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Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma

Lung adenocarcinoma (LUAD) usually contains heterogeneous histological subtypes, among which the micropapillary (MIP) subtype was associated with poor prognosis while the lepidic (LEP) subtype possessed the most favorable outcome. However, the genomic features of the MIP subtype responsible for its...

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Autores principales: Huo, Yansong, Sun, Leina, Yuan, Jie, Zhang, Hua, Zhang, Zhenfa, Zhang, Lianmin, Huang, Wuhao, Sun, Xiaoyan, Tang, Zhe, Feng, Yingnan, Mo, Huilan, Yang, Zuoquan, Zhang, Chao, Yu, Zicheng, Yue, Dongsheng, Zhang, Bin, Wang, Changli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381833/
https://www.ncbi.nlm.nih.gov/pubmed/35992814
http://dx.doi.org/10.3389/fonc.2022.931209
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author Huo, Yansong
Sun, Leina
Yuan, Jie
Zhang, Hua
Zhang, Zhenfa
Zhang, Lianmin
Huang, Wuhao
Sun, Xiaoyan
Tang, Zhe
Feng, Yingnan
Mo, Huilan
Yang, Zuoquan
Zhang, Chao
Yu, Zicheng
Yue, Dongsheng
Zhang, Bin
Wang, Changli
author_facet Huo, Yansong
Sun, Leina
Yuan, Jie
Zhang, Hua
Zhang, Zhenfa
Zhang, Lianmin
Huang, Wuhao
Sun, Xiaoyan
Tang, Zhe
Feng, Yingnan
Mo, Huilan
Yang, Zuoquan
Zhang, Chao
Yu, Zicheng
Yue, Dongsheng
Zhang, Bin
Wang, Changli
author_sort Huo, Yansong
collection PubMed
description Lung adenocarcinoma (LUAD) usually contains heterogeneous histological subtypes, among which the micropapillary (MIP) subtype was associated with poor prognosis while the lepidic (LEP) subtype possessed the most favorable outcome. However, the genomic features of the MIP subtype responsible for its malignant behaviors are substantially unknown. In this study, eight FFPE samples from LUAD patients were micro-dissected to isolate MIP and LEP components, then sequenced by whole-exome sequencing. More comprehensive analyses involving our samples and public validation cohorts on the two subtypes were performed to better decipher the key biological and evolutionary mechanisms. As expected, the LEP and MIP subtypes exhibited the largest disease-free survival (DFS) differences in our patients. EGFR was found with the highest mutation frequency. Additionally, shared mutations were observed between paired LEP and MIP components from single patients, and recurrent mutations were verified in the Lung-Broad, Lung-OncoSG, and TCGA-LUAD cohorts. Distinct biological processes or pathways were involved in the evolution of the two components. Besides, analyses of copy number variation (CNV) and intratumor heterogeneity (ITH) further discovered the possible immunosurveillance escape, the discrepancy between mutation and CNV level, ITH, and the pervasive DNA damage response and WNT pathway gene alternations in the MIP component. Phylogenetic analysis of five pairs of LEP and MIP components further confirmed the presence of ancestral EGFR mutations. Through comprehensive analyses combining our samples and public cohorts, PTP4A3, NAPRT, and RECQL4 were identified to be co-amplified. Multi-omics data also demonstrated the immunosuppression prevalence in the MIP component. Our results uncovered the evolutionary pattern of the concomitant LEP and MIP components from the same patient that they were derived from the same initiation cells and the pathway-specific mutations acquired after EGFR clonal mutation could shape the subtype-specificity. We also confirmed the immunosuppression prevalence in the MIP subtype by multi-omics data analyses, which may have resulted in its unfavorable prognosis.
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spelling pubmed-93818332022-08-18 Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma Huo, Yansong Sun, Leina Yuan, Jie Zhang, Hua Zhang, Zhenfa Zhang, Lianmin Huang, Wuhao Sun, Xiaoyan Tang, Zhe Feng, Yingnan Mo, Huilan Yang, Zuoquan Zhang, Chao Yu, Zicheng Yue, Dongsheng Zhang, Bin Wang, Changli Front Oncol Oncology Lung adenocarcinoma (LUAD) usually contains heterogeneous histological subtypes, among which the micropapillary (MIP) subtype was associated with poor prognosis while the lepidic (LEP) subtype possessed the most favorable outcome. However, the genomic features of the MIP subtype responsible for its malignant behaviors are substantially unknown. In this study, eight FFPE samples from LUAD patients were micro-dissected to isolate MIP and LEP components, then sequenced by whole-exome sequencing. More comprehensive analyses involving our samples and public validation cohorts on the two subtypes were performed to better decipher the key biological and evolutionary mechanisms. As expected, the LEP and MIP subtypes exhibited the largest disease-free survival (DFS) differences in our patients. EGFR was found with the highest mutation frequency. Additionally, shared mutations were observed between paired LEP and MIP components from single patients, and recurrent mutations were verified in the Lung-Broad, Lung-OncoSG, and TCGA-LUAD cohorts. Distinct biological processes or pathways were involved in the evolution of the two components. Besides, analyses of copy number variation (CNV) and intratumor heterogeneity (ITH) further discovered the possible immunosurveillance escape, the discrepancy between mutation and CNV level, ITH, and the pervasive DNA damage response and WNT pathway gene alternations in the MIP component. Phylogenetic analysis of five pairs of LEP and MIP components further confirmed the presence of ancestral EGFR mutations. Through comprehensive analyses combining our samples and public cohorts, PTP4A3, NAPRT, and RECQL4 were identified to be co-amplified. Multi-omics data also demonstrated the immunosuppression prevalence in the MIP component. Our results uncovered the evolutionary pattern of the concomitant LEP and MIP components from the same patient that they were derived from the same initiation cells and the pathway-specific mutations acquired after EGFR clonal mutation could shape the subtype-specificity. We also confirmed the immunosuppression prevalence in the MIP subtype by multi-omics data analyses, which may have resulted in its unfavorable prognosis. Frontiers Media S.A. 2022-08-03 /pmc/articles/PMC9381833/ /pubmed/35992814 http://dx.doi.org/10.3389/fonc.2022.931209 Text en Copyright © 2022 Huo, Sun, Yuan, Zhang, Zhang, Zhang, Huang, Sun, Tang, Feng, Mo, Yang, Zhang, Yu, Yue, Zhang and Wang 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
Huo, Yansong
Sun, Leina
Yuan, Jie
Zhang, Hua
Zhang, Zhenfa
Zhang, Lianmin
Huang, Wuhao
Sun, Xiaoyan
Tang, Zhe
Feng, Yingnan
Mo, Huilan
Yang, Zuoquan
Zhang, Chao
Yu, Zicheng
Yue, Dongsheng
Zhang, Bin
Wang, Changli
Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma
title Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma
title_full Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma
title_fullStr Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma
title_full_unstemmed Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma
title_short Comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma
title_sort comprehensive analyses unveil novel genomic and immunological characteristics of micropapillary pattern in lung adenocarcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381833/
https://www.ncbi.nlm.nih.gov/pubmed/35992814
http://dx.doi.org/10.3389/fonc.2022.931209
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