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2. Molecular profiling of advanced solid tumours. The impact of experimental molecular-matched therapies on cancer patient outcomes in early-phase trials: the MAST study

Author

Gambardella, Valentina, Lombardi, Pasquale, Carbonell-Asins, Juan Antonio, Tarazona, Noelia, Cejalvo, Juan Miguel, González-Barrallo, Inés, Martín-Arana, Jorge, Tébar-Martínez, Roberto, Viala, Alba, Bruixola, Gema, Hernando, Cristina, Blasco, Inma, Papaccio, Federica, Martínez-Ciarpaglini, Carolina, Alfaro-Cervelló, Clara, Seda-García, Enrique, Blesa, Sebastián, Chirivella, Isabel, Castillo, Josefa, Montón-Bueno, José Vicente, Roselló, Susana, Huerta, Marisol, Pérez-Fidalgo, Alejandro, Martín-Martorell, Paloma, Insa-Mollá, Amelia, Fleitas, Tania, Rentero-Garrido, Pilar, Zúñiga-Trejos, Sheila, Cervantes, Andrés, and Roda, Desamparados

Published
2021
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3. Prognostic Expression Signature of RB1, PTEN, and TP53 Genes in Patients with Metastatic Hormone-sensitive Prostate Cancer Treated with Androgen Receptor Pathway Inhibitors

Author

Garcia de Herreros, Marta, Jiménez, Natalia, Rodríguez-Carunchio, Leonardo, Lillo, Eva, Marín-Aguilera, Mercedes, Ferrer-Mileo, Laura, Aversa, Caterina, García-Esteve, Samuel, Padrosa, Joan, Trias, Isabel, Fernández-Mañas, Laia, Font, Albert, Chirivella, Isabel, Figols, Mariona, Climent, Miguel Ángel, Prat, Aleix, Reig, Òscar, and Mellado, Begoña

Published
2024
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4. Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS)

Author

Ramírez-Calvo, Marta, García-Casado, Zaida, Fernández-Serra, Antonio, de Juan, Inmaculada, Palanca, Sarai, Oltra, Silvestre, Soto, José Luis, Castillejo, Adela, Barbera, Víctor M, Juan-Fita, Ma José, Segura, Ángel, Chirivella, Isabel, Sánchez, Ana Beatriz, Tena, Isabel, Chaparro, Carolina, Salas, Dolores, and López-Guerrero, José Antonio

Published
2019
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6. Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel

Author

Jiménez, Natalia, primary, Reig, Òscar, additional, Marín-Aguilera, Mercedes, additional, Aversa, Caterina, additional, Ferrer-Mileo, Laura, additional, Font, Albert, additional, Rodriguez-Vida, Alejo, additional, Climent, Miguel Ángel, additional, Cros, Sara, additional, Chirivella, Isabel, additional, Domenech, Montserrat, additional, Figols, Mariona, additional, González-Billalabeitia, Enrique, additional, Jiménez Peralta, Daniel, additional, Rodríguez-Carunchio, Leonardo, additional, García-Esteve, Samuel, additional, Garcia de Herreros, Marta, additional, Ribal, Maria J., additional, Prat, Aleix, additional, and Mellado, Begoña, additional

Published
2022
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9. Abstract PS7-71: Breast cancer fast-track programme to shorten time between initial symptoms, diagnosis and initiation of treatment. 10 years update

Author

Martínez, Maria Teresa, primary, Moragon, Santiago, additional, Simon, Soraya, additional, Ortega, Belen, additional, Monton-Bueno, Jose Vicente, additional, Navarro, Jorge, additional, Sanmartin, Ana, additional, Julve, Ana, additional, Buch, Elvira, additional, Burgués, Octavio, additional, Hernando, Cristina, additional, Cejalvo, Juan Miguel, additional, Lluch, Ana, additional, Bermejo, Begoña, additional, Cervantes, Andrés, additional, and Chirivella, Isabel, additional

