (Elizabeth) van, Steele, L. (Linda), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), Ejlertsen, B. (Bent), Gerdes, A-M. (Anne-Marie), Hansen, T.V.O. (Thomas), Ramon Y Cajal, T., Osorio, A. (Ana), Benítez, J. (Javier), Godino, J. (Javier), Tejada, M.I., Duran, M. (Mercedes), Weitzel, J.N. (Jeffrey), Bobolis, K.A. (Kristie A.), Sand, S.R. (Sharon), Fontaine, A. (Annette), Savarese, A. (Antonella), Pasini, B. (Barbara), Peissel, B. (Bernard), Bonnani, B. (Bernardo), Zaffaroni, D. (Daniela), Vignolo-Lutati, F. (Francesca), Scuvera, G. (Giulietta), Giannini, G. (Giuseppe), Bernard, L. (Loris), Genuardi, M. (Maurizio), Radice, P. (Paolo), Dolcetti, R. (Riccardo), Manoukian, S. (Siranoush), Pensotti, V. (Valeria), Gismondi, V. (Viviana), Yannoukakos, D. (Drakoulis), Fostira, F. (Florentia), Garber, J. (Judy), Torres, D. (Diana), Rashid, M.U. (Muhammad), Hamann, U. (Ute), Peock, S. (Susan), Frost, D. (Debra), Platte, R. (Radka), Evans, D.G. (Gareth), Eeles, R. (Rosalind), Davidson, R. (Rosemarie), Eccles, D. (Diana), Cole, T. (Trevor), Cook, J. (Jackie), Brewer, C. (Carole), Hodgson, S. (Shirley), Morrison, P.J. (Patrick), Walker, L.J. (Lisa), Porteous, M.E. (Mary), Kennedy, M.J. (John), Izatt, L. (Louise), Adlard, L., Donaldson, A. (Alan), Ellis, S.D. (Steve), Sharma, P. (Priyanka), Schmutzler, R.K. (Rita), Wapenschmidt, B. (Barbara), Becker, A. (Alexandra), Rhiem, K. (Kerstin), Hahnen, E. (Eric), Engel, C. (Christoph), Meindl, A. (Alfons), Engert, S. (Stefanie), Ditsch, N. (Nina), Arnold, N. (Norbert), Plendl, H. (Hansjoerg), Mundhenke, C. (Christoph), Niederacher, D. (Dieter), Fleisch, M.C. (Markus), Sutter, C. (Christian), Bartram, C.R. (Claus), Dikow, N. (Nicola), Wang-Gohrke, S. (Shan), Gadzicki, D. (Dorothea), Steinemann, D. (Doris), Kast, K. (Karin), Beer, M. (Marit), Varon-Mateeva, R. (Raymonda), Gehrig, P.A. (Paola A.), Weber, B.H.F. (Bernhard), Stoppa-Lyonnet, D. (Dominique), Belotti, M. (Muriel), Gauthier-Villars, M. (Marion), Damiola, F. (Francesca), Boutry-Kryza, N. (N.), Lasset, C. (Christine), Sobol, H. (Hagay), Peyrat, J.-P., Muller, D.W. (Danièle), Fricker, J.P. (Jean Pierre), Collonge-Rame, M.-A., Mortemousque, I. (Isabelle), Nogues, C. (Catherine), Rouleau, E. (Etienne), Isaacs, C. (Claudine), Paepe, A. (Anne) de, Poppe, B. (Bruce), Claes, K. (Kathleen), De Leeneer, K. (Kim), Piedmonte, M. (Marion), Rodriguez, G. (Gustavo), Wakely, K. (Katie), Boggess, J.F. (John), Blank, S.V. (Stephanie), Basil, J. (Jack), Azodi, M. (Masoud), Phillips, K.-A. (Kelly-Anne), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Romero, A. (Atocha), Nevanlinna, H. (Heli), Aittomäki, K. (Kristiina), Hout, A.H. (Annemarie) van der, Hogervorst, F.B.L. (Frans), Verhoef, S., Collée, J.M. (Margriet), Seynaeve, C.M. (Caroline), Oosterwijk, J.C. (Jan), Gille, J.J. (Johan), Wijnen, J.T. (Juul), Gómez García, E.B. (Encarna), Kets, C.M. (Marleen), Ausems, M.G.E.M. (Margreet), Aalfs, C.M. (Cora), Devilee, P. (Peter), Mensenkamp, A.R. (Arjen), Kwong, A. (Ava), Olah, E., Papp, J. (Janos), Díez, O. (Orland), Lázaro, C. (Conxi), Darder, E. (Esther), Blanco, I. (Ignacio), Salinas, M., Jakubowska, A. (Anna), Lubinski, J. (Jan), Gronwald, J. (Jacek), Jaworska-Bieniek, K. (Katarzyna), Durda, K. (Katarzyna), Sukiennicki, G. (Grzegorz), Huzarski, T. (Tomasz), Byrski, T. (Tomasz), Cybulski, C. (Cezary), Toloczko-Grabarek, A. (Aleksandra), Złowocka-Perłowska, E. (Elzbieta), Menkiszak, J. (Janusz), Arason, A. (Adalgeir), Barkardottir, R.B. (Rosa), Simard, J. (Jacques), Laframboise, R. (Rachel), Montagna, M. (Marco), Agata, S. (Simona), Alducci, E. (Elisa), Peixoto, A. (Ana), Teixeira, P.J., Spurdle, A.B. (Amanda), Lee, M.H. (Min Hyuk), Park, S.K. (Sue), Kim, S.-W. (Sung-Won), Friebel, M.O.W. (Mark ), Couch, F.J. (Fergus), Lindor, N.M. (Noralane), Pankratz, V.S. (Shane), Guidugli, L. (Lucia), Wang, X. (Xianshu), Tischkowitz, M. (Marc), Foretova, L. (Lenka), Vijai, J. (Joseph), Offit, K. (Kenneth), Robson, M. (Mark), Rau-Murthy, R. (Rohini), Kauff, N. (Noah), Fink-Retter, A. (Anneliese), Singer, C.F. (Christian), Rappaport, C. (Christine), Gschwantler-Kaulich, D. (Daphne), Pfeiler, G. (Georg), Tea, M.-K., Berger, A. (Andreas), Greene, M.H. (Mark), Mai, P.L. (Phuong), Imyanitov, E.N. (Evgeny), Toland, A.E. (Amanda), Senter, L. (Leigha), Bojesen, A. (Anders), Pedersen, I.S. (Inge Sokilde), Skytte, A.-B. (Anne-Bine), Sunde, L. (Lone), Thomassen, M. (Mads), Moeller, S.T. (Sanne Traasdahl), Kruse, T.A. (Torben), Jensen, U.B., Caligo, M.A. (Maria), Aretini, P. (Paolo), Teo, S.-H. (Soo-Hwang), Selkirk, C.G. (Christina), Hulick, P.J. (Peter), and Andrulis, I.L. (Irene)
- Abstract
Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2. Design, Setting, and Participants: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Exposures: Mutations of BRCA1 or BRCA2. Main Outcomes and Measures: Breast and ovarian cancer risks. Results: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to
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- 2015
- Full Text
- View/download PDF
17. FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor
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Peterlongo, P, Catucci, I, Colombo, M, Caleca, L, Mucaki, E, Bogliolo, M, Marin, M, Damiola, F, Bernard, L, Pensotti, V, Volorio, S, Dall'Olio, V, Meindl, A, Bartram, C, Sutter, C, Surowy, H, Sornin, V, Dondon, M, Eon-Marchais, S, Stoppa-Lyonnet, D, Andrieu, N, Sinilnikova, O, Mitchell, G, James, P, Thompson, E, Kconfab, Marchetti, M, Verzeroli, C, Tartari, C, Capone, G, Putignano, A, Genuardi, M, Medici, V, Marchi, I, Federico, M, Tognazzo, S, Matricardi, L, Agata, S, Dolcetti, R, Della Puppa, L, Cini, G, Gismondi, V, Viassolo, V, Perfumo, C, Mencarelli, M, Baldassarri, M, Peissel, B, Roversi, G, Silvestri, V, Rizzolo, P, Spina, F, Vivanet, C, Tibiletti, M, Caligo, M, Gambino, G, Tommasi, S, Pilato, B, Tondini, C, Corna, C, Bonanni, B, Barile, M, Osorio, A, Benitez, J, Balestrino, L, Ottini, L, Manoukian, S, Pierotti, M, Renieri, A, Varesco, L, Couch, F, Wang, X, Devilee, P, Hilbers, F, van Asperen, C, Viel, A, Montagna, M, Cortesi, L, Diez, O, Balmaña, J, Hauke, J, Schmutzler, R, Papi, L, Pujana, M, Lázaro, C, Falanga, A, Offit, K, Vijai, J, Campbell, I, Burwinkel, B, Kvist, A, Ehrencrona, H, Mazoyer, S, Pizzamiglio, S, Verderio, P, Surralles, J, Rogan, P, Radice, P, Dondon, MG, Sinilnikova, OM, James, PA, kConFab, Putignano, AL, Mencarelli, MA, Tibiletti, MG, Caligo, MA, Pierotti, MA, Couch, FJ, Hilbers, FS, van