29 results on '"Torres-Esquius S"'
Search Results
2. Topic: AS07-Singular Entities/Subtypes/AS07c-Hereditary MDS including predisposition syndromes: HIGH PREVALENCE OF IDIOPATHIC DYPSLASIA OF UNDETERMINED SIGNIFICANCE (IDUS) AND CLONAL HEMATOPOIESIS OF INDETEMINATE POTENTIAL (CHIP) AMONG RELATIVES OF HEMATOLOGIC NEOPLASMS WITH GERMLINE PREDISPOSITION PATIENTS
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Novoa, S., primary, Torres-Esquius, S., additional, Tazón-Vega, B., additional, Blanco, A., additional, Saumell, S., additional, González, A. Pérez, additional, Yordi, A. Molero, additional, Garrido, S., additional, Bosch, M., additional, Valcárcel, D., additional, Jerez, A., additional, and Montoro, M.J., additional
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- 2023
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3. Topic: AS07-Singular Entities/Subtypes/AS07a-ARCH, CCUS, ICUS: PREVALENCE, DYNAMICS AND CLINICAL SIGNIFICANCE OF CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP) IN NEWLY DIAGNOSED CANCER PATIENTS
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González, A. Pérez, primary, Peralta-Garzón, S., additional, Palomo, L., additional, Navarro, V., additional, Yordi, A. Molero, additional, Tazón-Vega, B., additional, Calvete, O., additional, Salamero, O., additional, Saumell, S., additional, Rivero, E., additional, Zamora, E., additional, Saoudi, N., additional, Fariñas, L., additional, Torres-Esquius, S., additional, Novoa, S., additional, Garrido, S., additional, Sola, M., additional, Campelo, M., additional, Alfonso, A., additional, Montoro, M.J., additional, and Valcárcel, D., additional
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- 2023
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4. P109 - Topic: AS07-Singular Entities/Subtypes/AS07a-ARCH, CCUS, ICUS: PREVALENCE, DYNAMICS AND CLINICAL SIGNIFICANCE OF CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP) IN NEWLY DIAGNOSED CANCER PATIENTS
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González, A. Pérez, Peralta-Garzón, S., Palomo, L., Navarro, V., Yordi, A. Molero, Tazón-Vega, B., Calvete, O., Salamero, O., Saumell, S., Rivero, E., Zamora, E., Saoudi, N., Fariñas, L., Torres-Esquius, S., Novoa, S., Garrido, S., Sola, M., Campelo, M., Alfonso, A., Montoro, M.J., and Valcárcel, D.
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- 2023
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5. P114 - Topic: AS07-Singular Entities/Subtypes/AS07c-Hereditary MDS including predisposition syndromes: HIGH PREVALENCE OF IDIOPATHIC DYPSLASIA OF UNDETERMINED SIGNIFICANCE (IDUS) AND CLONAL HEMATOPOIESIS OF INDETEMINATE POTENTIAL (CHIP) AMONG RELATIVES OF HEMATOLOGIC NEOPLASMS WITH GERMLINE PREDISPOSITION PATIENTS
- Author
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Novoa, S., Torres-Esquius, S., Tazón-Vega, B., Blanco, A., Saumell, S., González, A. Pérez, Yordi, A. Molero, Garrido, S., Bosch, M., Valcárcel, D., Jerez, A., and Montoro, M.J.
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- 2023
- Full Text
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6. P113 - Topic: AS07-Singular Entities/Subtypes/AS07c-Hereditary MDS including predisposition syndromes: SECONDARY FINDINGS IN EXOME SEQUENCING IN 240 EARLY-ONSET ADULT MYELODYSPLASTIC SYNDROMES WITHOUT PREVIOUS DISORDER
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Montoro, M.J., Torres-Esquius, S., Verdejo-Sánchez, M., Carrillo-Tornel, S., Chen-Liang, T.H., Hernández-Mohedo, F., Martínez-Francés, A., Campelo, M., Valcárcel, D., and Jerez, A.
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- 2023
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7. 12P Prevalence of functional and genomic homologous recombination deficiency (HRD) in germline RAD51C/D patients
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Llop-Guevara, A., primary, Torres-Esquius, S., additional, Romey, M., additional, Gutierrez-Enriquez, S., additional, Nuciforo, P.G., additional, Diez, O., additional, Llort Pursals, G., additional, Teule, A., additional, Vallmajó, A., additional, Diaz De Corcuera, I., additional, Chirivella Gonzalez, I., additional, Gonzalez Santiago, S., additional, Sanchez Henarejos, P., additional, Sanz Buxo, J., additional, Guillen Ponce, C., additional, Sanchez, A.B., additional, Brunet Vidal, J.M., additional, Denkert, C., additional, Serra Elizalde, V., additional, and Balmaña, J., additional
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- 2022
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8. Prevalence of functional and genomic homologous recombination deficiency (HRD) in germline RAD51C/D patients
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Llop-Guevara A, Torres-Esquius S, Romey M, Gutierrez-Enriquez S, Nuciforo P, Diez O, Pursals G, Teule A, Vallmajo A, De Corcuera I, Gonzalez I, Santiago S, Henarejos P, Buxo J, Ponce C, Sanchez A, Vidal J, Denkert C, Elizalde V, and Balmana J
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- 2022
9. Characterization of the Cancer Spectrum in Men with Germline BRCA1 and BRCA2 Pathogenic Variants: Results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
