Contributors: [Martinez-Gregorio, Hector] Univ Nacl Autonoma Mexico, Fac Estudios Super Iztacala, UNAM, Posgrad Ciencias Biol, Mexico City 54090, DF, Mexico; [Martinez-Gregorio, Hector] Fac Estudios Super Iztacala, Lab Nacl Salud Diagnost Mol & Efecto Ambiental En, Tlalnepantla 54090, Mexico; [Rojas-Jimenez, Ernesto] Fac Estudios Super Iztacala, Lab Nacl Salud Diagnost Mol & Efecto Ambiental En, Tlalnepantla 54090, Mexico; [Diaz-Velasquez, Clara] Fac Estudios Super Iztacala, Lab Nacl Salud Diagnost Mol & Efecto Ambiental En, Tlalnepantla 54090, Mexico; [Quezada-Urban, Rosalia] Fac Estudios Super Iztacala, Lab Nacl Salud Diagnost Mol & Efecto Ambiental En, Tlalnepantla 54090, Mexico; [Vallejo-Lecuona, Fernando] Fac Estudios Super Iztacala, Lab Nacl Salud Diagnost Mol & Efecto Ambiental En, Tlalnepantla 54090, Mexico; [Ignacio Terrazas, Luis] Fac Estudios Super Iztacala, Lab Nacl Salud Diagnost Mol & Efecto Ambiental En, Tlalnepantla 54090, Mexico; [Vaca-Paniagua, Felipe] Fac Estudios Super Iztacala, Lab Nacl Salud Diagnost Mol & Efecto Ambiental En, Tlalnepantla 54090, Mexico; [Martinez-Gregorio, Hector] UNAM, Unidad Biomed, Fac Estudios Super Iztacala, Tlalnepantla 54090, Mexico; [Rojas-Jimenez, Ernesto] UNAM, Unidad Biomed, Fac Estudios Super Iztacala, Tlalnepantla 54090, Mexico; [Quezada-Urban, Rosalia] UNAM, Unidad Biomed, Fac Estudios Super Iztacala, Tlalnepantla 54090, Mexico; [Vallejo-Lecuona, Fernando] UNAM, Unidad Biomed, Fac Estudios Super Iztacala, Tlalnepantla 54090, Mexico; [de la Cruz-Montoya, Aldo] UNAM, Unidad Biomed, Fac Estudios Super Iztacala, Tlalnepantla 54090, Mexico; [Irasema Chirino, Yolanda] UNAM, Unidad Biomed, Fac Estudios Super Iztacala, Tlalnepantla 54090, Mexico; [Ignacio Terrazas, Luis] UNAM, Unidad Biomed, Fac Estudios Super Iztacala, Tlalnepantla 54090, Mexico; [Vaca-Paniagua, Felipe] UNAM, Unidad Biomed, Fac Estudios Super Iztacala, Tlalnepantla 54090, Mexico; [Cesar Mejia-Gomez, Javier] Univ Toronto, Mt Sinai Hosp, Dept Med Oncol, Div Breast Canc, Toronto, ON M5G 1X5, Canada; [Quezada-Urban, Rosalia] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3000, Australia; [Quezada-Urban, Rosalia] Peter MacCallum Canc Ctr, Canc Res Div, Melbourne, Vic 3000, Australia; [Iris Porras-Reyes, Fany] Inst Nacl Cancerol, Mexico City 14080, DF, Mexico; [Manuel Perez-Sanchez, Victor] Inst Nacl Cancerol, Mexico City 14080, DF, Mexico; [Aquiles Maldonado-Martinez, Hector] Inst Nacl Cancerol, Mexico City 14080, DF, Mexico; [Bargallo-Rocha, Enrique] Inst Nacl Cancerol, Mexico City 14080, DF, Mexico; [Cabrera-Galeana, Paula] Inst Nacl Cancerol, Mexico City 14080, DF, Mexico; [Ramos-Ramirez, Maritza] Inst Nacl Cancerol, Mexico City 14080, DF, Mexico; [Alonso Herrera, Luis] Inst Nacl Cancerol, Mexico City 14080, DF, Mexico; [Vaca-Paniagua, Felipe] Inst Nacl Cancerol, Mexico City 14080, DF, Mexico; [Robles-Estrada, Maybelline] Hosp Gen Pachuca SSA, Pachuca 42070, Hidalgo, Mexico; [Alonso Herrera, Luis] Inst Nacl Med Genom, Mexico City 14610, DF, Mexico; [Alonso Herrera, Luis] Inst Nacl Cancerol, Inst Invest Biomed, Unidad Invest Biomed Canc, Mexico City 14080, DF, Mexico; [Frecha, Cecilia] Hosp Reg Univ Malaga IBIMA Malaga, Unidad Prod Celular, Malaga 29010, Spain; [Oliver, Javier] Univ Malaga, Hosp Univ Reg & Virgen Victoria, Inst Biomed Res Malaga, Med Oncol Serv,CIMES, Malaga 29010, Spain; [Perdomo, Sandra] Int Agcy Res Canc IARC WHO, Genom Epidemiol Branch, 150 Cours Albert Thomas, F-69372 Lyon, France; UNAM PAPIIT; CONACyT Fondo Sectorial; Fondo SEP CONACyT; CONACYT National Laboratories 2021 project
نبذة مختصرة : 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.
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