Asperen, CJ, Schmutzler, RK, Pujana, MA, Rogan, PK, Peterlongo, P, Catucci, I, Colombo, M, Caleca, L, Mucaki, E, Bogliolo, M, Marin, M, Damiola, F, Bernard, L, Pensotti, V, Volorio, S, Dall'Olio, V, Meindl, A, Bartram, C, Sutter, C, Surowy, H, Sornin, V, Dondon, M, Eon-Marchais, S, Stoppa-Lyonnet, D, Andrieu, N, Sinilnikova, O, Mitchell, G, James, P, Thompson, E, Kconfab, Marchetti, M, Verzeroli, C, Tartari, C, Capone, G, Putignano, A, Genuardi, M, Medici, V, Marchi, I, Federico, M, Tognazzo, S, Matricardi, L, Agata, S, Dolcetti, R, Della Puppa, L, Cini, G, Gismondi, V, Viassolo, V, Perfumo, C, Mencarelli, M, Baldassarri, M, Peissel, B, Roversi, G, Silvestri, V, Rizzolo, P, Spina, F, Vivanet, C, Tibiletti, M, Caligo, M, Gambino, G, Tommasi, S, Pilato, B, Tondini, C, Corna, C, Bonanni, B, Barile, M, Osorio, A, Benitez, J, Balestrino, L, Ottini, L, Manoukian, S, Pierotti, M, Renieri, A, Varesco, L, Couch, F, Wang, X, Devilee, P, Hilbers, F, van Asperen, C, Viel, A, Montagna, M, Cortesi, L, Diez, O, Balmaña, J, Hauke, J, Schmutzler, R, Papi, L, Pujana, M, Lázaro, C, Falanga, A, Offit, K, Vijai, J, Campbell, I, Burwinkel, B, Kvist, A, Ehrencrona, H, Mazoyer, S, Pizzamiglio, S, Verderio, P, Surralles, J, Rogan, P, Radice, P, Dondon, MG, Sinilnikova, OM, James, PA, kConFab, Putignano, AL, Mencarelli, MA, Tibiletti, MG, Caligo, MA, Pierotti, MA, Couch, FJ, Hilbers, FS, van Asperen, CJ, Schmutzler, RK, Pujana, MA, and Rogan, PK
- Abstract
Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p. Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p. Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.
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- 2015
18. Phenotype-Genotype correlations in an extended family with adenomatous coli and an unusual APC gene mutation
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PONZ DE LEON M., VARESCO L, BENATTI P, SASSATELLI R, SCARANO MI, ROSSI GB, DI GREGORIO C, GISMONDI V, PERCESEPE A, RONCUCCI L., IZZO, PAOLA, DE ROSA, MARINA, PONZ DE LEON, M., Varesco, L, Benatti, P, Sassatelli, R, Izzo, Paola, Scarano, Mi, Rossi, Gb, DI GREGORIO, C, Gismondi, V, Percesepe, A, DE ROSA, Marina, and Roncucci, L.
- Abstract
ISSN 0012-3706
- Published
- 2001
19. Increased Risk of Colorectal Adenomas in Italian Subjects Carrying the p53 PIN3 A2-Pro72 Haplotype
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Perfumo, C, Bonelli, L, Menichini, P, Inga, A, Gismondi, V, Ciferri, E, Percivale, P, Bianchi, Giovanna, Nasti, Sabina, Fronza, G, and Varesco, L.
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- 2007
20. 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
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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.
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- 2013
21. A distinct splice form of APC is highly expressed in neurones but not commonly mutated in neuroepithelial tumours
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Steigerwald, K., Santoro, I. M., Kordich, Jj, Gismondi, V., Trzepacz, C., Badiali, M, Giangaspero, Felice, Balko, M. G., and Groden, J.
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- 2001
22. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers
- Author
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Ramus, S.J., Kartsonaki, C., Gayther, S.A., Pharoah, P.D., Sinilnikova, O.M., Beesley, J., Chen, X., McGuffog, L., Healey, S., Couch, F.J., Wang, X., Fredericksen, Z., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Allavena, A., Ottini, L., Papi, L., Gismondi, V., Capra, F., Radice, P., Greene, M.H., Mai, P.L., Andrulis, I.L., Glendon, G., Ozcelik, H., Thomassen, M., Gerdes, A.M., Kruse, T.A., Cruger, D., Jensen, U.B., Caligo, M.A., Olsson, H., Kristoffersson, U., Lindblom, A., Arver, B., Karlsson, P., Stenmark Askmalm, M., Borg, A., Neuhausen, S.L., Ding, Y.C., Nathanson, K.L., Domchek, S.M., Jakubowska, A., Lubinski, J., Huzarski, T., Byrski, T., Gronwald, J., Gorski, B., Cybulski, C., Debniak, T., Osorio, A., Duran, M., Tejada, M.I., Benitez, J., Hamann, U., Rookus, M.A., Verhoef, S., Tilanus-Linthorst, M.A., Vreeswijk, M.P., Bodmer, D., Ausems, M.G., Os, T.A. van, Asperen, C.J. van, Blok, M.J., Meijers-Heijboer, H.E., Peock, S., Cook, M., Oliver, C., Frost, D., Dunning, A.M., Evans, D.G., Eeles, R., Pichert, G., Cole, T., Hodgson, S., Brewer, C., Morrison, P.J., Porteous, M., Kennedy, M.J., Rogers, M.T., Side, L.E., Donaldson, A., Gregory, H., Godwin, A., Stoppa-Lyonnet, D., Moncoutier, V., Castera, L., Mazoyer, S., Barjhoux, L., Bonadona, V., Leroux, D., Faivre, L., Lidereau, R., Nogues, C., Bignon, Y.J., Prieur, F., Collonge-Rame, M.A., Venat-Bouvet, L., Ligtenberg, M.J.L., et al., Ramus, S.J., Kartsonaki, C., Gayther, S.A., Pharoah, P.D., Sinilnikova, O.M., Beesley, J., Chen, X., McGuffog, L., Healey, S., Couch, F.J., Wang, X., Fredericksen, Z., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., Allavena, A., Ottini, L., Papi, L., Gismondi, V., Capra, F., Radice, P., Greene, M.H., Mai, P.L., Andrulis, I.L., Glendon, G., Ozcelik, H., Thomassen, M., Gerdes, A.M., Kruse, T.A., Cruger, D., Jensen, U.B., Caligo, M.A., Olsson, H., Kristoffersson, U., Lindblom, A., Arver, B., Karlsson, P., Stenmark Askmalm, M., Borg, A., Neuhausen, S.L., Ding, Y.C., Nathanson, K.L., Domchek, S.M., Jakubowska, A., Lubinski, J., Huzarski, T., Byrski, T., Gronwald, J., Gorski, B., Cybulski, C., Debniak, T., Osorio, A., Duran, M., Tejada, M.I., Benitez, J., Hamann, U., Rookus, M.A., Verhoef, S., Tilanus-Linthorst, M.A., Vreeswijk, M.P., Bodmer, D., Ausems, M.G., Os, T.A. van, Asperen, C.J. van, Blok, M.J., Meijers-Heijboer, H.E., Peock, S., Cook, M., Oliver, C., Frost, D., Dunning, A.M., Evans, D.G., Eeles, R., Pichert, G., Cole, T., Hodgson, S., Brewer, C., Morrison, P.J., Porteous, M., Kennedy, M.J., Rogers, M.T., Side, L.E., Donaldson, A., Gregory, H., Godwin, A., Stoppa-Lyonnet, D., Moncoutier, V., Castera, L., Mazoyer, S., Barjhoux, L., Bonadona, V., Leroux, D., Faivre, L., Lidereau, R., Nogues, C., Bignon, Y.J., Prieur, F., Collonge-Rame, M.A., Venat-Bouvet, L., Ligtenberg, M.J.L., and et al.