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Joseph V., Easton D.F., Ejlertsen B., Engel C., Evans D.G., Feliubadalo L., Foretova L., Fostira F., Geczi L., Gerdes A.-M., Glendon G., Godwin A.K., Goldgar D.E., Hahnen E., Hogervorst F.B.L., Hopper J.L., Hulick P.J., Isaacs C., Izquierdo A., James P.A., Janavicius R., Jensen U.B., John E.M., Konstantopoulou I., Kurian A.W., Kwong A., Landucci E., Lesueur F., Loud J.T., Machackova E., Mai P.L., Majidzadeh-A K., Manoukian S., Montagna M., Moserle L., Mulligan A.M., Nathanson K.L., Nevanlinna H., Ngeow Yuen Ye J., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Osorio A., Papi L., Park S.K., Pedersen I.S., Perez-Segura P., Petersen A.H., Pinto P., Porfirio B., Pujana M.A., Radice P., Rantala J., Rashid M.U., Rosenzweig B., Rossing M., Santamarina M., Schmutzler R.K., Senter L., Simard J., Singer C.F., Solano A.R., Southey M.C., Steele L., Steinsnyder Z., Stoppa-Lyonnet D., Tan Y.Y., Teixeira M.R., Teo S.H., Terry M.B., Thomassen M., Toland A.E., Torres-Esquius S., Tung N., Van Asperen C.J., Vega A., Viel A., Vierstraete J., Wappenschmidt B., Weitzel J.N., Wieme G., Yoon S.-Y., Zorn K.K., Mcguffog L., Parsons M.T., Hamann U., Greene M.H., Kirk J.A., Neuhausen S.L., Rebbeck T.R., Tischkowitz M., Chenevix-Trench G., Antoniou A.C., Friedman E., Ottini L., Silvestri V., Leslie G., Barnes D.R., Agnarsson B.A., Aittomaki K., Alducci E., Andrulis I.L., Barkardottir R.B., Barroso A., Barrowdale D., Benitez J., Bonanni B., Borg A., Buys S.S., Caldes T., Caligo M.A., Capalbo C., Campbell I., Chung W.K., Claes K.B.M., Colonna S.V., Cortesi L., Couch F.J., De La Hoya M., Diez O., Ding Y.C., Domchek S., Joseph V., Easton D.F., Ejlertsen B., Engel C., Evans D.G., Feliubadalo L., Foretova L., Fostira F., Geczi L., Gerdes A.-M., Glendon G., Godwin A.K., Goldgar D.E., Hahnen E., Hogervorst F.B.L., Hopper J.L., Hulick P.J., Isaacs C., Izquierdo A., James P.A., Janavicius R., Jensen U.B., John E.M., Konstantopoulou I., Kurian A.W., Kwong A., Landucci E., Lesueur F., Loud J.T., Machackova E., Mai P.L., Majidzadeh-A K., Manoukian S., Montagna M., Moserle L., Mulligan A.M., Nathanson K.L., Nevanlinna H., Ngeow Yuen Ye J., Nikitina-Zake L., Offit K., Olah E., Olopade O.I., Osorio A., Papi L., Park S.K., Pedersen I.S., Perez-Segura P., Petersen A.H., Pinto P., Porfirio B., Pujana M.A., Radice P., Rantala J., Rashid M.U., Rosenzweig B., Rossing M., Santamarina M., Schmutzler R.K., Senter L., Simard J., Singer C.F., Solano A.R., Southey M.C., Steele L., Steinsnyder Z., Stoppa-Lyonnet D., Tan Y.Y., Teixeira M.R., Teo S.H., Terry M.B., Thomassen M., Toland A.E., Torres-Esquius S., Tung N., Van Asperen C.J., Vega A., Viel A., Vierstraete J., Wappenschmidt B., Weitzel J.N., Wieme G., Yoon S.-Y., Zorn K.K., Mcguffog L., Parsons M.T., Hamann U., Greene M.H., Kirk J.A., Neuhausen S.L., Rebbeck T.R., Tischkowitz M., Chenevix-Trench G., Antoniou A.C., Friedman E., Ottini L., Silvestri V., Leslie G., Barnes D.R., Agnarsson B.A., Aittomaki K., Alducci E., Andrulis I.L., Barkardottir R.B., Barroso A., Barrowdale D., Benitez J., Bonanni B., Borg A., Buys S.S., Caldes T., Caligo M.A., Capalbo C., Campbell I., Chung W.K., Claes K.B.M., Colonna S.V., Cortesi L., Couch F.J., De La Hoya M., Diez O., Ding Y.C., and Domchek S.
- Abstract
Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective(s): To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participant(s): Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Result(s): Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P <.001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P <.001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P <.001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P <.001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P =.008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P =.001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P =.003) of being a BRCA2 PV carrier. Conclusions and Relevance: Significant differences in the cancer spectrum w
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- 2021
10. Association of premenopausal risk-reducing salpingo-oophorectomy with breast cancer risk in BRCA1/2 mutation carriers: Maximising bias-reduction
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Stjepanovic, N, Villacampa, G, Nead, KT, Torres-Esquius, S, Melis, GG, Nathanson, KL, Teule, A, Brunet, J, Cajal, TRY, Llort, G, Dienstmann, R, Rue, M, Domchek, SM, and Balmana, J
- Subjects
BRCA1/2 ,Salpingo-oophorectomy ,Systematic review ,Risk reduction methodology ,Multi-state model ,Breast cancer risk - Abstract
Background: Whether risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 carriers reduces the breast cancer (BC) risk is conflicting, potentially due to methodological issues of prior analysis. We analysed the association between premenopausal RRSO and BC risk in BRCA1/2 carriers after adjusting for potential biases. Methods: We analysed data from 444 BRCA1 and 409 BRCA2 carriers under age 51 with no cancer prior to genetic testing or during first 6 months of surveillance (to avoid cancer-induced testing bias and prevalent-cancer bias). Observation started 6 months after genetic testing (to avoid event-free time bias), until BC diagnosis, risk-reducing mastectomy (RRM) or death. A multistate model with four states (non-RRSO, RRSO, RRM and BC) and five transitions was fitted to characterise outcomes and to calculate the BC risk reduction after premenopausal RRSO (before age 51). A systematic review was performed to assess the association between premenopausal RRSO and BC. Results: During a mean follow-up of 4.3 years, 96 women (11.3%) developed BC (54 BRCA1, 42 BRCA2). The risk of BC after premenopausal RRSO decreased significantly in BRCA1 carriers (hazard ratio (HR) = 0.45 [95% confidence interval (CI):0.22-0.92]), but was not conclusive in BRCA2 carriers (HR = 0.77 [95%CI:0.35-1.67]). The systematic review suggested that premenopausal RRSO is associated with a decrease of BC risk in both BRCA1 and BRCA2 carriers. Conclusions: Premenopausal RRSO was associated with BC risk reduction in BRCA1 carriers, which can help guide cancer risk-reducing strategies in this population. Longer follow-up and larger sample size may be needed to estimate the potential benefit in BRCA2 carriers. (C) 2020 Elsevier Ltd. All rights reserved.
