The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes
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 intra...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-10-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/20/5091 |
| _version_ | 1797515076735860736 |
|---|---|
| author | Héctor Martínez-Gregorio Ernesto Rojas-Jiménez Javier César Mejía-Gómez Clara Díaz-Velásquez Rosalía Quezada-Urban Fernando Vallejo-Lecuona Aldo de la Cruz-Montoya Fany Iris Porras-Reyes Víctor Manuel Pérez-Sánchez Héctor Aquiles Maldonado-Martínez Maybelline Robles-Estrada Enrique Bargalló-Rocha Paula Cabrera-Galeana Maritza Ramos-Ramírez Yolanda Irasema Chirino Luis Alonso Herrera Luis Ignacio Terrazas Cecilia Frecha Javier Oliver Sandra Perdomo Felipe Vaca-Paniagua |
| author_facet | Héctor Martínez-Gregorio Ernesto Rojas-Jiménez Javier César Mejía-Gómez Clara Díaz-Velásquez Rosalía Quezada-Urban Fernando Vallejo-Lecuona Aldo de la Cruz-Montoya Fany Iris Porras-Reyes Víctor Manuel Pérez-Sánchez Héctor Aquiles Maldonado-Martínez Maybelline Robles-Estrada Enrique Bargalló-Rocha Paula Cabrera-Galeana Maritza Ramos-Ramírez Yolanda Irasema Chirino Luis Alonso Herrera Luis Ignacio Terrazas Cecilia Frecha Javier Oliver Sandra Perdomo Felipe Vaca-Paniagua |
| author_sort | Héctor Martínez-Gregorio |
| collection | DOAJ |
| description | 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 <i>MCL1</i> amplifications. Metastatic lesions had deletions in <i>RB1</i> and <i>PTEN</i>, along with <i>TERT</i>, <i>AKT2</i>, and <i>CCNE1</i> 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. |
| first_indexed | 2024-03-10T06:40:29Z |
| format | Article |
| id | doaj.art-758f41e01ac44b809aa486769b1a0ffc |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T06:40:29Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-758f41e01ac44b809aa486769b1a0ffc2023-11-22T17:40:08ZengMDPI AGCancers2072-66942021-10-011320509110.3390/cancers13205091The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph NodesHéctor Martínez-Gregorio0Ernesto Rojas-Jiménez1Javier César Mejía-Gómez2Clara Díaz-Velásquez3Rosalía Quezada-Urban4Fernando Vallejo-Lecuona5Aldo de la Cruz-Montoya6Fany Iris Porras-Reyes7Víctor Manuel Pérez-Sánchez8Héctor Aquiles Maldonado-Martínez9Maybelline Robles-Estrada10Enrique Bargalló-Rocha11Paula Cabrera-Galeana12Maritza Ramos-Ramírez13Yolanda Irasema Chirino14Luis Alonso Herrera15Luis Ignacio Terrazas16Cecilia Frecha17Javier Oliver18Sandra Perdomo19Felipe Vaca-Paniagua20Posgrado en Ciencias Biológicas de la Universidad Nacional Autonóma de Mexico, Facultad de Estudios Superiores Iztacala, UNAM, Mexico City 54090, MexicoLaboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, MexicoDivision of Breast Cancer, Department of Medical Oncology, Mt. Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, CanadaLaboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, MexicoLaboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, MexicoLaboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, MexicoUnidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, MexicoInstituto Nacional de Cancerología, Mexico City 14080, MexicoInstituto Nacional de Cancerología, Mexico City 14080, MexicoInstituto Nacional de Cancerología, Mexico City 14080, MexicoHospital General de Pachuca SSA, Pachuca 42070, MexicoInstituto Nacional de Cancerología, Mexico City 14080, MexicoInstituto Nacional de Cancerología, Mexico City 14080, MexicoInstituto Nacional de Cancerología, Mexico City 14080, MexicoUnidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, MexicoInstituto Nacional de Cancerología, Mexico City 14080, MexicoLaboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, MexicoUnidad de Producción Celular del Hospital Regional Universitario de Málaga—IBIMA—Málaga, 29010 Málaga, SpainMedical Oncology Service, Hospitales Universitarios Regional y Virgen de la Victoria, Institute of Biomedical Research in Malaga, CIMES, University of Málaga, 29010 Málaga, SpainGenomic Epidemiology Branch, International Agency for Research on Cancer (IARC/WHO), 150 Cours Albert Thomas, 69372 Lyon, FranceLaboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, MexicoIn 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 <i>MCL1</i> amplifications. Metastatic lesions had deletions in <i>RB1</i> and <i>PTEN</i>, along with <i>TERT</i>, <i>AKT2</i>, and <i>CCNE1</i> 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.https://www.mdpi.com/2072-6694/13/20/5091triple-negative breast cancertumor evolutionmetastasislymph nodesearly divergencetargeted therapies |
| spellingShingle | Héctor Martínez-Gregorio Ernesto Rojas-Jiménez Javier César Mejía-Gómez Clara Díaz-Velásquez Rosalía Quezada-Urban Fernando Vallejo-Lecuona Aldo de la Cruz-Montoya Fany Iris Porras-Reyes Víctor Manuel Pérez-Sánchez Héctor Aquiles Maldonado-Martínez Maybelline Robles-Estrada Enrique Bargalló-Rocha Paula Cabrera-Galeana Maritza Ramos-Ramírez Yolanda Irasema Chirino Luis Alonso Herrera Luis Ignacio Terrazas Cecilia Frecha Javier Oliver Sandra Perdomo Felipe Vaca-Paniagua The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes Cancers triple-negative breast cancer tumor evolution metastasis lymph nodes early divergence targeted therapies |
| title | The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes |
| title_full | The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes |
| title_fullStr | The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes |
| title_full_unstemmed | The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes |
| title_short | The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes |
| title_sort | evolution of clinically aggressive triple negative breast cancer shows a large mutational diversity and early metastasis to lymph nodes |
| topic | triple-negative breast cancer tumor evolution metastasis lymph nodes early divergence targeted therapies |
| url | https://www.mdpi.com/2072-6694/13/20/5091 |
| work_keys_str_mv | AT hectormartinezgregorio theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT ernestorojasjimenez theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT javiercesarmejiagomez theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT claradiazvelasquez theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT rosaliaquezadaurban theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT fernandovallejolecuona theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT aldodelacruzmontoya theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT fanyirisporrasreyes theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT victormanuelperezsanchez theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT hectoraquilesmaldonadomartinez theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT maybellineroblesestrada theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT enriquebargallorocha theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT paulacabreragaleana theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT maritzaramosramirez theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT yolandairasemachirino theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT luisalonsoherrera theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT luisignacioterrazas theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT ceciliafrecha theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT javieroliver theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT sandraperdomo theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT felipevacapaniagua theevolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT hectormartinezgregorio evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT ernestorojasjimenez evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT javiercesarmejiagomez evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT claradiazvelasquez evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT rosaliaquezadaurban evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT fernandovallejolecuona evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT aldodelacruzmontoya evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT fanyirisporrasreyes evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT victormanuelperezsanchez evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT hectoraquilesmaldonadomartinez evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT maybellineroblesestrada evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT enriquebargallorocha evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT paulacabreragaleana evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT maritzaramosramirez evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT yolandairasemachirino evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT luisalonsoherrera evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT luisignacioterrazas evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT ceciliafrecha evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT javieroliver evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT sandraperdomo evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes AT felipevacapaniagua evolutionofclinicallyaggressivetriplenegativebreastcancershowsalargemutationaldiversityandearlymetastasistolymphnodes |