- Abstract
Item does not contain fulltext, BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. METHODS: We genotyped rs3814113 in 10,029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. RESULTS: The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 x 10(-9)) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 x 10(-4)). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. CONCLUSION: Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.
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- 2011
23. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers
- Author
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Ramus, S.J. (Susan), Kartsonaki, C. (Christiana), Gayther, S.A. (Simon), Pharoah, P.D.P. (Paul), Sinilnikova, O. (Olga), Beesley, J. (Jonathan), Chenevix-Trench, G. (Georgia), McGuffog, L. (Lesley), Healey, S. (Sue), Couch, F.J. (Fergus), Wang, X. (Xing), Fredericksen, Z. (Zachary), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Zaffaroni, D. (D.), Roversi, G. (Gaia), Barile, M. (Monica), Viel, A. (Alessandra), Allavena, A. (Anna), Ottini, L. (Laura), Papi, L. (Laura), Gismondi, V. (Viviana), Capra, F. (Fabio), Radice, P. (Paolo), Greene, M.H. (Mark), Mai, P.L. (Phuong), Andrulis, I.L. (Irene), Glendon, G. (Gord), Ozcelik, H. (Hilmi), Thomassen, M. (Mads), Gerdes, A-M. (Anne-Marie), Kruse, T.A. (Torben), Cruger, D. (Dorthe), Jensen, U.B., Caligo, M.A. (Maria), Olsson, H. (Hkan), Kristoffersson, U. (Ulf), Lindblom, A. (Annika), Arver, B. (Brita Wasteson), Karlsson, P. (Per), Stenmark-Askmalm, M. (M.), Borg, Å. (Åke), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Jakubowska, A. (Anna), Lubinski, J. (Jan), Huzarski, T. (Tomasz), Byrski, T. (Tomasz), Gronwald, J. (Jacek), Górski, B. (Bohdan), Cybulski, C. (Cezary), Dbniak, T. (Tadeusz), Osorio, A. (Ana), Durán, M. (Mercedes), Tejada, M.-I., Benitez, J. (Javier), Hamann, U. (Ute), Rookus, M.A. (Matti), Verhoef, S., Tilanus-Linthorst, M.M.A. (Madeleine), Vreeswijk, M.P. (Maaike), Bodmer, D. (Danielle), Ausems, M.G.E.M. (Margreet), Os, T.A.M. (Theo) van, Blok, M.J. (Marinus), Meijers-Heijboer, H. (Hanne), Peock, S. (Susan), Cook, M. (Margaret), Oliver, C.T. (Clare), Frost, D. (Debra), Dunning, A.M. (Alison), Evans, D.G. (Gareth), Eeles, R. (Rosalind), Pichert, G. (Gabriella), Cole, T.J. (Trevor), Hodgson, S.V. (Shirley), Brewer, C. (Carole), Morrison, P.J. (Patrick), Porteous, M.E. (Mary), Kennedy, M.J. (John), Rogers, M.T. (Mark), Side, L. (Lucy), Donaldson, A. (Alan), Gregory, H. (Helen), Godwin, A.K. (Andrew), Stoppa-Lyonnet, D. (Dominique), Moncoutier, V. (Virginie), Castera, L. (Laurent), Mazoyer, S. (Sylvie), Barjhoux, L. (Laure), Bonadona, V. (Valérie), Leroux, D. (Dominique), Faivre, L. (Laurence), Lidereau, R. (Rosette), Nogues, C. (Catherine), Bignon, Y.-J. (Yves-Jean), Prieur, F. (Fabienne), Collonge-Rame, M.-A., Vénat-Bouvet, L. (Laurence), Fert-Ferrer, S. (Sandra), Miron, A. (Alexander), Buys, S.S. (Saundra), Hopper, J. (John), Daly, M.J. (Mark), John, E.M. (Esther), Terry, M-B. (Mary-beth), Goldgar, D. (David), Hansen, T.V.O. (Thomas), Jønson, L. (Lars), Agnarsson, B.A. (Bjarni), Offit, K. (Kenneth), Kircchoff, T. (Tomas), Vijai, J. (Joseph), Dutra-Clarke, A. (Ana), Przybylo, J.A. (Jennifer), Montagna, M. (Marco), Casella, C. (Cinzia), Imyanitov, E.N. (Evgeny), Janavicius, R. (Ramunas), Blanco, I. (Ignacio), Lázaro, C. (Conxi), Moysich, K.B. (Kirsten), Karlan, B.Y. (Beth), Gross, J. (Jenny), Beattie, M.S. (Mary), Schmutzler, R.K. (Rita), Wapenschmidt, B. (Barbara), Meindl, A. (Alfons), Ruehl, I. (Ina), Fiebig, B. (Britta), Sutter, C. (Christian), Arnold, N. (Norbert), Deissler, H. (Helmut), Varon-Mateeva, R. (Raymonda), Kast, K. (Karin), Niederacher, D. (Dieter), Gadzicki, D. (Dorothea), Ejlertsen, B. (Bent), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Nevanlinna, H. (Heli), Aittomäki, K. (Kristiina), Simard, J. (Jacques), Soucy, P. (Penny), Spurdle, A.B. (Amanda), Holland, H. (Helene), Easton, D.F. (Douglas), Antoniou, A.C. (Antonis), Asperen, C.J. (Christi) van, Ramus, S.J. (Susan), Kartsonaki, C. (Christiana), Gayther, S.A. (Simon), Pharoah, P.D.P. (Paul), Sinilnikova, O. (Olga), Beesley, J. (Jonathan), Chenevix-Trench, G. (Georgia), McGuffog, L. (Lesley), Healey, S. (Sue), Couch, F.J. (Fergus), Wang, X. (Xing), Fredericksen, Z. (Zachary), Peterlongo, P. (Paolo), Manoukian, S. (Siranoush), Peissel, B. (Bernard), Zaffaroni, D. (D.), Roversi, G. (Gaia), Barile, M. (Monica), Viel, A. (Alessandra), Allavena, A. (Anna), Ottini, L. (Laura), Papi, L. (Laura), Gismondi, V. (Viviana), Capra, F. (Fabio), Radice, P. (Paolo), Greene, M.H. (Mark), Mai, P.L. (Phuong), Andrulis, I.L. (Irene), Glendon, G. (Gord), Ozcelik, H. (Hilmi), Thomassen, M. (Mads), Gerdes, A-M. (Anne-Marie), Kruse, T.A. (Torben), Cruger, D. (Dorthe), Jensen, U.B., Caligo, M.A. (Maria), Olsson, H. (Hkan), Kristoffersson, U. (Ulf), Lindblom, A. (Annika), Arver, B. (Brita Wasteson), Karlsson, P. (Per), Stenmark-Askmalm, M. (M.), Borg, Å. (Åke), Neuhausen, S.L. (Susan), Ding, Y.C. (Yuan), Nathanson, K.L. (Katherine), Domchek, S.M. (Susan), Jakubowska, A. (Anna), Lubinski, J. (Jan), Huzarski, T. (Tomasz), Byrski, T. (Tomasz), Gronwald, J. (Jacek), Górski, B. (Bohdan), Cybulski, C. (Cezary), Dbniak, T. (Tadeusz), Osorio, A. (Ana), Durán, M. (Mercedes), Tejada, M.-I., Benitez, J. (Javier), Hamann, U. (Ute), Rookus, M.A. (Matti), Verhoef, S., Tilanus-Linthorst, M.M.A. (Madeleine), Vreeswijk, M.P. (Maaike), Bodmer, D. (Danielle), Ausems, M.G.E.M. (Margreet), Os, T.A.M. (Theo) van, Blok, M.J. (Marinus), Meijers-Heijboer, H. (Hanne), Peock, S. (Susan), Cook, M. (Margaret), Oliver, C.T. (Clare), Frost, D. (Debra), Dunning, A.M. (Alison), Evans, D.G. (Gareth), Eeles, R. (Rosalind), Pichert, G. (Gabriella), Cole, T.J. (Trevor), Hodgson, S.V. (Shirley), Brewer, C. (Carole), Morrison, P.J. (Patrick), Porteous, M.E. (Mary), Kennedy, M.J. (John), Rogers, M.T. (Mark), Side, L. (Lucy), Donaldson, A. (Alan), Gregory, H. (Helen), Godwin, A.K. (Andrew), Stoppa-Lyonnet, D. (Dominique), Moncoutier, V. (Virginie), Castera, L. (Laurent), Mazoyer, S. (Sylvie), Barjhoux, L. (Laure), Bonadona, V. (Valérie), Leroux, D. (Dominique), Faivre, L. (Laurence), Lidereau, R. (Rosette), Nogues, C. (Catherine), Bignon, Y.-J. (Yves-Jean), Prieur, F. (Fabienne), Collonge-Rame, M.-A., Vénat-Bouvet, L. (Laurence), Fert-Ferrer, S. (Sandra), Miron, A. (Alexander), Buys, S.S. (Saundra), Hopper, J. (John), Daly, M.J. (Mark), John, E.M. (Esther), Terry, M-B. (Mary-beth), Goldgar, D. (David), Hansen, T.V.O. (Thomas), Jønson, L. (Lars), Agnarsson, B.A. (Bjarni), Offit, K. (Kenneth), Kircchoff, T. (Tomas), Vijai, J. (Joseph), Dutra-Clarke, A. (Ana), Przybylo, J.A. (Jennifer), Montagna, M. (Marco), Casella, C. (Cinzia), Imyanitov, E.N. (Evgeny), Janavicius, R. (Ramunas), Blanco, I. (Ignacio), Lázaro, C. (Conxi), Moysich, K.B. (Kirsten), Karlan, B.Y. (Beth), Gross, J. (Jenny), Beattie, M.S. (Mary), Schmutzler, R.K. (Rita), Wapenschmidt, B. (Barbara), Meindl, A. (Alfons), Ruehl, I. (Ina), Fiebig, B. (Britta), Sutter, C. (Christian), Arnold, N. (Norbert), Deissler, H. (Helmut), Varon-Mateeva, R. (Raymonda), Kast, K. (Karin), Niederacher, D. (Dieter), Gadzicki, D. (Dorothea), Ejlertsen, B. (Bent), Caldes, T. (Trinidad), Hoya, M. (Miguel) de La, Nevanlinna, H. (Heli), Aittomäki, K. (Kristiina), Simard, J. (Jacques), Soucy, P. (Penny), Spurdle, A.B. (Amanda), Holland, H. (Helene), Easton, D.F. (Douglas), Antoniou, A.C. (Antonis), and Asperen, C.J. (Christi) van
- Abstract
Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. Method sWe genotyped rs3814113 in 10029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. Results The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. Conclusion Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.