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- 2020
11. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.
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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
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, 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
13. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification
- Author
-
Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., and Lucci Cordisco E. (ORCID:0000-0002-6279-7604)
- Abstract
The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
- Published
- 2019
14. Genetic and functional homologous repair deficiency as biomarkers for platinum sensitivity in TNBC: A case report
- Author
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Gomez-Puerto, Diego, Llop Guevara, Alba, Cruellas Lapeña, Mara, Torres Esquius, Sara, De la Torre Fdez de Vega, Fco Javier, Peg Camara, Vicente, Balmaña Gelpí, Judith, Pimentel, Isabel, Institut Català de la Salut, [Gomez-Puerto D] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Llop-Guevara A] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Barcelona Hospital Universitari, Barcelona, Spain. [Cruellas M, Torres-Esquius S, Balmaña J] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [De La Torre J] Unitat de Ginecologia Oncològica i Patologia Mamària, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Peg V] Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Pimentel I] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Breast Cancer and Melanoma Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
ADN - Reparació ,Therapeutics::Combined Modality Therapy::Neoadjuvant Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Cancer Research ,Genetic Phenomena::DNA Repair [PHENOMENA AND PROCESSES] ,Oncology ,Mama - Càncer - Tractament ,Neoplasms::Neoplasms by Site::Breast Neoplasms::Triple Negative Breast Neoplasms [DISEASES] ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,terapéutica::tratamiento combinado::tratamiento neoadyuvante [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Quimioteràpia combinada ,fenómenos genéticos::reparación del ADN [FENÓMENOS Y PROCESOS] ,neoplasias::neoplasias por localización::neoplasias de la mama::neoplasias de mama triple negativos [ENFERMEDADES] - Abstract
HRD-biomarkers; Pathological complete response; Triple-negative breast cancer Biomarcadores HRD; Respuesta patológica completa; Cáncer de mama triple negativo Biomarcadors HRD; Resposta patològica completa; Càncer de mama triple negatiu Triple-negative breast cancer is the most aggressive subtype of mammary carcinoma. In the early stage, neoadjuvant chemotherapy (NAC) is the standard of care for prognostic stratification and the best adjuvant treatment strategy. A 30-year-old female presented in the emergency room because of a gigantic right breast associated with an ulcerated lump at the upper quadrants. The right axillary nodes were palpable. An ultrasound was performed, showing the ulcerated neoformation with enlarged right axillary lymph nodes observed to level III. A core biopsy of the breast lesion was performed, and the pathological examination revealed a nonspecial type, grade 3, invasive, triple-negative breast cancer. No distant disease was found in the PET-CT scan. A germline genetic panel by next-generation sequencing identified a likely pathogenic variant in RAD51D (c.898C>T). Assessment of the functionality of the DNA homologous recombination repair pathway by RAD51 foci in the tumor revealed a profile of homologous recombination deficiency. NAC consisting of weekly carboplatin and paclitaxel followed by dose-dense doxorubicin/cyclophosphamide was performed with a complete metabolic response achieved in the PET-CT scan. The patient underwent a modified radical mastectomy plus axillary lymphadenectomy with a pathological complete response in the breast and axilla and remains disease-free after 2 years of follow-up. We report a young female with a triple-negative breast cancer stage cT4bN3M0 and a hereditary pathogenic mutation in RAD51D. The tumor was highly proliferative and homologous recombination-deficient by RAD51. The patient received platinum-based NAC, achieving a pathologic complete response. More effort should be made to identify predictive functional biomarkers of treatment response, such as RAD51 foci, for platinum sensitivity.