Published
2021
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10. Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization

Author

Sánchez-Heras, A. Beatriz, primary, Castillejo, Adela, additional, García-Díaz, Juan D., additional, Robledo, Mercedes, additional, Teulé, Alexandre, additional, Sánchez, Rosario, additional, Zúñiga, Ángel, additional, Lastra, Enrique, additional, Durán, Mercedes, additional, Llort, Gemma, additional, Yagüe, Carmen, additional, Ramon y Cajal, Teresa, additional, López San Martin, Consol, additional, López-Fernández, Adrià, additional, Balmaña, Judith, additional, Robles, Luis, additional, Mesa-Latorre, José M., additional, Chirivella, Isabel, additional, Fonfria, María, additional, Perea Ibañez, Raquel, additional, Castillejo, M. Isabel, additional, Escandell, Inés, additional, Gomez, Luis, additional, Berbel, Pere, additional, and Soto, Jose Luis, additional

Published
2020
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11. HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women

Author

Oltra, Sara S., primary, Cejalvo, Juan Miguel, additional, Tormo, Eduardo, additional, Albanell, Marta, additional, Ferrer, Ana, additional, Nacher, Marta, additional, Bermejo, Begoña, additional, Hernando, Cristina, additional, Chirivella, Isabel, additional, Alonso, Elisa, additional, Burgués, Octavio, additional, Peña-Chilet, Maria, additional, Eroles, Pilar, additional, Lluch, Ana, additional, Ribas, Gloria, additional, and Martinez, María Teresa, additional

Published
2020
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12. Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization

Author

Universidad de Alicante. Departamento de Biotecnología, Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Sánchez-Heras, Ana Beatriz, Castillejo, Adela, García-Díaz, Juan D., Robledo, Mercedes, Teulé, Alexandre, Sánchez, Rosario, Zúñiga, Ángel, Lastra, Enrique, Durán, Mercedes, Llort, Gemma, Yagüe, Carmen, Ramon y Cajal, Teresa, López San Martin, Consol, López-Fernández, Adriá, Balmaña, Judith, Robles, Luis, Mesa-Latorre, José M., Chirivella, Isabel, Fonfria, María, Perea Ibañez, Raquel, Castillejo, María Isabel, Escandell, Inés, Gomez, Luis, Berbel, Pere, Soto, José Luis, Universidad de Alicante. Departamento de Biotecnología, Universidad de Alicante. Departamento de Fisiología, Genética y Microbiología, Sánchez-Heras, Ana Beatriz, Castillejo, Adela, García-Díaz, Juan D., Robledo, Mercedes, Teulé, Alexandre, Sánchez, Rosario, Zúñiga, Ángel, Lastra, Enrique, Durán, Mercedes, Llort, Gemma, Yagüe, Carmen, Ramon y Cajal, Teresa, López San Martin, Consol, López-Fernández, Adriá, Balmaña, Judith, Robles, Luis, Mesa-Latorre, José M., Chirivella, Isabel, Fonfria, María, Perea Ibañez, Raquel, Castillejo, María Isabel, Escandell, Inés, Gomez, Luis, Berbel, Pere, and Soto, José Luis

Abstract

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.

Published
2020

15. Additional file 2: of Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS)

Author

Ramírez-Calvo, Marta, García-Casado, Zaida, Fernández-Serra, Antonio, Juan, Inmaculada, Palanca, Sarai, Oltra, Silvestre, Soto, José, Castillejo, Adela, Barbera, Víctor M, Juan-Fita, Ma, Segura, Ángel, Chirivella, Isabel, Sánchez, Ana, Tena, Isabel, Chaparro, Carolina, Salas, Dolores, and López-Guerrero, José

Abstract

Table S2: Validation designed primer sequences. (DOCX 32 kb)

Published
2019
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16. Additional file 4: of Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS)