- Published
- 2011
- Full Text
- View/download PDF
24. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers
- Author
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Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Ramus, SJ, Gayther, SA, Pharoah, PDP, Sinilnikova, OM, McGuffog, L, Couch, FJ, Greene, MH, Mai, PL, Andrulis, IL, Kruse, TA, Jensen, UB, Caligo, MA, Neuhausen, SL, Ding, YC, Nathanson, KL, Domchek, SM, Rookus, MA, Tilanus Linthorst, MA, Vreeswijk, MP, Ausems, MGEM, van Os, TA, Asperen, CJ, Blok, MJ, Meijers Heijboer, HEJ, Dunning, AM, Evans, DG, Morrison, PJ, Kennedy, MJ, Rogers, MT, Side, LE, Buys, SS, Hopper, JL, Daly, MB, John, EM, Terry, MB, Hansen, TvO, Agnarsson, BA, Dutra Clarke, AVC, Przybylo, JA, Imyanitov, EN, Moysich, KB, Karlan, BY, Beattie, MS, Spurdle, AB, Easton, DF, Antoniou, AC, ROVERSI, GAIA, Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Ramus, SJ, Gayther, SA, Pharoah, PDP, Sinilnikova, OM, McGuffog, L, Couch, FJ, Greene, MH, Mai, PL, Andrulis, IL, Kruse, TA, Jensen, UB, Caligo, MA, Neuhausen, SL, Ding, YC, Nathanson, KL, Domchek, SM, Rookus, MA, Tilanus Linthorst, MA, Vreeswijk, MP, Ausems, MGEM, van Os, TA, Asperen, CJ, Blok, MJ, Meijers Heijboer, HEJ, Dunning, AM, Evans, DG, Morrison, PJ, Kennedy, MJ, Rogers, MT, Side, LE, Buys, SS, Hopper, JL, Daly, MB, John, EM, Terry, MB, Hansen, TvO, Agnarsson, BA, Dutra Clarke, AVC, Przybylo, JA, Imyanitov, EN, Moysich, KB, Karlan, BY, Beattie, MS, Spurdle, AB, Easton, DF, Antoniou, AC, and ROVERSI, GAIA
- Abstract
Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.
- Published
- 2011
25. Endometrial cancer and somatic G > T KRAS transversion in patients with constitutional MUTYH biallelic mutations
- Author
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Tricarico, R, Bettiol Furlan, Pierluigi, Ciambotti, B, Di Gregorio, Cristina, Gatteschi, B, Gismondi, V, Toschi, B, Tonelli, F, Varesco, L, Genuardi, Maurizio, Bet, P, Di Gregorio, C, Genuardi, M (ORCID:0000-0002-7410-8351), Tricarico, R, Bettiol Furlan, Pierluigi, Ciambotti, B, Di Gregorio, Cristina, Gatteschi, B, Gismondi, V, Toschi, B, Tonelli, F, Varesco, L, Genuardi, Maurizio, Bet, P, Di Gregorio, C, and Genuardi, M (ORCID:0000-0002-7410-8351)
- Abstract
MUTYH-associated polyposis (MAP) is an autosomal recessive condition predisposing to colorectal cancer, caused by constitutional biallelic mutations in the base excision repair (BER) gene MUTYH. Colorectal tumours from MAP patients display an excess of somatic G>T mutations in the APC and KRAS genes due to defective BER function. To date, few extracolonic manifestations have been observed in MAP patients, and the clinical spectrum of this condition is not yet fully established. Recently, one patient with a diagnosis of endometrial cancer and biallelic MUTYH mutations has been described. We here report on two additional unrelated MAP patients with biallelic MUTYH germline mutations who developed endometrioid endometrial carcinoma. The endometrial tumours were evaluated for MEN, PIK3CA, KRAS, BRAF and CTNNB1 mutations. A G>T transversion at codon 12 of the KRAS gene was observed in one tumour. A single 1 bp frameshift deletion of PTEN was observed in the same sample. Overall, these findings suggest that endometrial carcinoma is a phenotypic manifestations of MAP and that inefficient repair of oxidative damage can be involved in its pathogenesis. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
- Published
- 2009
26. Genotype-phenotype correlation in familial adenomatous polyposis (FAP): variation within and among families in 91 pedigrees of the Italian Registry
- Author
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Presciuttini, Silvano, Varesco, L, Sala, P, Gismondi, V, Radice, P, Giarola, M, Mareni, C, Aste, H, Marchese, C, de Leon MP, and Bertario, L.
- Published
- 1997
27. Absence of ocular patches (CHRPE) in a family with familial adenomatous polyposis and mutation at codon 843 of the APC gene
- Author
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Scarcello, E, Deluca, M, Gismondi, V, Varesco, L, Carotighelli, C, Mosca, F, Cetta, F, Civitelli, S, Petracci, M, and Presciuttini, Silvano
- Published
- 1996
28. Absence of ocular patches (CHRPE) in a family with Familial Adenomatous Polyposis and mutation at codon 843 of the APC
- Author
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Scarcello, E., De Luca, M., Gismondi, V., Varesco, L., Caroti Ghelli, C., Mosca, F., Cetta, F., Civitelli, Serenella, Petracci, M., and Presciuttini, S.
- Published
- 1996
29. Identification of APC gene mutations in Italian adenomatous polyposis coli patients by PCR-SSCP analysis
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Varesco, L, Gismondi, V, James, R, Robertson, M, Grammatico, Paola, Groden, J, Casarino, L, DE BENEDETTI, L, Bafico, A, Bertario, L, Sala, P, and Sassatelli, R.
