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In-depth characterization of intratumoral heterogeneity in refractory B-cell non-Hodgkin lymphoma through the lens of a Research Autopsy Program

Intratumoral heterogeneity (ITH) provides the substrate for tumor evolution and treatment resistance, yet is remarkably understudied in lymphoma, due to the often limited amount of tissue that gets sampled during the routine diagnostic process, generally from a single nodal or extranodal site. Furth...

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Autores principales: Isaev, Keren, Liu, Ting, Bakhtiari, Mehran, Tong, Kit, Goswami, Rashmi, Lam, Bernard, Lungu, Ilinca, Krzyzanowski, Paul M., Oza, Amit, Dhani, Neesha, Prica, Anca, Crump, Michael, Kridel, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827161/
https://www.ncbi.nlm.nih.gov/pubmed/35734926
http://dx.doi.org/10.3324/haematol.2022.280900
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author Isaev, Keren
Liu, Ting
Bakhtiari, Mehran
Tong, Kit
Goswami, Rashmi
Lam, Bernard
Lungu, Ilinca
Krzyzanowski, Paul M.
Oza, Amit
Dhani, Neesha
Prica, Anca
Crump, Michael
Kridel, Robert
author_facet Isaev, Keren
Liu, Ting
Bakhtiari, Mehran
Tong, Kit
Goswami, Rashmi
Lam, Bernard
Lungu, Ilinca
Krzyzanowski, Paul M.
Oza, Amit
Dhani, Neesha
Prica, Anca
Crump, Michael
Kridel, Robert
author_sort Isaev, Keren
collection PubMed
description Intratumoral heterogeneity (ITH) provides the substrate for tumor evolution and treatment resistance, yet is remarkably understudied in lymphoma, due to the often limited amount of tissue that gets sampled during the routine diagnostic process, generally from a single nodal or extranodal site. Furthermore, the trajectory of how lymphoma, and especially non-Hodgkin lymphoma, spreads throughout the human body remains poorly understood. Here, we present a detailed characterization of ITH by applying whole-genome sequencing to spatially separated tumor samples harvested at the time of autopsy (n=24) and/or diagnosis (n=3) in three patients presenting with refractory B-cell non-Hodgkin lymphoma. Through deconvolution of bulk samples into clonal mixtures and inference of phylogenetic trees, we found evidence that polyclonal seeding underlies tumor dissemination in lymphoma. We identify mutation signatures associated with ancestral and descendant clones. In our series of patients with highly refractory lymphoma, the determinants of resistance were often harbored by founding clones, although there was also evidence of positive selection of driver mutations, likely under the influence of therapy. Lastly, we show that circulating tumor DNA is suitable for the detection of ancestral mutations but may miss a significant proportion of private mutations that can be detected in tissue. Our study clearly shows the existence of intricate patterns of regional and anatomical evolution that can only be disentangled through multi-regional tumor tissue profiling.
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spelling pubmed-98271612023-01-20 In-depth characterization of intratumoral heterogeneity in refractory B-cell non-Hodgkin lymphoma through the lens of a Research Autopsy Program Isaev, Keren Liu, Ting Bakhtiari, Mehran Tong, Kit Goswami, Rashmi Lam, Bernard Lungu, Ilinca Krzyzanowski, Paul M. Oza, Amit Dhani, Neesha Prica, Anca Crump, Michael Kridel, Robert Haematologica Article - Non-Hodgkin Lymphoma Intratumoral heterogeneity (ITH) provides the substrate for tumor evolution and treatment resistance, yet is remarkably understudied in lymphoma, due to the often limited amount of tissue that gets sampled during the routine diagnostic process, generally from a single nodal or extranodal site. Furthermore, the trajectory of how lymphoma, and especially non-Hodgkin lymphoma, spreads throughout the human body remains poorly understood. Here, we present a detailed characterization of ITH by applying whole-genome sequencing to spatially separated tumor samples harvested at the time of autopsy (n=24) and/or diagnosis (n=3) in three patients presenting with refractory B-cell non-Hodgkin lymphoma. Through deconvolution of bulk samples into clonal mixtures and inference of phylogenetic trees, we found evidence that polyclonal seeding underlies tumor dissemination in lymphoma. We identify mutation signatures associated with ancestral and descendant clones. In our series of patients with highly refractory lymphoma, the determinants of resistance were often harbored by founding clones, although there was also evidence of positive selection of driver mutations, likely under the influence of therapy. Lastly, we show that circulating tumor DNA is suitable for the detection of ancestral mutations but may miss a significant proportion of private mutations that can be detected in tissue. Our study clearly shows the existence of intricate patterns of regional and anatomical evolution that can only be disentangled through multi-regional tumor tissue profiling. Fondazione Ferrata Storti 2022-06-23 /pmc/articles/PMC9827161/ /pubmed/35734926 http://dx.doi.org/10.3324/haematol.2022.280900 Text en Copyright© 2023 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article - Non-Hodgkin Lymphoma
Isaev, Keren
Liu, Ting
Bakhtiari, Mehran
Tong, Kit
Goswami, Rashmi
Lam, Bernard
Lungu, Ilinca
Krzyzanowski, Paul M.
Oza, Amit
Dhani, Neesha
Prica, Anca
Crump, Michael
Kridel, Robert
In-depth characterization of intratumoral heterogeneity in refractory B-cell non-Hodgkin lymphoma through the lens of a Research Autopsy Program
title In-depth characterization of intratumoral heterogeneity in refractory B-cell non-Hodgkin lymphoma through the lens of a Research Autopsy Program
title_full In-depth characterization of intratumoral heterogeneity in refractory B-cell non-Hodgkin lymphoma through the lens of a Research Autopsy Program
title_fullStr In-depth characterization of intratumoral heterogeneity in refractory B-cell non-Hodgkin lymphoma through the lens of a Research Autopsy Program
title_full_unstemmed In-depth characterization of intratumoral heterogeneity in refractory B-cell non-Hodgkin lymphoma through the lens of a Research Autopsy Program
title_short In-depth characterization of intratumoral heterogeneity in refractory B-cell non-Hodgkin lymphoma through the lens of a Research Autopsy Program
title_sort in-depth characterization of intratumoral heterogeneity in refractory b-cell non-hodgkin lymphoma through the lens of a research autopsy program
topic Article - Non-Hodgkin Lymphoma
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9827161/
https://www.ncbi.nlm.nih.gov/pubmed/35734926
http://dx.doi.org/10.3324/haematol.2022.280900
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