Author

Ramírez-Calvo, Marta, García-Casado, Zaida, Fernández-Serra, Antonio, Juan, Inmaculada, Palanca, Sarai, Oltra, Silvestre, Soto, José, Castillejo, Adela, Barbera, Víctor M, Juan-Fita, Ma, Segura, Ángel, Chirivella, Isabel, Sánchez, Ana, Tena, Isabel, Chaparro, Carolina, Salas, Dolores, and López-Guerrero, José

Abstract

Table S4: Detailed classification of variants per sample. (DOCX 46 kb)

Published
2019
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17. Additional file 3: of Implementation of massive sequencing in the genetic diagnosis of hereditary cancer syndromes: diagnostic performance in the Hereditary Cancer Programme of the Valencia Community (FamCan-NGS)

Author

Ramírez-Calvo, Marta, García-Casado, Zaida, Fernández-Serra, Antonio, Juan, Inmaculada, Palanca, Sarai, Oltra, Silvestre, Soto, José, Castillejo, Adela, Barbera, Víctor M, Juan-Fita, Ma, Segura, Ángel, Chirivella, Isabel, Sánchez, Ana, Tena, Isabel, Chaparro, Carolina, Salas, Dolores, and López-Guerrero, José

Abstract

Table S3: Sequencing metrics of analyzed samples. (DOCX 45 kb)

Published
2019
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19. Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer.

Author

Torres-Esquius, Sara, Llop-Guevara, Alba, Gutiérrez-Enríquez, Sara, Romey, Marcel, Teulé, Àlex, Llort, Gemma, Herrero, Ana, Sánchez-Henarejos, Pilar, Vallmajó, Anna, González-Santiago, Santiago, Chirivella, Isabel, Cano, Juana Maria, Graña, Begoña, Simonetti, Sara, Díaz de Corcuera, Isabela, Ramon y Cajal, Teresa, Sanz, Judit, Serrano, Sara, Otero, Andrea, and Churruca, Cristina

Published
2024
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20. Biochemical markers of bone turnover and clinical outcome in patients with renal cell and bladder carcinoma with bone metastases following treatment with zoledronic acid: The TUGAMO study

Author

Alcaraz, A., González-López, Raquel, Morote, J., De La Piedra, Concepción, Meseguer, Cristina, Esteban, Emilio, Climent, Miguel Ángel, González-Gragera, B., Álvarez-Ossorio, Jose Luis, Chirivella, Isabel, Mellado, Begoña, Lara, Pedro Carlos, Vázquez, Fernando Javier, Contreras Viedma, José Antonio, Carles, Joan, Murias, Adolfo, Calderero, Verónica, Comet-Batlle, Josep, González Del Alba, Aránzazu, León Mateos, Luis A., Mañas, Ana, Segarra, José, Lassa, A., González Enguita, Carmen, Méndez, Míriam J., Samper, Pilar María, Unda, Miguel, Mahillo, Ignacio, Bellmunt, Joaquim, Contreras, José Antonio Viedma, and UAM. Departamento de Cirugía

Subjects
Oncology, Male, Cancer Research, Bone markers, humanos, fragmentos peptídicos, carcinoma, Zoledronic Acid, Bone remodeling, Renal cell carcinoma, estudios prospectivos, Medicine, Overall survival, Prospective Studies, Prospective cohort study, neoplasias de la vejiga, mediana edad, Aged, 80 and over, Univariate analysis, anciano, Bone Density Conservation Agents, Diphosphonates, resultado del tratamiento, Bladder cancer, Imidazoles, adulto, Middle Aged, Kidney Neoplasms, procolágeno, Treatment Outcome, bladder cancer, Female, Bone Remodeling, Skeletal-related events, Procollagen, medicine.drug, Adult, medicine.medical_specialty, renal cell carcinoma, Medicina, overall survival, Urinary Bladder, huesos, Bone Neoplasms, conservadores de la densidad ósea, Bone and Bones, Collagen Type I, bone markers, disease progression, N-terminal telopeptide, progresión de la enfermedad, Internal medicine, colágeno de tipo I, fosfatasa alcalina, vejiga urinaria, Carcinoma, Biomarkers, Tumor, Humans, difosfonatos, Molecular Diagnostics, Carcinoma, Renal Cell, neoplasias óseas, Aged, Disease progression, neoplasias renales, business.industry, medicine.disease, Alkaline Phosphatase, skeletal-related events, Peptide Fragments, Endocrinology, Zoledronic acid, Urinary Bladder Neoplasms, remodelación ósea, business
Abstract