- Published
- 2022
15. BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort
- Author
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Rofes, Paula, Del Valle, Jesús, Torres Esquius, Sara, Feliubadaló, Lídia, Stradella, Agostina, Moreno-Cabrera, José Marcos, López-Doriga, Adriana, Munté, Elisabet, de Cid, R., Campos, Olga, Cuesta, Raquel, Teulé, Álex, Grau, Èlia, Sanz, Judit, Capellá, G. (Gabriel), Diez, Orland, Brunet, Joan, Balmaña Gelpí, Judith, Lázaro, Conxi, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Rofes P, Del Valle J, Feliubadaló L, Moreno-Cabrera JM] Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat, Spain. Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L’Hospitalet de Llobregat, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. [Torres-Esquius S, Balmaña J] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Stradella A] Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat, Spain. Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L’Hospitalet de Llobregat, Spain. Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, L’Hospitalet de Llobregat, Spain. [Díez O] Institut Català de la Salut, Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,lcsh:QH426-470 ,Moderate cancer risk ,Hereditary breast and ovarian cancer ,Càncer d'ovari ,Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES] ,Ovaris - Càncer - Aspectes genètics ,hereditary breast and ovarian cancer ,Germline ,Article ,Càncer de mama ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,breast cancer ,Triple-negative breast cancer ,Ovarian cancer ,Internal medicine ,Genetics ,medicine ,BARD1 ,Genetics (clinical) ,Genetic testing ,fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS] ,moderate cancer risk ,medicine.diagnostic_test ,business.industry ,Odds ratio ,medicine.disease ,Penetrance ,neoplasias::neoplasias por localización::neoplasias de la mama::neoplasias de mama triple negativos [ENFERMEDADES] ,lcsh:Genetics ,030104 developmental biology ,Neoplasms::Neoplasms::Neoplasms::Neoplastic Syndromes, Hereditary::Hereditary Breast and Ovarian Cancer Syndrome [DISEASES] ,ovarian cancer ,030220 oncology & carcinogenesis ,Cohort ,Neoplasms::Neoplasms by Site::Breast Neoplasms::Triple Negative Breast Neoplasms [DISEASES] ,triple-negative breast cancer ,Mama - Càncer - Aspectes genètics ,neoplasias::neoplasias::neoplasias::síndromes neoplásicos hereditarios::síndrome hereditario de cáncer de mama y ovario [ENFERMEDADES] ,business - Abstract
Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78, CI = 2.10&ndash, 6.48, p = 1.16 ×, 10&minus, 5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18, 7.70, p = 5.45 ×, 5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40, CI = 1.77&ndash, 18.15, p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.
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- 2021
16. Germline assessment for alloHSCT candidates over 50 years: A 'Fast-Track' screening in myeloid neoplasms.
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Torres-Esquius S, Beas F, Chen-Liang TH, Pomares H, Santiago M, Varela ND, Liquori A, Hernandez F, Xicoy B, Hermosín L, Arnan M, Tazón-Vega B, Blanco A, Cervera J, Diez-Campelo M, Lozano ML, Valcárcel D, Bosch F, Montoro MJ, and Jerez A
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- Humans, Middle Aged, Male, Female, Aged, Genetic Testing methods, Genetic Predisposition to Disease, Myeloproliferative Disorders genetics, Myeloproliferative Disorders diagnosis, Exome Sequencing, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Germ-Line Mutation
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Patients aged 50 or above diagnosed with myeloid neoplasms (MNs) are typically not candidates for germline testing. However, approximately 8% carry pathogenic germline variants. Allogeneic haematopoietic stem cell transplantation (alloHSCT) remains an option for those aged over 50; neglecting germline testing could mask the risk for relative donor cell-derived MN. We propose a germline-augmented somatic panel (GASP), combining MN predisposition genes with a myeloid somatic panel for timely germline variant identification when initial testing is not indicated. Out of our 133 whole-exome-sequenced MN cases aged over 50 years, 9% had pathogenic/likely variants. GASP detected 92%, compared to 50% with somatic-only panel. Our study highlights the relevance of germline screening in MN, particularly for alloHSCT candidates without established germline-testing recommendations., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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17. Risk of endometrial cancer after RRSO in BRCA 1/2 carriers: a multicentre cohort study.
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Pla-Juher H, Pardo M, Izquierdo ÀJ, Darder E, Carbó A, Munté E, Torres-Esquius S, Balmaña J, Lázaro C, Brunet JM, and Barretina-Ginesta MP
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- Humans, Female, Salpingo-oophorectomy, BRCA1 Protein genetics, Ovariectomy, BRCA2 Protein genetics, Genes, BRCA1, Genes, BRCA2, Mutation, Cohort Studies, Genetic Predisposition to Disease, Endometrial Neoplasms epidemiology, Endometrial Neoplasms genetics, Ovarian Neoplasms pathology
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Objective: To know the risk of endometrial cancer (EC) in a population of women with BRCA 1/2 pathogenic or likely pathogenic variants after risk-reducing salpingo-oophorectomy (RRSO)., Methods: The study cohort included data from 857 women with BRCA mutations who underwent RRSO visited four hospitals in Catalonia, Spain, from January 1, 1999 to April 30, 2019. Standardized incidence ratio (SIR) of EC was calculated in these patients using data from a regional population-based cancer registry., Results: After RRSO, eight cases of EC were identified. Four in BRCA 1 carriers and four in BRCA2 carriers. The expected number of cases of EC was 3.67 cases, with a SIR of 2.18 and a 95% CI (0.93-3.95)., Conclusions: In our cohort, the risk of EC in BRCA1/2 carriers after RRSO is not greater than expected. Hysterectomy is not routinely recommended for these patients., (© 2023. The Author(s).)
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- 2024
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18. Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer.
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Torres-Esquius S, Llop-Guevara A, Gutiérrez-Enríquez S, Romey M, Teulé À, Llort G, Herrero A, Sánchez-Henarejos P, Vallmajó A, González-Santiago S, Chirivella I, Cano JM, Graña B, Simonetti S, Díaz de Corcuera I, Ramon Y Cajal T, Sanz J, Serrano S, Otero A, Churruca C, Sánchez-Heras AB, Servitja S, Guillén-Ponce C, Brunet J, Denkert C, Serra V, and Balmaña J
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- Adult, Female, Humans, DNA-Binding Proteins genetics, Genetic Predisposition to Disease, Prevalence, Retrospective Studies, Spain epidemiology, Breast Neoplasms genetics, Breast Neoplasms epidemiology, Germ-Line Mutation, Homologous Recombination genetics, Ovarian Neoplasms genetics, Ovarian Neoplasms epidemiology, Rad51 Recombinase genetics
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Importance: RAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival., Objective: To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status., Design, Setting, and Participants: This retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023., Main Outcomes and Measures: Clinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test., Results: A total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 [19.6%]) and c.709C>T (9 of 56 [16.1%]) in RAD51C and c.694C>T (20 of 35 [57.1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD., Conclusions and Relevance: In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor-positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate-ribose] polymerase) inhibitors.
