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Peer-reviewedCC BY 4.0Frontiers in Oncology

A predefined sulphur-handling transcriptional programme is associated with colorectal cancer molecular subtypes

  • Shaheryar Shafi1,2
  • Arslan Hamid3
  • Jiao Yang4
  • Xiaoxia Cheng5
  • Minxuan Sun1,2
5 affiliations
  1. 1School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China
  2. 2Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences
  3. 3Universitätsklinikum Bonn Medizinische Klinik und Poliklinik II
  4. 4Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University
  5. 5Department of Clinical Laboratory, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University
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Abstract

Background: Colorectal cancer (CRC) exhibits substantial metabolic and transcriptomic heterogeneity, but the relationship between sulphur-handling transcriptional programmes and consensus molecular subtypes (CMS) remains incompletely resolved.

Methods: We analysed a predefined 14-gene sulphur-handling panel across The Cancer Genome Atlas colon and rectal adenocarcinoma cohorts (TCGA-COAD/READ) and six independent HG-U133 validation cohorts ( n = 1,337 tumours). Analytical workflows integrated differential expression comparing tumours with adjacent-normal mucosa, CMS association modelling, random-effects meta-analysis, adjustment for three orthogonal tumour-purity estimators (ESTIMATE, consensus purity estimates, and ABSOLUTE), reference-based single-cell deconvolution with independent cross-atlas verification, and direction-aware therapeutic triage.

Results: Colorectal tumours demonstrated branch-specific transcriptional alterations, marked by coordinated downregulation of sulphur oxidation and clearance genes ( SQOR , ETHE1 , TST ) and of the cysteine-catabolism genes CDO1 and CTH , and selective upregulation of SLC7A11 and AHCY , whereas CBS was not significantly altered. The composite programme score differed across CMS subtypes and was consistently lower in mesenchymal CMS4 tumours than in non-CMS4 tumours across all discovery and validation series. This association remained statistically detectable after adjustment for three global tumour-purity metrics. The programme score showed no statistically detectable independent association with overall, recurrence-free, or disease-free survival. Single-cell deconvolution supported expression across epithelial, stromal, and immune compartments. Direction-aware therapeutic triage prioritised SLC7A11/xCT inhibition as an exploratory candidate for preclinical testing.

Conclusion: Sulphur-handling transcriptional architecture is reproducibly linked to CRC molecular taxonomy and is not fully explained by measured tumour purity variation, providing a computational framework for future functional and compartment-resolved investigation of sulphur metabolism in stratified CRC populations.

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Cite

BibTeXRIS
BibTeX
@article{shafi2026predefined,
  title = {{A predefined sulphur-handling transcriptional programme is associated with colorectal cancer molecular subtypes}},
  author = {Shaheryar Shafi and Arslan Hamid and Jiao Yang and Xiaoxia Cheng and Minxuan Sun},
  journal = {Frontiers in Oncology},
  year = {2026},
  month = oct,
  doi = {10.3389/fonc.2026.1976885},
  url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1976885/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A predefined sulphur-handling transcriptional programme is associated with colorectal cancer molecular subtypes
AU  - Shaheryar Shafi
AU  - Arslan Hamid
AU  - Jiao Yang
AU  - Xiaoxia Cheng
AU  - Minxuan Sun
PY  - 2026
DA  - 2026/10/16
JO  - Frontiers in Oncology
DO  - 10.3389/fonc.2026.1976885
UR  - https://www.frontiersin.org/articles/10.3389/fonc.2026.1976885/full
AB  - Background: Colorectal cancer (CRC) exhibits substantial metabolic and transcriptomic heterogeneity, but the relationship between sulphur-handling transcriptional programmes and consensus molecular subtypes (CMS) remains incompletely resolved.  Methods: We analysed a predefined 14-gene sulphur-handling panel across The Cancer Genome Atlas colon and rectal adenocarcinoma cohorts (TCGA-COAD/READ) and six independent HG-U133 validation cohorts ( n = 1,337 tumours). Analytical workflows integrated differential expression comparing tumours with adjacent-normal mucosa, CMS association modelling, random-effects meta-analysis, adjustment for three orthogonal tumour-purity estimators (ESTIMATE, consensus purity estimates, and ABSOLUTE), reference-based single-cell deconvolution with independent cross-atlas verification, and direction-aware therapeutic triage.  Results: Colorectal tumours demonstrated branch-specific transcriptional alterations, marked by coordinated downregulation of sulphur oxidation and clearance genes ( SQOR , ETHE1 , TST ) and of the cysteine-catabolism genes CDO1 and CTH , and selective upregulation of SLC7A11 and AHCY , whereas CBS was not significantly altered. The composite programme score differed across CMS subtypes and was consistently lower in mesenchymal CMS4 tumours than in non-CMS4 tumours across all discovery and validation series. This association remained statistically detectable after adjustment for three global tumour-purity metrics. The programme score showed no statistically detectable independent association with overall, recurrence-free, or disease-free survival. Single-cell deconvolution supported expression across epithelial, stromal, and immune compartments. Direction-aware therapeutic triage prioritised SLC7A11/xCT inhibition as an exploratory candidate for preclinical testing.  Conclusion: Sulphur-handling transcriptional architecture is reproducibly linked to CRC molecular taxonomy and is not fully explained by measured tumour purity variation, providing a computational framework for future functional and compartment-resolved investigation of sulphur metabolism in stratified CRC populations.
SN  - 2234-943X
ER  -