Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities

Clinical Proteomic Tumor Analysis Consortium

Research output: Contribution to journalArticle

Abstract

We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development. A systematic proteogenomic analysis of colon cancer reveals vulnerabilities of potential clinical value inaccessible from genomic assessment alone.

Original languageEnglish (US)
Pages (from-to)1035-1049.e19
JournalCell
Volume177
Issue number4
DOIs
StatePublished - May 2 2019

Fingerprint

Colonic Neoplasms
Tumors
Microsatellite Instability
Glycolysis
Neoplasms
Phosphorylation
Proteomics
Microsatellite Repeats
Therapeutics
Testicular Neoplasms
T-cells
Biomarkers
Colon
Infiltration
Proteogenomics
Apoptosis
T-Lymphocytes
Antigens
Mutation
Association reactions

Keywords

  • biomarkers
  • colon cancer
  • drug targets
  • glycolysis
  • immune evasion
  • proteogenomics
  • proteomics
  • RB1
  • SOX9
  • tumor antigen

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities. / Clinical Proteomic Tumor Analysis Consortium.

In: Cell, Vol. 177, No. 4, 02.05.2019, p. 1035-1049.e19.

Research output: Contribution to journalArticle

Clinical Proteomic Tumor Analysis Consortium 2019, 'Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities', Cell, vol. 177, no. 4, pp. 1035-1049.e19. https://doi.org/10.1016/j.cell.2019.03.030
Clinical Proteomic Tumor Analysis Consortium. / Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities. In: Cell. 2019 ; Vol. 177, No. 4. pp. 1035-1049.e19.
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