- Subjects
Adult ,Genes, APC ,Polymorphism, Genetic ,Adolescent ,Base Sequence ,DNA Mutational Analysis ,Molecular Sequence Data ,DNA, Single-Stranded ,Exons ,Original Articles ,Middle Aged ,Polymerase Chain Reaction ,APC ,Adenomatous Polyposis Coli ,Italy ,Mutation ,Humans ,Nucleic Acid Conformation ,Electrophoresis, Polyacrylamide Gel ,Child ,Frameshift Mutation ,Sequence Deletion - Abstract
The APC gene is a putative human tumor-suppressor gene responsible for adenomatous polyposis coli (APC), an inherited, autosomal dominant predisposition to colon cancer. It is also implicated in the development of sporadic colorectal tumors. The characterization of APC gene mutations in APC patients is clinically important because DNA-based tests can be applied for presymptomatic diagnosis once a specific mutation has been identified in a family. Moreover, the identification of the spectrum of APC gene mutations in patients is of great interest in the study of the biological properties of the APC gene product. We analyzed the entire coding region of the APC gene by the PCR–single-strand conformation polymorphism method in 42 unrelated Italian APC patients. Mutations were found in 12 cases. These consist of small (5–14 bp) base-pair deletions leading to frameshifts; all are localized within exon 15. Two of these deletions, a 5-bp deletion at position 3183–3187 and a 5-bp deletion at position 3926–3930, are present in 3/42 and 7/42 cases of our series, respectively, indicating the presence of mutational hot spots at these two sites.
- Published
- 1993
30. Identification of APC gene mutations in Italian APC patients by PCR-SSCP analysis
- Author
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Varesco, L., Gismondi, V., James, R., Robertson, M., Grammatico, P., Groden, J., Casarino, L., De Benedetti, L., Bafico, A., Bertario, L., Sala, P., PONZ DE LEON, Maurizio, Sassatelli, R., Biasco, G., Allegretti, A., Aste, H., De Sanctis, S., Rossetti, C., Illeni, Mt, Sciarra, A., Del Porto, G., White, R., and Ferrara, Gb
- Published
- 1993
31. Prevalence of the E1317Q Variant of the APC Gene in Italian Patients with Colorectal Adenomas
- Author
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Gismondi, V., primary, Bonelli, L., additional, Sciallero, S., additional, Margiocco, P., additional, Viel, A., additional, Radice, P., additional, Mondini, P., additional, Sala, P., additional, Montera, M.P., additional, Mareni, C., additional, Quaia, M., additional, Fornasarig, M., additional, Gentile, M., additional, Pietro, G., additional, Rossini, P., additional, Arrigoni, A., additional, Meucci, G.M., additional, Bruzzi, P., additional, and Varesco, L., additional
- Published
- 2002
- Full Text
- View/download PDF
32. Analysis of K-ras, p53, bcl-2 and Rb expression in non-small cell lung cancer cell lines
- Author
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Loprevite, M, primary, Varesco, L, additional, Favoni, R, additional, Ferrara, G, additional, Moro, F, additional, Ottaggio, L, additional, Fronza, G, additional, Campomenosi, P, additional, Abbondandolo, A, additional, Cutrona, G, additional, Roncella, S, additional, Albini, A, additional, Aluigi, M, additional, Pozzi, S, additional, Pera, C, additional, Biticchi, R, additional, Gismondi, V, additional, Grossi, F, additional, Pennucci, M, additional, and Ardizzoni, A, additional
- Published
- 1997
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- View/download PDF
33. P914. Family history of cancer in Italian women attending a breast unit: evaluation of criteria for referral to a genetics clinic and for BRCA1 and BRCA2 testing
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Angiolini, C., primary, Rossi, C., additional, Bonelli, L., additional, Varesco, L., additional, Gismondi, V., additional, Massa, T., additional, Parodi, G.C., additional, Crotti, N., additional, Bruzzi, P., additional, and Santi, L., additional
- Published
- 1997
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34. Clinical and Biologic Features of Adenomatosis Coli in Northern Italy
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de Pietri, S., primary, Sassatelli, R., additional, Roncucci, L., additional, Bertoni, G., additional, Landi, P., additional, Sabadini, G., additional, Tansini, P., additional, Cavallini, G., additional, Cantoni, E., additional, Mareni, C., additional, Montera, M., additional, Varesco, L., additional, Gismondi, V., additional, Davighi, C., additional, and de Leon, M. Ponz, additional
- Published
- 1995
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35. Age of onset in familial adenomatous polyposis: heterogeneity within families and among APC mutations
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PRESCIUTTINI, S., primary, VARESCO, L., additional, SALA, P., additional, GISMONDI, V., additional, ROSSETTI, C., additional, BAFICO, A., additional, FERRARA, G. B., additional, and BERTARIO, L., additional
- Published
- 1994
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36. Common inactivating APC gene mutations in Italian familial polyposis coli patients
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Varesco, L, primary, Gismondi, V, additional, James, R, additional, Benedetti, L De, additional, Bertario, L, additional, Sala, P, additional, Biasco, G, additional, Aste, H, additional, Grammatico, P, additional, de Leon, M Ponz, additional, Porto, G Del, additional, and Ferrara, G B, additional
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- 1993
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37. K-ras, p53 and APC mutations in sporadic colorectal adenomas
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Varesco, L, primary, Benedetti, L De, additional, James, R, additional, Gismondi, V, additional, Sciallero, S, additional, Bonelli, L, additional, Pellegata, N S, additional, Losi, L, additional, Ranzani, G N, additional, Aste, H, additional, and Ferrara, G B, additional
- Published
- 1993
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38. Cytogenetic and molecular study of 30 malignant melanoma primary cell cultures
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Grammatico, P., primary, Varesco, L., additional, Bottoni, U., additional, Roccella, F., additional, Casarino, L., additional, Heouaine, A., additional, Gismondi, V., additional, Roccella, M., additional, De Benedetti, L., additional, Grammatico, B., additional, Carlesimo, O.A., additional, Ferrara, G.B., additional, and Del Porto, G., additional
- Published
- 1991
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39. Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis.
- Author
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Bertario, L., Russo, A., Sala, P., Eboli, M., Giarola, M., D'amico, F., Gismondi, V., Varesco, L., Pierotti, M.A., and Radice, P.
- Published
- 2001
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- View/download PDF
40. Association of APC Gene Mutations and Histological Characteristics of Colorectal Adenomas
- Author
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Benedetti, L. D., Maria Stefania Sciallero, Gismondi, V., James, R., Bafico, A., Biticchi, R., Masetti, E., Bonelli, L., Heouaine, A., Picasso, M., Groden, J., Robertson, M., Risio, M., Caprilli, R., Bruzzi, P., White, R. L., Aste, H., Santi, L., Varesco, L., and Ferrara, G. B.
41. Genetic events in sporadic colorectal adenomas: K-ras and p53 heterozygous mutations are not sufficient for malignant progression
- Author
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Benedetti, L., Varesco, L., Pellegata, N. S., Losi, L., Gismondi, V., Casarino, L., Sciallero, S., Bonelli, L., Biticchi, R., Bafico, A., Masetti, E., James, R., Heouaine, A., Guglielmina Ranzani, Aste, H., and Ferrara, G.
- Subjects
Adenoma ,Adult ,Aged, 80 and over ,Male ,p53 ,colorectal adenomas ,K-ras ,LOH ,Middle Aged ,Genes, p53 ,Polymerase Chain Reaction ,Genes, ras ,Humans ,Point Mutation ,Female ,Chromosome Deletion ,Codon ,Colorectal Neoplasms ,Aged ,Chromosomes, Human, Pair 17 - Abstract
Twenty-four sporadic colorectal adenomas were analysed for the presence of allelic loss on the short arm of chromosome 17 as well as mutations in the K-ras and p53 genes. Chromosome 17p13 allelic loss was not present in 14 out of 14 informative cases. K-ras mutations were observed in 15 out of 24 cases. A p53 gene mutation (GGC--GAC at codon 245) was detected in two biopsies taken at a four year interval from a recurrent rectal villous adenoma. Both biopsies also contained the same K-ras gene mutation (GGT--GTT at codon 12). The data from the recurrent rectal adenoma provide in vivo evidence that K-ras and p53 heterozygous mutations confer a proliferative advantage but together are not sufficient for malignant transformation.
42. A distinct splice form of APC is highly expressed in neurones but not commonly mutated in neuroepithelial tumours [7]
- Author
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Steigerwald, K., Santoro, I. M., Kordich, J. J., Gismondi, V., Trzepacz, C., Badiali, M., FELICE GIANGASPERO, Balko, M. G., Graham, J. S., Ratner, N., Lowy, A. M., Varesco, L., and Groden, J.
43. A silent mutation in exon 14 of the APC gene is associated with exon skipping in a FAP family [5]
- Author
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Montera, M., Piaggio, F., Marchese, C., Gismondi, V., Stella, A., Nicoletta Resta, Varesco, L., Guanti, G., and Mareni, C.