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- 2024
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19. Two Germline Pathogenic Variants in Cancer Susceptibility Genes and Their Null Implication in Breast Cancer Pathogenesis: The Importance of Tumoral Homologous Recombination Deficiency Testing.
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Rezqallah A, Torres-Esquius S, Llop-Guevara A, Cruellas M, Martinez MT, Romey M, Denkert C, Serra V, Chirivella I, and Balmaña J
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- Humans, Female, Genetic Predisposition to Disease genetics, Germ-Line Mutation genetics, Homologous Recombination genetics, Germ Cells pathology, Breast Neoplasms diagnosis, Breast Neoplasms genetics, Breast Neoplasms pathology
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Homologous recombination proficiency in patients with breast cancer despite germline PALB2/RAD51C pathogenic variants.
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- 2024
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20. Role of psychological background in cancer susceptibility genetic testing distress: It is not only about a positive result.
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López-Fernández A, Villacampa G, Salinas M, Grau E, Darder E, Carrasco E, Solanes A, Velasco A, Torres M, Munté E, Iglesias S, Torres-Esquius S, Tuset N, Diez O, Lázaro C, Brunet J, Corbella S, and Balmaña J
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- Humans, Female, Genetic Testing, Genetic Counseling psychology, Anxiety psychology, Stress, Psychological psychology, Neoplasms genetics
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Clinical and familial factors predict psychological distress after genetic testing for cancer susceptibility. However, the contribution of an individual's psychological background to such distress is unclear. This study aims to analyze the psychological impact of genetic testing and to identify the profile of individuals at higher risk. This is a longitudinal multicenter study of individuals undergoing genetic testing for cancer susceptibility. Demographic, clinical, genetic, familial, and psychological (personality types, cancer worry) characteristics were assessed by validated questionnaires the day of genetic testing. Distress, uncertainty, and positive experience perception (MICRA scale) were evaluated at the results disclosure visit, and 3 and 12 months afterwards. Multivariate analysis was performed. A total of 714 individuals were included. A high neuroticism score, high baseline cancer worry, and a positive genetic test result were independently associated with higher psychological impact (p-value < 0.05). The highest risk profile (10% of the cohort) included women with high level of neuroticism and a positive result. Uncertainty was mainly associated with a high level of neuroticism, regardless of the genetic test result. A holistic approach to personalized germline genetic counseling should include the assessment of personality dimensions., (© 2023 National Society of Genetic Counselors.)
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- 2023
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21. Clinical and psychological implications of secondary and incidental findings in cancer susceptibility genes after exome sequencing in patients with rare disorders.
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Carrasco E, López-Fernández A, Codina-Sola M, Valenzuela I, Cueto-González AM, Villacampa G, Navarro V, Torres-Esquius S, Palau D, Cruellas M, Torres M, Perez-Dueñas B, Abulí A, Diez O, Sábado-Álvarez C, García-Arumí E, Tizzano EF, Moreno L, and Balmaña J
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- Humans, Female, Exome Sequencing, Incidental Findings, Genes, BRCA2, Genetic Predisposition to Disease, Breast Neoplasms genetics
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Background/objectives: Exome sequencing may identify pathogenic variants unrelated with the purpose of the analysis. We investigated the frequency of secondary and incidental findings (SF/IF) in cancer susceptibility genes (CSG), their clinical actionability and the psychological impact in individuals with an SF/IF (cases) compared with individuals tested due to their cancer history (controls)., Methods: This study analysed 533 exomes ordered for non-cancer conditions. Medical records were reviewed for clinical actionability of SF/IF. Psychological impact was analysed using the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale and compared between cases and controls with a propensity score weighting method., Results: The frequency of SF/IF in CSG was 2.1% (95% CI 1.1% to 3.8%): three BRCA2 , three PMS2 , two SDHB , and one each in BRCA1 , MLH1 and RAD51C . Among the relatives, 18 were carriers. Twenty enrolled for surveillance, and a neoplasm was diagnosed in 20%: three paragangliomas and one breast cancer. Cases presented higher MICRA mean scores than controls (21.3 vs 16.2 in MICRA total score, 6.3 vs 4.2 in the distress subscale, and 8.3 vs 6.6 in the uncertainty subscale; all p<0.001)., Conclusion: SF/IF in CSG were identified in 2.1% of patients. Despite a numerically higher psychological impact, the identification of SF/IF allowed early detection and cancer prevention in families without cancer history., Competing Interests: Competing interests: JB has received a speaker’s fee from AstraZeneca and Pfizer and has served AstraZeneca in an advisory role. GV has received a speaker’s fee/research honoraria from MSD and Pierre Fabre and has served AstraZeneca in an advisory role. LM is member of the data monitoring committees for clinical trials sponsored by Novartis, Actuate Therapeutics, Shionogi, Incyte, University of Southampton and Royal Marsden NHS Foundation Trust; had a consulting role for Novartis, Norgine, Boehringer, Y-mAbs and Shionogi; and participated in educational activities organised by Bayer and Eusa Pharma. LM is member of the Executive Committee of SIOPEN (European neuroblastoma research cooperative group), an organisation which receives royalties for sales of dinutuximab beta. EFT has received grant support to conduct clinical trials on SMA from Ionis/Biogen and serves as a consultant to Biogen, Novartis, AveXis, Roche, Biologix and Cytokinetics., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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22. A case of Rothmund-Thomson syndrome originally thought to be a case of Bloom syndrome.