Background: Levels of bone turnover markers (BTM) might be correlated with outcome in terms of skeletal-related events (SRE), disease progression, and death in patients with bladder cancer (BC) and renal cell carcinoma (RCC) with bone metastases (BM). We try to evaluate this possible correlation in patients who receive treatment with zoledronic acid (ZOL). Methods: This observational, prospective, and multicenter study analysed BTM and clinical outcome in these patients. Serum levels of bone alkaline phosphatase (BALP), procollagen type I amino-terminal propeptide (PINP), and beta-isomer of carboxyterminal telopeptide of type I collagen (beta-CTX) were analysed. Results: Patients with RCC who died or progressed had higher baseline beta-CTX levels and those who experienced SRE during follow-up showed high baseline BALP levels. In BC, a poor rate of survival was related with high baseline beta-CTX and BALP levels, and new SRE with increased PINP levels. Cox univariate analysis showed that beta-CTX levels were associated with higher mortality and disease progression in RCC and higher mortality in BC. Bone alkaline phosphatase was associated with increased risk of premature SRE appearance in RCC and death in BC. Conclusion: Beta-isomer of carboxy-terminal telopeptide of type I collagen and BALP can be considered a complementary tool for prediction of clinical outcomes in patients with BC and RCC with BM treated with ZOL., As this was a multicenter study, Adknoma Health Research (Barcelona, Spain) collected and ordered data throughout the study. We especially thank Margarida Garcia from Adknoma who followed carefully the development of the study. And we thank Novartis Oncology Spain for supporting this study.

Published
2013

21. Impact on clinical practice of the implementation of guidelines for the toxicity management of targeted therapies in kidney cancer. The protect-2 study

Author

Lainez, Nuria, primary, García-Donas, Jesús, additional, Esteban, Emilio, additional, Puente, Javier, additional, Sáez, M. Isabel, additional, Gallardo, Enrique, additional, Pinto-Marín, Álvaro, additional, Vázquez-Estévez, Sergio, additional, León, Luis, additional, García-Carbonero, Icíar, additional, Suárez-Rodríguez, Cristina, additional, Molins, Carmen, additional, Climent-Duran, Miguel A., additional, Lázaro-Quintela, Martín, additional, González del Alba, Aranzazu, additional, Méndez-Vidal, María José, additional, Chirivella, Isabel, additional, Afonso, Francisco J., additional, López-Brea, Marta, additional, Sala-González, Nuria, additional, Domenech, Montserrat, additional, Basterretxea, Laura, additional, Santander-Lobera, Carmen, additional, Gil-Arnáiz, Irene, additional, Fernández, Ovidio, additional, Caballero-Díaz, Cristina, additional, Mellado, Begoña, additional, Marrupe, David, additional, García-Sánchez, José, additional, Sánchez-Escribano, Ricardo, additional, Fernández Parra, Eva, additional, Villa Guzmán, José C., additional, Martínez-Ortega, Esther, additional, Belén González, María, additional, Morán, Marina, additional, Suarez-Paniagua, Beatriz, additional, Lecumberri, María J., additional, and Castellano, Daniel, additional

Published
2016
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22. Mammographic density and breast cancer in women from high risk families

