Identification of unique rectal cancer-specific subtypes.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
26 Mar 2024
26 Mar 2024
Historique:
received:
03
11
2023
accepted:
08
03
2024
revised:
05
03
2024
medline:
27
3
2024
pubmed:
27
3
2024
entrez:
27
3
2024
Statut:
aheadofprint
Résumé
Existing colorectal cancer subtyping methods were generated without much consideration of potential differences in expression profiles between colon and rectal tissues. Moreover, locally advanced rectal cancers at resection often have received neoadjuvant chemoradiotherapy which likely has a significant impact on gene expression. We collected mRNA expression profiles for rectal and colon cancer samples (n = 2121). We observed that (i) Consensus Molecular Subtyping (CMS) had a different prognosis in treatment-naïve rectal vs. colon cancers, and (ii) that neoadjuvant chemoradiotherapy exposure produced a strong shift in CMS subtypes in rectal cancers. We therefore clustered 182 untreated rectal cancers to find rectal cancer-specific subtypes (RSSs). We identified three robust subtypes. We observed that RSS1 had better, and RSS2 had worse disease-free survival. RSS1 showed high expression of MYC target genes and low activity of angiogenesis genes. RSS2 exhibited low regulatory T cell abundance, strong EMT and angiogenesis signalling, and high activation of TGF-β, NF-κB, and TNF-α signalling. RSS3 was characterised by the deactivation of EGFR, MAPK and WNT pathways. We conclude that RSS subtyping allows for more accurate prognosis predictions in rectal cancers than CMS subtyping and provides new insight into targetable disease pathways within these subtypes.
Sections du résumé
BACKGROUND
BACKGROUND
Existing colorectal cancer subtyping methods were generated without much consideration of potential differences in expression profiles between colon and rectal tissues. Moreover, locally advanced rectal cancers at resection often have received neoadjuvant chemoradiotherapy which likely has a significant impact on gene expression.
METHODS
METHODS
We collected mRNA expression profiles for rectal and colon cancer samples (n = 2121). We observed that (i) Consensus Molecular Subtyping (CMS) had a different prognosis in treatment-naïve rectal vs. colon cancers, and (ii) that neoadjuvant chemoradiotherapy exposure produced a strong shift in CMS subtypes in rectal cancers. We therefore clustered 182 untreated rectal cancers to find rectal cancer-specific subtypes (RSSs).
RESULTS
RESULTS
We identified three robust subtypes. We observed that RSS1 had better, and RSS2 had worse disease-free survival. RSS1 showed high expression of MYC target genes and low activity of angiogenesis genes. RSS2 exhibited low regulatory T cell abundance, strong EMT and angiogenesis signalling, and high activation of TGF-β, NF-κB, and TNF-α signalling. RSS3 was characterised by the deactivation of EGFR, MAPK and WNT pathways.
CONCLUSIONS
CONCLUSIONS
We conclude that RSS subtyping allows for more accurate prognosis predictions in rectal cancers than CMS subtyping and provides new insight into targetable disease pathways within these subtypes.
Identifiants
pubmed: 38532103
doi: 10.1038/s41416-024-02656-0
pii: 10.1038/s41416-024-02656-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Science Foundation Ireland (SFI)
ID : 16/US/3301
Organisme : Science Foundation Ireland (SFI)
ID : 18/CRT/6214
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions)
ID : H2020-MSCA-COFUND-2019-945385
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA208179
Organisme : PHA | Health and Social Care Research and Development Division (HCS R&D)
ID : STL/5715/15
Informations de copyright
© 2024. The Author(s).
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