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Marmolejo Castañeda DH, Cruellas Lapeña M, Carrasco López E, Aparicio Español G, Valverde Morales C, López-Fernández A, Pérez Ballesteros E, Torres-Esquius S, Pardo Muñoz M, and Balmaña Gelpi J
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- Male, Humans, Middle Aged, RecQ Helicases genetics, Rothmund-Thomson Syndrome diagnosis, Rothmund-Thomson Syndrome genetics, Bloom Syndrome diagnosis, Bloom Syndrome genetics
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Rothmund-Thomson syndrome, a heterogeneous genodermatosis with autosomal recessive hereditary pattern, is an uncommon cancer susceptibility genetic syndrome. To date, only 400 cases have been reported in the literature, and the severity of the features varies among individuals with the condition. Here, we describe a 55-year-old male who had been diagnosed with Bloom Syndrome during childhood due to the suggestive physical features such as short stature, chronic facial erythema, poikiloderma in face and extremities, microtia and microcephaly. However, the genetic test demonstrated that the patient carried two pathogenic variants resulting in compound heterozygous in the RECQL4 gene (c.2269C>T and c.2547_2548delGT). He subsequently developed a calcaneal osteosarcoma, which was successfully treated, and has currently been oncologic disease-free for 3 years., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)
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- 2023
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23. Patients' and professionals' perspective of non-in-person visits in hereditary cancer: predictors and impact of the COVID-19 pandemic.
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López-Fernández A, Villacampa G, Grau E, Salinas M, Darder E, Carrasco E, Torres-Esquius S, Iglesias S, Solanes A, Gadea N, Velasco A, Urgell G, Torres M, Tuset N, Brunet J, Corbella S, and Balmaña J
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- Cohort Studies, Communicable Disease Control, Genetic Predisposition to Disease, Humans, Pandemics, Prospective Studies, SARS-CoV-2, COVID-19, Neoplasms
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Purpose: To identify predictors of patient acceptance of non-in-person cancer genetic visits before and after the COVID-19 pandemic and assess the preferences of health-care professionals., Methods: Prospective multicenter cohort study (N = 578, 1 February 2018-20 April 2019) and recontacted during the COVID-19 lockdown in April 2020. Health-care professionals participated in May 2020. Association of personality traits and clinical factors with acceptance was assessed with multivariate analysis., Results: Before COVID-19, videoconference was more accepted than telephone-based visits (28% vs. 16% pretest, 30% vs. 19% post-test). Predictors for telephone visits were age (pretest, odds ratio [OR] 10-year increment = 0.79; post-test OR 10Y = 0.78); disclosure of panel testing (OR = 0.60), positive results (OR = 0.52), low conscientiousness group (OR = 2.87), and post-test level of uncertainty (OR = 0.93). Predictors for videoconference were age (pretest, OR 10Y = 0.73; post-test, OR 10Y = 0.75), educational level (pretest: OR = 1.61), low neuroticism (pretest, OR = 1.72), and post-test level of uncertainty (OR = 0.96). Patients' reported acceptance for non-in-person visits after COVID-19 increased to 92% for the pretest and 85% for the post-test. Health-care professionals only preferred non-in-person visits for disclosure of negative results (83%)., Conclusion: These new delivery models need to recognize challenges associated with age and the psychological characteristics of the population and embrace health-care professionals' preferences., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)
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- 2021
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24. Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).
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Silvestri V, Leslie G, Barnes DR, Agnarsson BA, Aittomäki K, Alducci E, Andrulis IL, Barkardottir RB, Barroso A, Barrowdale D, Benitez J, Bonanni B, Borg A, Buys SS, Caldés T, Caligo MA, Capalbo C, Campbell I, Chung WK, Claes KBM, Colonna SV, Cortesi L, Couch FJ, de la Hoya M, Diez O, Ding YC, Domchek S, Easton DF, Ejlertsen B, Engel C, Evans DG, Feliubadalò L, Foretova L, Fostira F, Géczi L, Gerdes AM, Glendon G, Godwin AK, Goldgar DE, Hahnen E, Hogervorst FBL, Hopper JL, Hulick PJ, Isaacs C, Izquierdo A, James PA, Janavicius R, Jensen UB, John EM, Joseph V, Konstantopoulou I, Kurian AW, Kwong A, Landucci E, Lesueur F, Loud JT, Machackova E, Mai PL, Majidzadeh-A K, Manoukian S, Montagna M, Moserle L, Mulligan AM, Nathanson KL, Nevanlinna H, Ngeow J, Nikitina-Zake L, Offit K, Olah E, Olopade OI, Osorio A, Papi L, Park SK, Pedersen IS, Perez-Segura P, Petersen AH, Pinto P, Porfirio B, Pujana MA, Radice P, Rantala J, Rashid MU, Rosenzweig B, Rossing M, Santamariña M, Schmutzler RK, Senter L, Simard J, Singer CF, Solano AR, Southey MC, Steele L, Steinsnyder Z, Stoppa-Lyonnet D, Tan YY, Teixeira MR, Teo SH, Terry MB, Thomassen M, Toland AE, Torres-Esquius S, Tung N, van Asperen CJ, Vega A, Viel A, Vierstraete J, Wappenschmidt B, Weitzel JN, Wieme G, Yoon SY, Zorn KK, McGuffog L, Parsons MT, Hamann U, Greene MH, Kirk JA, Neuhausen SL, Rebbeck TR, Tischkowitz M, Chenevix-Trench G, Antoniou AC, Friedman E, and Ottini L
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- Adolescent, Adult, Aged, Aged, 80 and over, Germ-Line Mutation, Humans, Male, Middle Aged, Neoplasms diagnosis, Phenotype, Retrospective Studies, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Neoplasms genetics
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Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population., Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers., Design, Setting, and Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected., Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview., Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier., Conclusions and Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.
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- 2020
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25. Association of premenopausal risk-reducing salpingo-oophorectomy with breast cancer risk in BRCA1/2 mutation carriers: Maximising bias-reduction.