Author

Ramón y Cajal, Teresa, primary, Chirivella, Isabel, additional, Miranda, Josefa, additional, Teule, Alexandre, additional, Izquierdo, Ángel, additional, Balmaña, Judith, additional, Sánchez-Heras, Ana Beatriz, additional, Llort, Gemma, additional, Fisas, David, additional, Lope, Virginia, additional, Hernández-Agudo, Elena, additional, Juan-Fita, María José, additional, Tena, Isabel, additional, Robles, Luis, additional, Guillén-Ponce, Carmen, additional, Pérez-Segura, Pedro, additional, Luque-Molina, Mari Sol, additional, Hernando-Polo, Susana, additional, Salinas, Mónica, additional, Brunet, Joan, additional, Salas-Trejo, María Dolores, additional, Barnadas, Agustí, additional, and Pollán, Marina, additional

Published
2015
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23. Coexistencia de dos tumores germinales seminomatoso y no seminomatoso con una presentación clínica inhabitual

Author

Soriano Sarrió, Pilar, Chirivella, Isabel, and Navarro Fos, Samuel

Subjects
Testicular malignant neoplasia, Tumor mixto germinal testicular, Neoplasia maligna testicular, Mixed germ cell tumours, Metástasis, Carcinoma embrionario testicular, Testicular embryonal carcinoma, Seminoma, Metastasis
Abstract

Objetivos: La existencia de tumores mixtos germinales no seminomatosos es un hecho frecuente en patología oncológica urológica. Sin embargo, la presencia de componente seminomatoso y no seminomatoso en un tumor germinal es una situación infrecuente. Métodos: Presentamos un caso de un seminoma puro testicular con metástasis ganglionar por carcinoma embrionario puro con un completo estudio inmunohistoquímico diferencial y evolución clínica del paciente. Resultados: Este caso corresponde a un varón de 34 años que acude a urgencias por notar una tumoración supraclavicular de 3 cm. En TAC de control se detecta adenopatías múltiples de gran tamaño a nivel supraclavicular y retroperitoneal con metástasis (M+) numerosas a nivel pulmonar, renal, hepática y suprarrenal izquierda.Siendo los marcadores tumorales negativos en sangre, se realiza una biopsia de la adenopatía supraclavicular con diagnóstico de M+ ganglionar por carcinoma embrionario de probable origen testicular. Posteriormente se realiza ecografía testicular observándose nódulo hipoecoico en teste derecho de 6mm, realizándose orquiectomía derecha cuyo estudio histopatológico revela un tumor sólido de 1cm histologicamente tipificable como seminoma clásico con extensión pagetoide a rete testes, la albugínea y el cordón espermático estaban libres de infiltración. Actualmente el paciente esta en tratamiento quimioterápico ( 2º ciclo del esquema BEP- bleomicina, etopósido, y cisplatino -). Conclusiones: El interés del caso es tanto por la presentación clínica agresiva inhabitual del este tumor así como por la revisión bibliográfica donde se abordan las posibles teorías del porque los tumores de células germinales testiculares suelen presentar diversos tipos de diferenciación así como por la posible regresión espontánea de los mismos. Objectives: The existence of non seminomatous mixed germ cell tumors of the testis is a frequent event in urologic oncology. Nevertheless, the presence of both components, seminomatous and non seminomatous, in a germ cell tumor is unusual. Methods: We present a case of pure classic seminoma of the testis with a lymph node metastasis of pure embryonal carcinoma, with confirmatory immuohistochemical study and clinical outcome of the patient. Results: A 34 year old man presented with 3 cm supraclavicular tumor. CT scan also revealed multiple metastases in lymph nodes, liver, kidney and left adrenal gland. Tumor markers were negative and the biopsy performed discovered a lymph node metastasis of embryonal carcinoma of probable testicular origin. Ultrasound revealed a 6 mm hypoechoic nodule in the right testis. Orchyectomy was performed and pathologic analysis demonstrated a tu-mor, 1 cm of diameter, histopathologically compatible with classical seminoma with pagetoid extension to rete testis. Albuginea and spermatic cord did not present neoplastic involvement. Currently the patient is being treated with chemotherapy. Conclusion: The interest of the case is to remark an unusual aggressive clinical presentation as well as to perform a bibliographic review with emphasis in the theories regarding heterogeneous differentiation and spontaneous regression of germ cell tumors of the testis.