44. Clustered protocadherins methylation alterations in cancer
- Author
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Giuseppina Cabras, Eleonora Loi, Patrizia Zavattari, Antonella Arcella, Felice Giangaspero, Silvia Giordano, Matteo Canale, Luca Faloppi, Loredana Moi, Pierluigi Cocco, Pina Ziranu, Mario Scartozzi, Giannina Satta, Manuela Badiali, Mariagrazia Zucca, Luigi Zorcolo, Maria Grazia Ennas, Viviana Gismondi, Amedeo Columbano, Angelo Restivo, Isabella Morra, Andrea Casadei-Gardini, Manila Antonelli, Ana Florencia Vega-Benedetti, Sara Erika Bellomo, Liliana Varesco, Marco Puzzoni, Antonio Fadda, Daniele Canzio, Sylvain Blois, Vega-Benedetti, A. F., Loi, E., Moi, L., Blois, S., Fadda, A., Antonelli, M., Arcella, A., Badiali, M., Giangaspero, F., Morra, I., Columbano, A., Restivo, A., Zorcolo, L., Gismondi, V., Varesco, L., Bellomo, S. E., Giordano, S., Canale, M., Casadei-Gardini, A., Faloppi, L., Puzzoni, M., Scartozzi, M., Ziranu, P., Cabras, G., Cocco, P., Ennas, M. G., Satta, G., Zucca, M., Canzio, D., and Zavattari, P.
- Subjects
0301 basic medicine ,Biliary tract cancer ,BTC ,Cancer methylation alteration ,Chronic lymphocytic leukemia ,CLL ,Clustered PCDH ,Colorectal adenoma ,Colorectal carcinoma ,CpG islands ,CRA ,CRC ,CTCF ,Gastric cancer ,GC ,LGG ,Low grade glioma ,PA ,Pilocytic astrocytoma ,Epigenesis, Genetic ,0302 clinical medicine ,Neoplasms ,2.1 Biological and endogenous factors ,Aetiology ,Promoter Regions, Genetic ,Genetics (clinical) ,Cancer ,High-Throughput Nucleotide Sequencing ,Methylation ,Cadherins ,Colo-Rectal Cancer ,Gene Expression Regulation, Neoplastic ,CpG site ,030220 oncology & carcinogenesis ,Multigene Family ,DNA methylation ,Sequence Analysis ,Clinical Sciences ,Biology ,biliary tract cancer ,cancer methylation alteration ,chronic lymphocytic leukemia ,clustered PCDH ,colorectal adenoma ,colorectal carcinoma ,gastric cancer ,low grade glioma ,pilocytic astrocytoma ,Promoter Regions ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Rare Diseases ,Genetic ,medicine ,Genetics ,Humans ,Molecular Biology ,Gene ,Neoplastic ,Research ,Human Genome ,Chromosome ,DNA ,Sequence Analysis, DNA ,DNA Methylation ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Cancer research ,Digestive Diseases ,Developmental Biology ,Epigenesis - Abstract
Background Clustered protocadherins (PCDHs) map in tandem at human chromosome 5q31 and comprise three multi-genes clusters: α-, β- and γ-PCDH. The expression of this cluster consists of a complex mechanism involving DNA hub formation through DNA-CCTC binding factor (CTCF) interaction. Methylation alterations can affect this interaction, leading to transcriptional dysregulation. In cancer, clustered PCDHs undergo a mechanism of long-range epigenetic silencing by hypermethylation. Results In this study, we detected frequent methylation alterations at CpG islands associated to these clustered PCDHs in all the solid tumours analysed (colorectal, gastric and biliary tract cancers, pilocytic astrocytoma), but not hematologic neoplasms such as chronic lymphocytic leukemia. Importantly, several altered CpG islands were associated with CTCF binding sites. Interestingly, our analysis revealed a hypomethylation event in pilocytic astrocytoma, suggesting that in neuronal tissue, where PCDHs are highly expressed, these genes become hypomethylated in this type of cancer. On the other hand, in tissues where PCDHs are lowly expressed, these CpG islands are targeted by DNA methylation. In fact, PCDH-associated CpG islands resulted hypermethylated in gastrointestinal tumours. Conclusions Our study highlighted a strong alteration of the clustered PCDHs methylation pattern in the analysed solid cancers and suggested these methylation aberrations in the CpG islands associated with PCDH genes as powerful diagnostic biomarkers. Electronic supplementary material The online version of this article (10.1186/s13148-019-0695-0) contains supplementary material, which is available to authorized users.
- Published
- 2019
45. PCR-SSCP analysis of the APC c-ene in Italian familial polyposis coli patients
- Author
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Varesco, L., Gismondi, V., James, R., Casarino, L., DeBenedetti, L., Grammatico, P., Bertario, L., Ponzdeleon, M., Sassatelli, R., Biasco, G., Aste, H., Sala, P., Allegretti, A., Illeni, M.T., DelPorto, G., and Ferrara, G.B.
- Published
- 1992
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46. FANCM c.5791C > T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor
- Author
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Laura Ottini, Bernard Peissel, Carmen J Tartari, Peter Devilee, Silvia Tognazzo, Anders Kvist, Lara Della Puppa, Mara Colombo, Isabella Marchi, Conxi Lázaro, Caterina Vivanet, Jordi Surrallés, Valeria Viassolo, Joseph Vijai, Kenneth Offit, Paolo Radice, Veronica Medici, Ana Osorio, Francesca Spina, Stefania Tommasi, Carlo Tondini, Marina Marchetti, Chiara Corna, Eliseos J. Mucaki, Gabriele Lorenzo Capone, Piera Rizzolo, Maurizio Genuardi, Alessandra Renieri, Jan Hauke, Laura Cortesi, Laura Caleca, Dominique Stoppa-Lyonnet, Paolo Peterlongo, Christi J. van Asperen, Hans Ehrencrona, Fergus J. Couch, Ian G. Campbell, Valeria Pensotti, Irene Catucci, Miguel Angel Pujana, Sylvie Mazoyer, Massimo Federico, Paolo Verderio, Alfons Meindl, Brunella Pilato, Claus R. Bartram, Valentina Dall'Olio, Paul A. James, Massimo Bogliolo, Loris Bernard, Maria Marín, Valérie Sornin, Luisa Balestrino, Gaia Roversi, Judith Balmaña, Marie-Gabrielle Dondon, Simona Agata, Rita K. Schmutzler, Barbara Burwinkel, Viviana Gismondi, Giulia Cini, Ella R. Thompson, Nadine Andrieu, Sara Volorio, Maria Grazia Tibiletti, Francesca Damiola, Harald Surowy, Alessandra Viel, Peter K. Rogan, Laura Matricardi, Anna Laura Putignano, Cristina Verzeroli, Anna Falanga, Chiara Perfumo, Marco Montagna, Margherita Baldassarri, Monica Barile, Riccardo Dolcetti, Florentine Hilbers, Javier Benitez, Laura Papi, Maria Antonietta Mencarelli, Séverine Eon-Marchais, Gillian Mitchell, Orland Diez, Siranoush Manoukian, Maria A. Caligo, Christian Sutter, Gaetana Gambino, Xianshu Wang, Marco A. Pierotti, Bernardo Bonanni, Sara Pizzamiglio, Liliana Varesco, Valentina Silvestri, Olga M. Sinilnikova, Peterlongo, P, Catucci, I, Colombo, M, Caleca, L, Mucaki, E, Bogliolo, M, Marin, M, Damiola, F, Bernard, L, Pensotti, V, Volorio, S, Dall'Olio, V, Meindl, A, Bartram, C, Sutter, C, Surowy, H, Sornin, V, Dondon, M, Eon-Marchais, S, Stoppa-Lyonnet, D, Andrieu, N, Sinilnikova, O, Mitchell, G, James, P, Thompson, E, Kconfab, Marchetti, M, Verzeroli, C, Tartari, C, Capone, G, Putignano, A, Genuardi, M, Medici, V, Marchi, I, Federico, M, Tognazzo, S, Matricardi, L, Agata, S, Dolcetti, R, Della Puppa, L, Cini, G, Gismondi, V, Viassolo, V, Perfumo, C, Mencarelli, M, Baldassarri, M, Peissel, B, Roversi, G, Silvestri, V, Rizzolo, P, Spina, F, Vivanet, C, Tibiletti, M, Caligo, M, Gambino, G, Tommasi, S, Pilato, B, Tondini, C, Corna, C, Bonanni, B, Barile, M, Osorio, A, Benitez, J, Balestrino, L, Ottini, L, Manoukian, S, Pierotti, M, Renieri, A, Varesco, L, Couch, F, Wang, X, Devilee, P, Hilbers, F, van Asperen, C, Viel, A, Montagna, M, Cortesi, L, Diez, O, Balmaña, J, Hauke, J, Schmutzler, R, Papi, L, Pujana, M, Lázaro, C, Falanga, A, Offit, K, Vijai, J, Campbell, I, Burwinkel, B, Kvist, A, Ehrencrona, H, Mazoyer, S, Pizzamiglio, S, Verderio, P, Surralles, J, Rogan, P, and Radice, P
- Subjects
DNA Repair ,Heterogeneous Nuclear Ribonucleoprotein A1 ,DNA Mutational Analysis ,Gene Expression ,medicine.disease_cause ,Settore MED/03 - GENETICA MEDICA ,0302 clinical medicine ,Gene Frequency ,Risk Factors ,Genetics ,Genetics (clinical) ,Molecular Biology ,Genotype ,Heterogeneous-Nuclear Ribonucleoprotein Group A-B ,FANCM ,Age of Onset ,0303 health sciences ,Mutation ,Association Studies Articles ,General Medicine ,Exons ,Middle Aged ,3. Good health ,ddc ,Codon, Nonsense ,030220 oncology & carcinogenesis ,Female ,Protein Binding ,Adult ,Alleles ,Binding Sites ,Breast Neoplasms ,Case-Control Studies ,DNA Helicases ,Genetic Association Studies ,Genetic Predisposition to Disease ,Humans ,Meta-Analysis as Topic ,Nucleotide Motifs ,Position-Specific Scoring Matrices ,Young Adult ,Alternative Splicing ,PALB2 ,Nonsense mutation ,Biology ,breast cancer, risk factor ,03 medical and health sciences ,Breast cancer ,T+nonsense+mutation+%28rs144567652%22">FANCM c.5791C>T nonsense mutation (rs144567652 ,medicine ,Risk factor ,Codon ,030304 developmental biology ,medicine.disease ,Exon skipping ,FANCM, familial breast cancer ,Nonsense ,Cancer research - Abstract
© The Author 2015. Published by Oxford University Press. All rights reserved. Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p. Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p. Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.