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Stjepanovic N, Villacampa G, Nead KT, Torres-Esquius S, Melis GG, Nathanson KL, Teule A, Brunet J, Y Cajal TR, Llort G, Dienstmann R, Rue M, Domchek SM, and Balmaña J
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- Adult, Breast Neoplasms genetics, Breast Neoplasms pathology, Female, Follow-Up Studies, Genetic Testing, Humans, Middle Aged, Prognosis, Prospective Studies, Retrospective Studies, Young Adult, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms surgery, Germ-Line Mutation, Premenopause, Risk Reduction Behavior, Salpingo-oophorectomy methods
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Background: Whether risk-reducing salpingo-oophorectomy (RRSO) in BRCA1/2 carriers reduces the breast cancer (BC) risk is conflicting, potentially due to methodological issues of prior analysis. We analysed the association between premenopausal RRSO and BC risk in BRCA1/2 carriers after adjusting for potential biases., Methods: We analysed data from 444 BRCA1 and 409 BRCA2 carriers under age 51 with no cancer prior to genetic testing or during first 6 months of surveillance (to avoid cancer-induced testing bias and prevalent-cancer bias). Observation started 6 months after genetic testing (to avoid event-free time bias), until BC diagnosis, risk-reducing mastectomy (RRM) or death. A multistate model with four states (non-RRSO, RRSO, RRM and BC) and five transitions was fitted to characterise outcomes and to calculate the BC risk reduction after premenopausal RRSO (before age 51). A systematic review was performed to assess the association between premenopausal RRSO and BC., Results: During a mean follow-up of 4.3 years, 96 women (11.3%) developed BC (54 BRCA1, 42 BRCA2). The risk of BC after premenopausal RRSO decreased significantly in BRCA1 carriers (hazard ratio (HR) = 0.45 [95% confidence interval (CI):0.22-0.92]), but was not conclusive in BRCA2 carriers (HR = 0.77 [95%CI:0.35-1.67]). The systematic review suggested that premenopausal RRSO is associated with a decrease of BC risk in both BRCA1 and BRCA2 carriers., Conclusions: Premenopausal RRSO was associated with BC risk reduction in BRCA1 carriers, which can help guide cancer risk-reducing strategies in this population. Longer follow-up and larger sample size may be needed to estimate the potential benefit in BRCA2 carriers., Competing Interests: Conflict of interest statement The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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26. Incorporation of semi-quantitative analysis of splicing alterations for the clinical interpretation of variants in BRCA1 and BRCA2 genes.
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Montalban G, Bonache S, Moles-Fernández A, Gadea N, Tenés A, Torres-Esquius S, Carrasco E, Balmaña J, Diez O, and Gutiérrez-Enríquez S
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- Electrophoresis, Capillary, Female, Gene Expression Regulation, Neoplastic, Germ-Line Mutation, Humans, Polymorphism, Genetic, RNA, Messenger genetics, Sequence Analysis, DNA, Alternative Splicing, BRCA1 Protein genetics, BRCA2 Protein genetics, Genetic Testing methods, Hereditary Breast and Ovarian Cancer Syndrome genetics
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BRCA1 and BRCA2 (BRCA1/2) genetic variants that disrupt messenger RNA splicing are commonly associated with increased risks of developing breast/ovarian cancer. The majority of splicing studies published to date rely on qualitative methodologies (i.e., Sanger sequencing), but it is necessary to incorporate semi-quantitative or quantitative approaches to accurately interpret the clinical significance of spliceogenic variants. Here, we characterize the splicing impact of 31 BRCA1/2 variants using semi-quantitative capillary electrophoresis of fluorescent amplicons (CE), Sanger sequencing and allele-specific assays. A total of 14 variants were found to disrupt splicing. Allelic-specific assays could be performed for BRCA1 c.302-1G>A and BRCA2 c.516+2T>A, c.1909+1G>A, c.8332-13T>G, c.8332-2A>G, c.8954-2A>T variants, showing a monoallelic contribution to full-length transcript expression that was concordant with semi-quantitative data. The splicing fraction of alternative and aberrant transcripts was also measured by CE, facilitating variant interpretation. Following Evidence-based Network for the Interpretation of Germline Mutant Alleles criteria, we successfully classified eight variants as pathogenic (Class 5), five variants as likely pathogenic (Class 4), and 14 variants as benign (Class 1). We also provide splicing data for four variants classified as uncertain (Class 3), which produced a "leaky" splicing effect or introduced a missense change in the protein sequence, that will require further assessment to determine their clinical significance., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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27. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.
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Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, Barbieri E, Bartram CR, Blanco A, Blümcke B, Bonache S, Bonanni B, Borg Å, Bortesi B, Brunet J, Bruzzone C, Bucksch K, Cagnoli G, Caldés 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 HCR, Gambino G, Gehrig A, Gensini F, Gerdes AM, Germani A, Giesecke J, Gismondi V, Gómez C, Gómez Garcia EB, González S, Grau E, Grill S, Gross E, Guerrieri-Gonzaga A, Guillaud-Bataille M, Gutiérrez-Enríquez S, Haaf T, Hackmann K, Hansen TVO, Harris M, Hauke J, Heinrich T, Hellebrand H, Herold KN, Honisch E, Horvath J, Houdayer C, Hübbel V, Iglesias S, Izquierdo A, James PA, Janssen LAM, Jeschke U, Kaulfuß S, Keupp K, Kiechle M, Kölbl 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, López-Fernández A, Lucci-Cordisco E, Maass N, Manoukian S, Marabelli M, Matricardi L, Meindl A, Michelli RD, Moghadasi S, Moles-Fernández A, Montagna M, Montalban G, Monteiro AN, Montes E, Mori L, Moserle L, Müller CR, Mundhenke C, Naldi N, Nathanson KL, Navarro M, Nevanlinna H, Nichols CB, Niederacher D, Nielsen HR, Ong KR, Pachter N, Palmero EI, 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, Sánchez 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 SV, Teo SH, Teulé A, Thomassen M, Tibiletti MG, Tischkowitz M, Tognazzo S, Toland AE, Tornero E, Törngren 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 Á, Vesper AS, Viel A, Vreeswijk MPG, Wagner SA, Waha A, Walker LC, Walters RJ, Wang-Gohrke S, Weber BHF, Weichert W, Wieland K, Wiesmüller L, Witzel I, Wöckel A, Woodward ER, Zachariae S, Zampiga V, Zeder-Göß C, Lázaro C, De Nicolo A, Radice P, Engel C, Schmutzler RK, Goldgar DE, and Spurdle AB
- Subjects
- Alternative Splicing, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Humans, Likelihood Functions, Male, Multifactorial Inheritance, Neoplasms genetics, BRCA1 Protein genetics, BRCA2 Protein genetics, Computational Biology methods, Mutation, Missense, Neoplasms diagnosis
- 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., (© 2019 Wiley Periodicals, Inc.)