Published
2008

24. Safety and effectiveness of vinflunine in patients with metastatic transitional cell carcinoma of the urothelial tract after failure of one platinum-based systemic therapy in clinical practice

Author

Castellano, Daniel, primary, Puente, Javier, additional, de Velasco, Guillermo, additional, Chirivella, Isabel, additional, López-Criado, Pilar, additional, Mohedano, Nicolás, additional, Fernández, Ovidio, additional, García-Carbonero, Icíar, additional, González, María Belén, additional, and Grande, Enrique, additional

Published
2014
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25. Phase I Safety, Pharmacokinetics, and Inhibition of Src Activity Study of Saracatinib in Patients with Solid Tumors

Author

Baselga, José, primary, Cervantes, Andres, additional, Martinelli, Erika, additional, Chirivella, Isabel, additional, Hoekman, Klaas, additional, Hurwitz, Herbert I., additional, Jodrell, Duncan I., additional, Hamberg, Paul, additional, Casado, Esther, additional, Elvin, Paul, additional, Swaisland, Alan, additional, Iacona, Renee, additional, and Tabernero, Josep, additional

Published
2010
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26. The Average Cumulative Risks of Breast and Ovarian Cancer for Carriers of Mutations in BRCA1 and BRCA2 Attending Genetic Counseling Units in Spain

Author

Milne, Roger L., primary, Osorio, Ana, additional, Cajal, Teresa Ramón y, additional, Vega, Ana, additional, Llort, Gemma, additional, de la Hoya, Miguel, additional, Díez, Orland, additional, Alonso, M. Carmen, additional, Lazaro, Conxi, additional, Blanco, Ignacio, additional, Sánchez-de-Abajo, Ana, additional, Caldés, Trinidad, additional, Blanco, Ana, additional, Graña, Begoña, additional, Durán, Mercedes, additional, Velasco, Eladio, additional, Chirivella, Isabel, additional, Cardeñosa, Eva Esteban, additional, Tejada, María-Isabel, additional, Beristain, Elena, additional, Miramar, María-Dolores, additional, Calvo, María-Teresa, additional, Martínez, Eduardo, additional, Guillén, Carmen, additional, Salazar, Raquel, additional, San Román, Carlos, additional, Antoniou, Antonis C., additional, Urioste, Miguel, additional, and Benítez, Javier, additional

Published
2008
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27. Mammographic density and breast cancer in women from high risk families.

Author

Cajal, Teresa Ramón y, Chirivella, Isabel, Miranda, Josefa, Teule, Alexandre, Izquierdo, Ángel, Balmaña, Judith, Sánchez-Heras, Ana Beatriz, Llort, Gemma, Fisas, David, Lope, Virginia, Hernández-Agudo, Elena, Juan-Fita, María José, Tena, Isabel, Robles, Luis, Guillén-Ponce, Carmen, Pérez-Segura, Pedro, Luque-Molina, Mari Sol, Hernando-Polo, Susana, Salinas, Mónica, and Brunet, Joan

Subjects
BREAST cancer risk factors, MAMMOGRAMS, BRCA genes, PHENOTYPES, LOGISTIC regression analysis, CONFIDENCE intervals
Abstract

Introduction: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. Methods: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (<10 %, 10-25 %, 25-50 %, 50-75 %, >75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. Results: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. Conclusions: Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context. [ABSTRACT FROM AUTHOR]

Published
2015
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28. Immunohistochemical, genetic and epigenetic profiles of hereditary and triple negative breast cancers. Relevance in personalized medicine.