- Published
- 2015
47. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers
- Author
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Thomas v O Hansen, Amanda B. Spurdle, Anne-Marie Gerdes, Sue Healey, Per Karlsson, Tomasz Huzarski, Mary B. Daly, Mary Porteous, T. Caldes, Ulf Kristoffersson, Ignacio Blanco, A. Miron, Laurence Faivre, Barbara Wappenschmidt, Laurence Venat-Bouvet, Marie Stenmark Askmalm, Olga M. Sinilnikova, Susan Peock, Alessandra Viel, Conxi Lázaro, Katherine L. Nathanson, Laurent Castera, Douglas F. Easton, Susan L. Neuhausen, Jan Lubinski, Phuong L. Mai, Virginie Moncoutier, Paolo Radice, Heli Nevanlinna, Christi J Asperen, Xianshu Wang, Brita Arver, Christian Sutter, Senno Verhoef, Rosette Lidereau, Mary S Beattie, Bjarni A Agnarsson, Ina Ruehl, Monica Barile, Bent Ejlertsen, Laura Ottini, Catherine Noguès, Jennifer A. Przybylo, Cinzia Casella, Trevor Cole, Norbert Arnold, Sandra Fert-Ferrer, Hilmi Ozcelik, Irene L. Andrulis, Susan M. Domchek, Valérie Bonadona, Kirsten B. Moysich, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Beth Y. Karlan, Jenny Gross, Gaia Roversi, Tadeusz Dębniak, Hanne Meijers-Heijboer, Susan J. Ramus, Dorthe G. Crüger, Zachary S. Fredericksen, Siranoush Manoukian, Viviana Gismondi, Maria A. Caligo, Helene Holland, Laure Barjhoux, Gord Glendon, Ana Osorio, Jacques Simard, John L. Hopper, Mercedes Durán, Kristiina Aittomäki, Håkan Olsson, Mads Thomassen, Fabio Capra, Patrick J. Morrison, Britta Fiebig, Mary Beth Terry, Marinus J. Blok, Evgeny N. Imyanitov, Joseph Vijai, Javier Benitez, Mark T. Rogers, D. Gareth Evans, Helmut Deissler, Tomasz Byrski, Sylvie Mazoyer, Laura Papi, Dominique Stoppa-Lyonnet, Marco Montagna, Kenneth Offit, Cezary Cybulski, Dominique Leroux, Georgia Chenevix-Trench, Danielle Bodmer, Lucy Side, Margaret Cook, Ros Eeles, Alan Donaldson, Christiana Kartsonaki, Carole Brewer, Matti A. Rookus, Jacek Gronwald, Dorothea Gadzicki, Shirley Hodgson, Jonathan Beesley, Gabriella Pichert, Andrew K. Godwin, Dieter Niederacher, Yuan Chun Ding, Torben A Kruse, Paolo Peterlongo, Rita K. Schmutzler, Xiaoqing Chen, Annika Lindblom, Fergus J. Couch, Maaike P.G. Vreeswijk, Mark H. Greene, Esther M. John, Raymonda Varon-Mateeva, Simon A. Gayther, Margreet G. E. M. Ausems, Tomas Kirchhoff, Lars Jønson, Madeleine M. A. Tilanus-Linthorst, Ute Hamann, Marie-Agnès Collonge-Rame, Antonis C. Antoniou, M John Kennedy, Karin Kast, Theo A. M. van Os, Penny Soucy, Debra Frost, Alison M. Dunning, Daniela Zaffaroni, Anna Allavena, Maria-Isabel Tejada, Yves-Jean Bignon, Lesley McGuffog, Bohdan Górski, Åke Borg, Fabienne Prieur, Bernard Peissel, Helen Gregory, Clare Oliver, Saundra S. Buys, Ana Dutra-Clarke, Alfons Meindl, Ramunas Janavicius, Uffe Birk Jensen, Miguel de la Hoya, Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Faculteit Medische Wetenschappen/UMCG, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Klinische Genetica, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Clinical Genetics, Pediatric Surgery, Human genetics, CCA - Oncogenesis, and Human Genetics
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Oncology ,Cancer Research ,endocrine system diseases ,Genes, BRCA2 ,Genes, BRCA1 ,Genome-wide association study ,FAMILIES ,0302 clinical medicine ,Risk Factors ,Retrospective Studie ,Genotype ,Odds Ratio ,skin and connective tissue diseases ,POPULATION ,Genetics ,Ovarian Neoplasms ,Aged, 80 and over ,Allele ,0303 health sciences ,education.field_of_study ,Likelihood Functions ,Articles ,GERMLINE MUTATIONS ,Middle Aged ,Likelihood Function ,female genital diseases and pregnancy complications ,3. Good health ,030220 oncology & carcinogenesis ,Female ,Chromosomes, Human, Pair 9 ,Human ,Adult ,[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT] ,medicine.medical_specialty ,Heterozygote ,SUSCEPTIBILITY LOCI ,PROTEINS ,Population ,Biology ,Polymorphism, Single Nucleotide ,BASONUCLIN-2 ,03 medical and health sciences ,Breast cancer ,Germline mutation ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,BREAST-CANCER ,Humans ,GENOME-WIDE ASSOCIATION ,education ,Alleles ,Germ-Line Mutation ,030304 developmental biology ,Retrospective Studies ,Aged ,IDENTIFICATION ,Risk Factor ,Ovarian Neoplasm ,Editorials ,Cancer ,medicine.disease ,Minor allele frequency ,Ovarian cancer - Abstract
[Background]: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. [Methods]: We genotyped rs3814113 in 10 029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. [Results]: The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. [Conclusion]: Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation., Spanish National Cancer Center (CNIO) and the Spanish Consortium: Partially supported by Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, and the Spanish Ministry of Science and Innovation (FIS PI08 1120).
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- 2011
48. Changes in 24-hour blood pressure profile after 12 weeks of dapagliflozin treatment in patients with diabetic kidney disease: an Italian multicenter prospective study.