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- 2019
- Full Text
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28. Alternative transcript imbalance underlying breast cancer susceptibility in a family carrying PALB2 c.3201+5G>T.
- Author
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Duran-Lozano L, Montalban G, Bonache S, Moles-Fernández A, Tenés A, Castroviejo-Bermejo M, Carrasco E, López-Fernández A, Torres-Esquius S, Gadea N, Stjepanovic N, Balmaña J, Gutiérrez-Enríquez S, and Diez O
- Subjects
- Female, Gene Expression Profiling, Genetic Predisposition to Disease, Humans, Loss of Heterozygosity, Middle Aged, Pedigree, Sequence Analysis, RNA, Alternative Splicing, Breast Neoplasms genetics, Fanconi Anemia Complementation Group N Protein genetics, Germ-Line Mutation, Polymorphism, Single Nucleotide
- Abstract
Purpose: Disruption of splicing motifs by genetic variants can affect the correct generation of mature mRNA molecules leading to aberrant transcripts. In some cases, variants may alter the physiological transcription profile composed of several transcripts, and an accurate in vitro evaluation is crucial to establish their pathogenicity. In this study, we have characterized a novel PALB2 variant c.3201+5G>T identified in a breast cancer family., Methods: Peripheral blood RNA was analyzed in two carriers and ten controls by RT-PCR and Sanger sequencing. The splicing profile was also characterized by semi-quantitative capillary electrophoresis and quantitative PCR. RAD51 foci formation and PALB2 LOH status were evaluated in primary breast tumor samples from the carriers., Results: PALB2 c.3201+5G>T disrupts intron 11 donor splice site and modifies the abundance of several alternative transcripts (∆11, ∆12, and ∆11,12), also present in control samples. All transcripts are predicted to encode for non-functional proteins. Semi-quantitative and quantitative analysis of PALB2 full-length transcript indicated haploinsufficiency in carriers. One tumor exhibited PALB2 LOH and RAD51 assay indicated homologous recombination deficiency in both tumors., Conclusions: Our results support a pathogenic classification for PALB2 c.3201+5G>T, highlighting the impact of variants causing an imbalanced expression of natural RNA isoforms in cancer susceptibility.
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- 2019
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29. Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings.
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Bonache S, Esteban I, Moles-Fernández A, Tenés A, Duran-Lozano L, Montalban G, Bach V, Carrasco E, Gadea N, López-Fernández A, Torres-Esquius S, Mancuso F, Caratú G, Vivancos A, Tuset N, Balmaña J, Gutiérrez-Enríquez S, and Diez O
- Subjects
- Adult, Alleles, Computational Biology methods, Female, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Middle Aged, Neoplasm Staging, Sequence Analysis, DNA, Spain, Young Adult, Biomarkers, Tumor, Genes, BRCA1, Genes, BRCA2, Hereditary Breast and Ovarian Cancer Syndrome diagnosis, Hereditary Breast and Ovarian Cancer Syndrome genetics
- Abstract
Purpose: Few and small studies have been reported about multigene testing usage by massively parallel sequencing in European cancer families. There is an open debate about what genes should be tested, and the actionability of some included genes is under research., Methods: We investigated a panel of 34 known high/moderate-risk cancer genes, including 16 related to breast or ovarian cancer (BC/OC) genes, and 63 candidate genes to BC/OC in 192 clinically suspicious of hereditary breast/ovarian cancer (HBOC) Spanish families without pathogenic variants in BRCA1 or BRCA2 (BRCA1/2)., Results: We identified 16 patients who carried a high- or moderate-risk pathogenic variant in eight genes: 4 PALB2, 3 ATM, 2 RAD51D, 2 TP53, 2 APC, 1 BRIP1, 1 PTEN and 1 PMS2. These findings led to increased surveillance or prevention options in 12 patients and predictive testing in their family members. We detected 383 unique variants of uncertain significance in known cancer genes, of which 35 were prioritized in silico. Eighteen loss-of-function variants were detected in candidate BC/OC genes in 17 patients (1 BARD1, 1 ERCC3, 1 ERCC5, 2 FANCE, 1 FANCI, 2 FANCL, 1 FANCM, 1 MCPH1, 1 PPM1D, 2 RBBP8, 3 RECQL4 and 1 with SLX4 and XRCC2), three of which also carry pathogenic variants in known cancer genes., Conclusions: Eight percent of the BRCA1/2 negative patients carry pathogenic variants in other actionable genes. The multigene panel usage improves the diagnostic yield in HBOC testing and it is an effective tool to identify potentially new candidate genes.
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- 2018
- Full Text
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