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Transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme B

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with a 5% 5-year survival rate for metastatic disease, yet with limited therapeutic advancements due to insufficient understanding of and inability to accurately capture high-risk CRC patients who are most likely to rec...

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Autores principales: Daemen, Anneleen, Udyavar, Akshata R., Sandmann, Thomas, Li, Congfen, Bosch, Linda J. W., O’Gorman, William, Li, Yijin, Au-Yeung, Amelia, Takahashi, Chikara, Kabbarah, Omar, Bourgon, Richard, Hegde, Priti, Bais, Carlos, Das Thakur, Meghna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719661/
https://www.ncbi.nlm.nih.gov/pubmed/34972191
http://dx.doi.org/10.1371/journal.pone.0262198
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author Daemen, Anneleen
Udyavar, Akshata R.
Sandmann, Thomas
Li, Congfen
Bosch, Linda J. W.
O’Gorman, William
Li, Yijin
Au-Yeung, Amelia
Takahashi, Chikara
Kabbarah, Omar
Bourgon, Richard
Hegde, Priti
Bais, Carlos
Das Thakur, Meghna
author_facet Daemen, Anneleen
Udyavar, Akshata R.
Sandmann, Thomas
Li, Congfen
Bosch, Linda J. W.
O’Gorman, William
Li, Yijin
Au-Yeung, Amelia
Takahashi, Chikara
Kabbarah, Omar
Bourgon, Richard
Hegde, Priti
Bais, Carlos
Das Thakur, Meghna
author_sort Daemen, Anneleen
collection PubMed
description BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with a 5% 5-year survival rate for metastatic disease, yet with limited therapeutic advancements due to insufficient understanding of and inability to accurately capture high-risk CRC patients who are most likely to recur. We aimed to improve high-risk classification by identifying biological pathways associated with outcome in adjuvant stage II/III CRC. METHODS AND FINDINGS: We included 1062 patients with stage III or high-risk stage II colon carcinoma from the prospective three-arm randomized phase 3 AVANT trial, and performed expression profiling to identify a prognostic signature. Data from validation cohort GSE39582, The Cancer Genome Atlas, and cell lines were used to further validate the prognostic biology. Our retrospective analysis of the adjuvant AVANT trial uncovered a prognostic signature capturing three biological functions—stromal, proliferative and immune—that outperformed the Consensus Molecular Subtypes (CMS) and recurrence prediction signatures like Oncotype Dx in an independent cohort. Importantly, within the immune component, high granzyme B (GZMB) expression had a significant prognostic impact while other individual T-effector genes were less or not prognostic. In addition, we found GZMB to be endogenously expressed in CMS2 tumor cells and to be prognostic in a T cell independent fashion. A limitation of our study is that these results, although robust and derived from a large dataset, still need to be clinically validated in a prospective study. CONCLUSIONS: This work furthers our understanding of the underlying biology that propagates stage II/III CRC disease progression and provides scientific rationale for future high-risk stratification and targeted treatment evaluation in biomarker defined subpopulations of resectable high-risk CRC. Our results also shed light on an alternative GZMB source with context-specific implications on the disease’s unique biology.
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spelling pubmed-87196612022-01-01 Transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme B Daemen, Anneleen Udyavar, Akshata R. Sandmann, Thomas Li, Congfen Bosch, Linda J. W. O’Gorman, William Li, Yijin Au-Yeung, Amelia Takahashi, Chikara Kabbarah, Omar Bourgon, Richard Hegde, Priti Bais, Carlos Das Thakur, Meghna PLoS One Research Article BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with a 5% 5-year survival rate for metastatic disease, yet with limited therapeutic advancements due to insufficient understanding of and inability to accurately capture high-risk CRC patients who are most likely to recur. We aimed to improve high-risk classification by identifying biological pathways associated with outcome in adjuvant stage II/III CRC. METHODS AND FINDINGS: We included 1062 patients with stage III or high-risk stage II colon carcinoma from the prospective three-arm randomized phase 3 AVANT trial, and performed expression profiling to identify a prognostic signature. Data from validation cohort GSE39582, The Cancer Genome Atlas, and cell lines were used to further validate the prognostic biology. Our retrospective analysis of the adjuvant AVANT trial uncovered a prognostic signature capturing three biological functions—stromal, proliferative and immune—that outperformed the Consensus Molecular Subtypes (CMS) and recurrence prediction signatures like Oncotype Dx in an independent cohort. Importantly, within the immune component, high granzyme B (GZMB) expression had a significant prognostic impact while other individual T-effector genes were less or not prognostic. In addition, we found GZMB to be endogenously expressed in CMS2 tumor cells and to be prognostic in a T cell independent fashion. A limitation of our study is that these results, although robust and derived from a large dataset, still need to be clinically validated in a prospective study. CONCLUSIONS: This work furthers our understanding of the underlying biology that propagates stage II/III CRC disease progression and provides scientific rationale for future high-risk stratification and targeted treatment evaluation in biomarker defined subpopulations of resectable high-risk CRC. Our results also shed light on an alternative GZMB source with context-specific implications on the disease’s unique biology. Public Library of Science 2021-12-31 /pmc/articles/PMC8719661/ /pubmed/34972191 http://dx.doi.org/10.1371/journal.pone.0262198 Text en © 2021 Daemen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Daemen, Anneleen
Udyavar, Akshata R.
Sandmann, Thomas
Li, Congfen
Bosch, Linda J. W.
O’Gorman, William
Li, Yijin
Au-Yeung, Amelia
Takahashi, Chikara
Kabbarah, Omar
Bourgon, Richard
Hegde, Priti
Bais, Carlos
Das Thakur, Meghna
Transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme B
title Transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme B
title_full Transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme B
title_fullStr Transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme B
title_full_unstemmed Transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme B
title_short Transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme B
title_sort transcriptomic profiling of adjuvant colorectal cancer identifies three key prognostic biological processes and a disease specific role for granzyme b
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719661/
https://www.ncbi.nlm.nih.gov/pubmed/34972191
http://dx.doi.org/10.1371/journal.pone.0262198
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