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Borrelli S, Garofalo C, Reboldi G, Coppola A, Chiodini P, Simeoni M, Mazzieri A, Volpe LD, Gallieni M, Zummo C, Cottone S, Ravera M, Aucella F, Aucella F, Stallone G, Gismondi V, Alberici F, Gregori M, Castellano G, Vettoretti S, Cozzolino M, Ruotolo C, Minutolo R, and De Nicola L
- Abstract
Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) lower ambulatory blood pressure (ABP) in patients with type 2 diabetes mellitus; whether the same holds true in diabetic kidney disease (DKD) is unknown. This information is critical to the knowledge of mechanisms of nephroprotection and safety of this therapy., Methods: This multicenter prospective study evaluates the changes in ABP after 12 weeks of dapagliflozin 10 mg/day in a cohort of patients with type 2 DKD and glomerular filtration rate (GFR) >25 mL/min/1.73 m
2 . Primary endpoint was the change of nighttime systolic blood pressure (SBP). Changes of daytime SBP, prevalence of normal dipping (day/night SBP ratio <0.9) and changes in ABP patterns, that is, sustained uncontrolled hypertension (SUCH), white coat uncontrolled hypertension (WUCH), masked uncontrolled hypertension (MUCH) and controlled hypertension (CH) were secondary endpoints., Results: Eighty-three of 96 patients completed the study [age 68.7 ± 8.9 years, 73.5% males, GFR 49 ± 17 mL/min/1.73 m2 , median albuminuria: 0.18 (interquartile range 0.10-0.38) g/24 h]. After 12 weeks of dapagliflozin, nighttime SBP declined by -3.0 mmHg (95% confidence interval -5.2/-0.8 mmHg; P = .010) with an improvement of nighttime SBP goal (<110 mmHg) from 18.0% to 27.0% ( P < .001). Similarly, the prevalence of normal dipping increased (from 31.3% to 50.6%, P = .005). A decrease in daytime (-2.4 mmHg; P = .046) and office (-7.9 mmHg; P = .009) SBP was also found. The decline of ambulatory and office SBP was associated with increased prevalence of CH (from 6.0% to 18.0%) and significant improvement of SUCH, WUCH and MUCH ( P = .009). Albuminuria decreased ( P < .001), whereas eGFR did not change ( P = .297). Urinary tract infection (4.2%) and acute kidney injury (3.6%) were the main causes of drop-out. Only one patient showed a drop of nighttime SBP below 90 mmHg., Conclusions: Dapagliflozin is associated with improvement in circadian blood pressure rhythm with no major safety signal related to excessive blood pressure decrease., Competing Interests: A.C., C.G. and D.I. have no conflict to disclose. S.B. has received fees for lectures by AstraZeneca, Baxter, Mayoli and Vifor Pharma. L.D.N. has received fees for scientific consultation and/or lectures by Astellas, AstraZeneca, Mundibiopharma and Vifor Pharma. R.M. has been member of Advisory Boards for Astellas, Bayer, GSK and Amgen, and has been an invited speaker at meetings supported by Amgen, Astellas and Vifor Pharma. M.C. is member of the CKJ Editorial Board and has been member of Advisory Boards for Astellas, Bayer, GSK, Vifor Pharma and Amgen, and has been an invited speaker at meetings supported by Amgen, Astellas and Vifor Pharma. Filippo Au.: fees for lectures and scientific consultations by CSL-Vifor, AstraZeneca, Bayer., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)- Published
- 2024
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49. Streamlining the diagnostic pathway for Lynch syndrome in colorectal cancer patients: a 10-year experience in a single Italian Cancer Center.
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Puccini A, Nardin S, Trevisan L, Lastraioli S, Gismondi V, Ricciotti I, Damiani A, Bregni G, Murialdo R, Pastorino A, Martelli V, Gandini A, Mastracci L, Varesco L, Dono M, Battistuzzi L, Grillo F, and Sciallero S
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- Humans, Female, Male, Middle Aged, Italy epidemiology, Aged, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics, Colorectal Neoplasms epidemiology, Proto-Oncogene Proteins B-raf genetics, Adult, DNA Methylation, Genetic Counseling, Mutation, Early Detection of Cancer methods, Early Detection of Cancer statistics & numerical data, Retrospective Studies, Follow-Up Studies, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Genetic Testing methods, DNA Mismatch Repair genetics, MutL Protein Homolog 1 genetics
- Abstract
Background: Universal screening of colorectal cancer (CRC) patients for Lynch syndrome (LS) through MisMatch Repair (MMR) testing is recommended. BRAF V600E mutation and/or MLH1 promoter methylation (Reflex Testing, RefT)generally rule out LS in MLH1-deficient (dMLH1) patients. We estimated the impact of RefTon genetic counseling (GC) and on the diagnostic yield of genetic testing (GT)., Methods: Overall, 3199 CRC patients were referred to our center between 2011 and 2021. Patients referred until January 2019 (n=2536) underwent universal MMR testing and were termed 'Cohort A'; among patients after February 2019 (n=663), 'Cohort B', RefT was also performed in dMLH1 patients., Results: Overall, 401/3199 patients (12.5%) were MMR-deficient (dMMR); 312 (77.8%) in cohort A and 89 (22.2%) inB; 346/401 were dMLH1 (86.3%), 262/312 (83.9%) in cohort A and 84/89 (94.3%) in B. In Cohort A, 91/312 (29.1%) dMMR patients were referred to GC, 69/91 (75.8%) were in the dMLH1 group; 57/69 (82.6%) dMLH1 patients underwent GT and 1/57 (1.7%) had LS. In Cohort B, 3/84 dMLH1 patients did not undergo BRAF testing. Three BRAF wt and not hypermethylated of the remaining 81 dMLH1 patients were referred to GC and GT, and one had LS. This diagnostic pathway reduced GC referrals by 96% (78/81) in Cohort B and increased the diagnostic yield of GT by about 20 times., Conclusion: Our findings support RefT in dMLH1 CRC patients within the LS diagnostic pathway, as it reduces the number of GC sessions needed and increases the diagnostic yield of GT., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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50. Cascade testing in Italian Hereditary Breast Ovarian Cancer families: a missed opportunity for cancer prevention?
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Trevisan L, Godino L, Battistuzzi L, Innella G, Luppi E, Buzzatti G, Gismondi V, Blondeaux E, Bonelli LA, Turchetti D, and Varesco L
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- Humans, Female, Italy, Middle Aged, Adult, BRCA2 Protein genetics, Aged, BRCA1 Protein genetics, Ovarian Neoplasms genetics, Ovarian Neoplasms prevention & control, Ovarian Neoplasms diagnosis, Breast Neoplasms genetics, Breast Neoplasms prevention & control, Breast Neoplasms diagnosis, Hereditary Breast and Ovarian Cancer Syndrome genetics, Hereditary Breast and Ovarian Cancer Syndrome diagnosis, Hereditary Breast and Ovarian Cancer Syndrome prevention & control, Genetic Testing methods, Genetic Predisposition to Disease
- Abstract
Healthy carriers of BRCA1/2 pathogenic variants (PVs) may benefit from risk-reducing measures of proven efficacy. The main approach to identify these individuals is cascade testing, and strategies to support this complex process are under investigation. In Italy, cascade testing has received little attention; therefore, we analyzed the uptake and characteristics of BRCA1/2 cascade testing in families diagnosed with HBOC between 2017 and 2019 at two Italian genetics centers. All blood relatives aged 18 years or older at September 2022 and who could be involved in the first step of cascade testing (i.e., all the living relatives closest to the proband) were included. In addition to first-degree relatives, individuals who were second-, third- or fourth-degree relatives were included if the closest relative(s) was/were deceased. Overall, 213 families were included (103, Genoa; 110, Bologna). Most probands were women affected by breast and/or ovarian cancer (86.4%, Genoa; 84.5%, Bologna), and the branch segregating the PV was known/suspected in 62% of families (62.1%, Genoa; 60.9%, Bologna). Overall, the uptake of cascade testing was 22.8% (25.8%, Genoa; 19.9%, Bologna; OR = 0.59: 95%CI 0.43-0.82). It was strongly associated with female gender (OR = 3.31, 95%CI 2.38-4.59), age ≤ 70 years (< 30 years OR = 3.48, 95%CI 1.85-6.56; 30-70 years OR = 3.08, 95%CI 2.01-4.71), first-degree relationship with the proband (OR = 16.61, 95%CI 10.50-26.28) and segregation of the PV in both the maternal (OR = 2.54, 95%CI 1.72-3.75) and the paternal branch (OR = 4.62, 95%CI 3.09-6.91). These real-world data may be important to inform the design and implementation of strategies aimed at improving the uptake of HBOC cascade testing in Italy., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)
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- 2024
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