The evolution of clinically aggressive triple-negative breast cancer shows a large mutational diversity and early metastasis to lymph nodes
Por:
Martínez-Gregorio H., Rojas-Jiménez E., Mejía-Gómez J.C., Díaz-Velásquez C., Quezada-Urban R., Vallejo-Lecuona F., de la Cruz-Montoya A., Porras-Reyes F.I., Pérez-Sánchez V.M., Maldonado-Martínez H.A., Robles-Estrada M., Bargalló-Rocha E., Cabrera-Galeana P., Ramos-Ramírez M., Chirino Y.I., Herrera L.A., Terrazas L.I., Frecha C., Oliver J., Perdomo S., Vaca-Paniagua F.
Publicada:
1 ene 2021
Resumen:
In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemotherapy achieve a pathological complete response after treatment and more than 90% die due to metastasis formation. The diverse clinical responses and metastatic developments are attributed to extensive intrapatient genetic heterogeneity and tumor evolution acting on this neoplasm. In this work, we aimed to evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease. We sequenced the whole exome of 16 lesions from four patients who did not respond to therapy, and took several follow-up samples, including samples from tumors before and after treatment, as well as from the lymph nodes and skin metastases. We found substantial intrapatient genetic heterogeneity, with a variable tumor mutational composition. Early truncal events were MCL1 amplifications. Metastatic lesions had deletions in RB1 and PTEN, along with TERT, AKT2, and CCNE1 amplifications. Mutational signatures 06 and 12 were mainly detected in skin metastases and lymph nodes. According to phylogenetic analysis, the lymph node metastases occurred at an early stage of TNBC development. Finally, each patient had three to eight candidate driving mutations for targeted treatments. This study delves into the genomic complexity and the phylogenetic and evolutionary development of aggressive TNBC, supporting early metastatic development, and identifies specific genetic alterations associated with a response to targeted therapies. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Filiaciones:
Martínez-Gregorio H.:
Posgrado en Ciencias Biológicas de la Universidad Nacional Autonóma de Mexico, Facultad de Estudios Superiores Iztacala, UNAM, Mexico City, 54090, Mexico
Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, 54090, Mexico
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, 54090, Mexico
Rojas-Jiménez E.:
Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, 54090, Mexico
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, 54090, Mexico
Mejía-Gómez J.C.:
Division of Breast Cancer, Department of Medical Oncology, Mt. Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada
Díaz-Velásquez C.:
Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, 54090, Mexico
Quezada-Urban R.:
Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, 54090, Mexico
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, 54090, Mexico
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3000, Australia
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
Vallejo-Lecuona F.:
Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, 54090, Mexico
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, 54090, Mexico
de la Cruz-Montoya A.:
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, 54090, Mexico
Porras-Reyes F.I.:
Instituto Nacional de Cancerología, Mexico City, 14080, Mexico
Pérez-Sánchez V.M.:
Instituto Nacional de Cancerología, Mexico City, 14080, Mexico
Maldonado-Martínez H.A.:
Instituto Nacional de Cancerología, Mexico City, 14080, Mexico
Robles-Estrada M.:
Hospital General de Pachuca SSA, Pachuca, 42070, Mexico
Bargalló-Rocha E.:
Instituto Nacional de Cancerología, Mexico City, 14080, Mexico
Cabrera-Galeana P.:
Instituto Nacional de Cancerología, Mexico City, 14080, Mexico
Ramos-Ramírez M.:
Instituto Nacional de Cancerología, Mexico City, 14080, Mexico
Chirino Y.I.:
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, 54090, Mexico
Herrera L.A.:
Instituto Nacional de Cancerología, Mexico City, 14080, Mexico
Instituto Nacional de Medicina Genómica, Mexico City, 14610, Mexico
Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas—Instituto Nacional de Cancerología, Mexico City, 14080, Mexico
Terrazas L.I.:
Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, 54090, Mexico
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, 54090, Mexico
Frecha C.:
Unidad de Producción Celular del Hospital Regional Universitario de Málaga—IBIMA—Málaga, Málaga, 29010, Spain
Oliver J.:
Medical Oncology Service, Hospitales Universitarios Regional y Virgen de la Victoria, Institute of Biomedical Research in Malaga, CIMES, University of Málaga, Málaga, 29010, Spain
Perdomo S.:
Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), 150 Cours Albert Thomas, Lyon, 69372, France
Vaca-Paniagua F.:
Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla, 54090, Mexico
Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, 54090, Mexico
Instituto Nacional de Cancerología, Mexico City, 14080, Mexico
Green Published, gold, All Open Access, Gold, Green
|