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Genomic Landscape in Neoplasm-Like Stroma Reveals Distinct Prognostic Subtypes of Pancreatic Ductal Adenocarcinoma

As a main component of the tumor microenvironment, the stroma is critical in development, progression, and metastasis of pancreatic ductal adenocarcinoma (PDAC). The genomic status and its relationship of neoplastic and stromal components remain unclear in PDAC. We performed targeted sequencing for...

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Autores principales: Jiang, Jiahong, Xu, Yaping, Chang, Lianpeng, Ru, Guoqing, Xia, Xuefeng, Yang, Ling, Yi, Xin, Chen, Zheling, Huang, Dong-Sheng, Yang, Liu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558555/
https://www.ncbi.nlm.nih.gov/pubmed/34733795
http://dx.doi.org/10.3389/fonc.2021.771247
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author Jiang, Jiahong
Xu, Yaping
Chang, Lianpeng
Ru, Guoqing
Xia, Xuefeng
Yang, Ling
Yi, Xin
Chen, Zheling
Huang, Dong-Sheng
Yang, Liu
author_facet Jiang, Jiahong
Xu, Yaping
Chang, Lianpeng
Ru, Guoqing
Xia, Xuefeng
Yang, Ling
Yi, Xin
Chen, Zheling
Huang, Dong-Sheng
Yang, Liu
author_sort Jiang, Jiahong
collection PubMed
description As a main component of the tumor microenvironment, the stroma is critical in development, progression, and metastasis of pancreatic ductal adenocarcinoma (PDAC). The genomic status and its relationship of neoplastic and stromal components remain unclear in PDAC. We performed targeted sequencing for 1,021 cancer-suspected genes on parallel microdissected stromal and neoplastic components from 50 operable PDAC patients. Clonality analysis of mutations was conducted to reconstruct the evolutionary trajectory, and then molecular subtypes were established. Multi-lineage differentiation potential and mesenchymal transformation of KRAS-mutant cell line Panc1 were evaluated using RT-PCR and immunofluorescence staining. In this study, 39 (78.0%) were genomically altered in stroma, with KRAS (71.8%), TP53 (61.5%), and CDKN2A (23.1%) as the most commonly mutated genes. The majority of stromal mutations (89.8%) were detected in matched neoplastic components. Patients with KRAS/TP53-mut stroma demonstrated a higher tumor cell fraction (TCF) than did those with wild-type (WT) stroma (p = 0.0371, p = 0.0014). In both components, mutants KRAS and TP53 often occurred as clonal events, and the allele frequencies presented linear correlation in the same specimen. All neoplasm-like stroma (characterized with all or initial neoplastic clones and driver events in stroma) harbored KRAS or TP53 mutations. Neoplasm-like and KRAS-mutant stroma was associated with shorter disease-free survival. It is a new finding for the existence of driver gene mutations in PDAC stroma. These data suggest that genomic features of stromal components may serve as prognostic biomarkers in resectable PDAC and might help to guide a more precise treatment paradigm in therapeutic options.
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spelling pubmed-85585552021-11-02 Genomic Landscape in Neoplasm-Like Stroma Reveals Distinct Prognostic Subtypes of Pancreatic Ductal Adenocarcinoma Jiang, Jiahong Xu, Yaping Chang, Lianpeng Ru, Guoqing Xia, Xuefeng Yang, Ling Yi, Xin Chen, Zheling Huang, Dong-Sheng Yang, Liu Front Oncol Oncology As a main component of the tumor microenvironment, the stroma is critical in development, progression, and metastasis of pancreatic ductal adenocarcinoma (PDAC). The genomic status and its relationship of neoplastic and stromal components remain unclear in PDAC. We performed targeted sequencing for 1,021 cancer-suspected genes on parallel microdissected stromal and neoplastic components from 50 operable PDAC patients. Clonality analysis of mutations was conducted to reconstruct the evolutionary trajectory, and then molecular subtypes were established. Multi-lineage differentiation potential and mesenchymal transformation of KRAS-mutant cell line Panc1 were evaluated using RT-PCR and immunofluorescence staining. In this study, 39 (78.0%) were genomically altered in stroma, with KRAS (71.8%), TP53 (61.5%), and CDKN2A (23.1%) as the most commonly mutated genes. The majority of stromal mutations (89.8%) were detected in matched neoplastic components. Patients with KRAS/TP53-mut stroma demonstrated a higher tumor cell fraction (TCF) than did those with wild-type (WT) stroma (p = 0.0371, p = 0.0014). In both components, mutants KRAS and TP53 often occurred as clonal events, and the allele frequencies presented linear correlation in the same specimen. All neoplasm-like stroma (characterized with all or initial neoplastic clones and driver events in stroma) harbored KRAS or TP53 mutations. Neoplasm-like and KRAS-mutant stroma was associated with shorter disease-free survival. It is a new finding for the existence of driver gene mutations in PDAC stroma. These data suggest that genomic features of stromal components may serve as prognostic biomarkers in resectable PDAC and might help to guide a more precise treatment paradigm in therapeutic options. Frontiers Media S.A. 2021-10-18 /pmc/articles/PMC8558555/ /pubmed/34733795 http://dx.doi.org/10.3389/fonc.2021.771247 Text en Copyright © 2021 Jiang, Xu, Chang, Ru, Xia, Yang, Yi, Chen, Huang and Yang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Jiang, Jiahong
Xu, Yaping
Chang, Lianpeng
Ru, Guoqing
Xia, Xuefeng
Yang, Ling
Yi, Xin
Chen, Zheling
Huang, Dong-Sheng
Yang, Liu
Genomic Landscape in Neoplasm-Like Stroma Reveals Distinct Prognostic Subtypes of Pancreatic Ductal Adenocarcinoma
title Genomic Landscape in Neoplasm-Like Stroma Reveals Distinct Prognostic Subtypes of Pancreatic Ductal Adenocarcinoma
title_full Genomic Landscape in Neoplasm-Like Stroma Reveals Distinct Prognostic Subtypes of Pancreatic Ductal Adenocarcinoma
title_fullStr Genomic Landscape in Neoplasm-Like Stroma Reveals Distinct Prognostic Subtypes of Pancreatic Ductal Adenocarcinoma
title_full_unstemmed Genomic Landscape in Neoplasm-Like Stroma Reveals Distinct Prognostic Subtypes of Pancreatic Ductal Adenocarcinoma
title_short Genomic Landscape in Neoplasm-Like Stroma Reveals Distinct Prognostic Subtypes of Pancreatic Ductal Adenocarcinoma
title_sort genomic landscape in neoplasm-like stroma reveals distinct prognostic subtypes of pancreatic ductal adenocarcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558555/
https://www.ncbi.nlm.nih.gov/pubmed/34733795
http://dx.doi.org/10.3389/fonc.2021.771247
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