Author

Murria R, Palanca S, de Juan I, Alenda C, Egoavil C, Seguí FJ, García-Casado Z, Juan MJ, Sánchez AB, Segura Á, Santaballa A, Chirivella I, Llop M, Pérez G, Barragán E, Salas D, and Bolufer P

Abstract

This study aims to identify the profile of immunohistochemical (IHC) parameters, copy number aberrations (CNAs) and epigenetic alterations [promoter methylation (PM) and miR expression] related to hereditary (H) and triple negative (TN) breast cancer (BC). This profile could be of relevance for guiding tumor response to treatment with targeting therapy. The study comprises 278 formalin fixed paraffin-embedded BCs divided into two groups: H group, including 88 hereditary BC (HBC) and 190 non hereditary (NHBC), and TN group, containing 79 TNBC and 187 non TNBC (NTNBC). We assessed IHC parameters (Ki67, ER, PR, HER2, CK5/6, CK18 and Cadherin-E), CNA of 20 BC related genes, and PM of 24 tumor suppressor genes employing MLPA/MS-MLPA (MRC Holland, Amsterdam). MiR-4417, miR-423-3p, miR-590-5p and miR-187-3p expression was assessed by quantitative RT-PCR (Applied Biosystems). Binary logistic regression was applied to select the parameters that better differentiate the HBC or TN groups. For HBC we found that, ER expression, ERBB2 CNA and PM in RASSF1 and TIMP3 were associated with NHBC whereas; MYC and AURKA CNA were linked to HBC. For TNBC, we found that CDC6 CNA, GSTP1 and RASSF1 PM and miR-423-3p hyperexpression were characteristic of NTNBC, while MYC aberrations, BRCA1 hypermethylation and miR-590-5p and miR-4417 hyperexpression were more indicative of TNBC. The selected markers allow establishing BC subtypes, which are characterized by showing similar etiopathogenetic mechanisms, some of them being molecular targets for known drugs or possible molecular targets. These results could be the basis to implement a personalized therapy.

Published
2015

29. Methylation of tumor suppressor genes is related with copy number aberrations in breast cancer.

Author

Murria R, Palanca S, de Juan I, Egoavil C, Alenda C, García-Casado Z, Juan MJ, Sánchez AB, Santaballa A, Chirivella I, Segura Á, Hervás D, Llop M, Barragán E, and Bolufer P

Abstract

This study investigates the relationship of promoter methylation in tumor suppressor genes with copy-number aberrations (CNA) and with tumor markers in breast cancer (BCs). The study includes 98 formalin fixed paraffin-embedded BCs in which promoter methylation of 24 tumour suppressor genes were assessed by Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA), CNA of 20 BC related genes by MLPA and ER, PR, HER2, CK5/6, CK18, EGFR, Cadherin-E, P53, Ki-67 and PARP expression by immunohistochemistry (IHC). Cluster analysis classed BCs in two groups according to promoter methylation percentage: the highly-methylated group (16 BCs), containing mostly hyper-methylated genes, and the sparsely-methylated group (82 BCs) with hypo-methylated genes. ATM, CDKN2A, VHL, CHFR and CDKN2B showed the greatest differences in the mean methylation percentage between these groups. We found no relationship of the IHC parameters or pathological features with methylation status, except for Catherin-E (p = 0.008). However the highly methylated BCs showed higher CNA proportion than the sparsely methylated BCs (p < 0.001, OR = 1.62; IC 95% [1.26, 2.07]). CDC6, MAPT, MED1, PRMD14 and AURKA showed the major differences in the CNA percentage between the two groups, exceeding the 22%. Methylation in RASSF1, CASP8, DAPK1 and GSTP1 conferred the highest probability of harboring CNA. Our results show a new link between promoter methylation and CNA giving support to the importance of methylation events to establish new BCs subtypes. Our findings may be also of relevance in personalized therapy assessment, which could benefit the hyper methylated BC patients group.

Published
2014

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