Distinct Molecular Phenotype of Sporadic Colorectal Cancers Among Young Patients Based on Multiomics Analysis

Andreana N Holowatyj, Biljana Gigic, Esther Herpel, Augustin Scalbert, Martin Schneider, Cornelia M Ulrich, MetaboCCC Consortium, ColoCare Study, David Achaintre, Stefanie Brezina, Franzel J B van Duijnhoven, Andrea Gsur, Pekka Keski-Rahkonen, Matty P Weijenberg, Clare Abbenhardt-Martin, Juergen Boehm, Kenneth Boucher, Nina Habermann, Mariam Haffa, Sheetal Hardikar, Caroline Himbert, Hans-Ulrich Kauczor, Matthias Kloor, Paul D Lampe, Tengda Lin, Jennifer Ose, Dominique Scherer, Peter Schirmacher, Petra Schrotz-King, Magnus von Knebel-Doeberitz, Christy A Warby, Yuzheng Zhang, Alexis B Ulrich, Eric A Swanson, Sean V Tavtigian, Andreana N Holowatyj, Biljana Gigic, Esther Herpel, Augustin Scalbert, Martin Schneider, Cornelia M Ulrich, MetaboCCC Consortium, ColoCare Study, David Achaintre, Stefanie Brezina, Franzel J B van Duijnhoven, Andrea Gsur, Pekka Keski-Rahkonen, Matty P Weijenberg, Clare Abbenhardt-Martin, Juergen Boehm, Kenneth Boucher, Nina Habermann, Mariam Haffa, Sheetal Hardikar, Caroline Himbert, Hans-Ulrich Kauczor, Matthias Kloor, Paul D Lampe, Tengda Lin, Jennifer Ose, Dominique Scherer, Peter Schirmacher, Petra Schrotz-King, Magnus von Knebel-Doeberitz, Christy A Warby, Yuzheng Zhang, Alexis B Ulrich, Eric A Swanson, Sean V Tavtigian

No abstract available

Keywords: Colorectal Cancer; Early-Onset; Sporadic; Young-Onset.

Conflict of interest statement

Declaration of Interests

The authors declare no conflicts of interest with this work. C.M.U. has as cancer center director oversight over research funded by several pharmaceutical companies, but has not received funding directly herself.

Figures

Fig.1.. Imbalanced redox status is a distinct molecular hallmark of sporadic colorectal cancer among young patients (diagnosed before age 50 years).

(A) Alterations in NRF2-mediated oxidative stress response may play a distinct role in young-onset sporadic colorectal carcinogenesis. Ingenuity Pathway Analysis results of molecular pathways enriched in the n=312 genes differentially expressed (∣FC∣>1.5; FDR[β1]<0.05) in colorectal tumor tissues of young patients that also demonstrated a significant interaction effect between colorectal tumor tissue and age (FDR[β1intersect; β3intersect]<0.05) after adjustment for patient sex, tumor site and stage. Top ten canonical pathways are ranked by P-value. NRF2, nuclear factor (erythroid-derived 2)-like 2. (B) Integrated tissue transcriptomics and plasma metabolomics analysis reveals systemic imbalance in glutathione metabolism. Over-representation analysis results of joint gene-metabolite pathways for the significant gene (n=312 genes from transcriptomic analysis) and metabolite (n=35 metabolites from metabolomics analysis) set. Hypergeometric testing conducted using MetaboAnalyst version 4.0 software. Node color based on P-value and node radius determined based on impact values from pathway topology analysis. (C) Plasma proteome profiles do not distinguish young-onset versus older-onset sporadic colorectal cancer patients. Volcano plot of plasma proteomic differences between young-onset and older-onset colorectal cancer patient case signals for each antibody, adjusted for patient sex, tumor stage and site. Dashed line indicates P=0.05. Proteins displaying differences at P<0.05 (n=206) are indicated by grey circles. (D) Serum inflammatory biomarker profile corroborates imbalanced redox status as distinct molecular phenotype in patients with young-onset microsatellite stable colorectal cancers. Systemic inflammation biomarker levels measured in patient sera associated with differential expression levels between young-onset versus older-onset (referent) colorectal cancer patients, adjusted for patient sex, tumor site and stage, and body mass index. Biomarkers displaying differences at FDR<0.05 are marked with asterisks. CRP, C-reactive protein; CXCL12/SDF1a, CXC-motif chemokine 12/stromal cell-derived factor 1a; IL-6, interleukin-6; IL-8/CXCL8, interleukin-8/CXC-motif chemokine 8; MCP1/CCL2, monocyte chemoattractant protein-1; SAA, serum amyloid a; sICAM-1/CD54, soluble intercellular adhesion molecule 1/cluster of differentiation 54; sVCAM-1/CD106, soluble vascular adhesion molecule 1/cluster of differentiation 106; TNF-a, tumor-necrosis factor-a.