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Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer.

Publication ,  Journal Article
Dienstmann, R; Villacampa, G; Sveen, A; Mason, MJ; Niedzwiecki, D; Nesbakken, A; Moreno, V; Warren, RS; Lothe, RA; Guinney, J
Published in: Ann Oncol
October 1, 2019

BACKGROUND: It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor-node-metastasis (TNM) staging and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC). PATIENTS AND METHODS: We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological [ClinPath], genomics [Gen: MSI, BRAF and KRAS mutations], CMS scores [CMS] and microenvironment cells [MicroCells: CytoLym+CAF]). RESULTS: In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata [HR=0.71 (0.6-0.9); P = 0.004]. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04). CONCLUSIONS: Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns.

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Published In

Ann Oncol

DOI

EISSN

1569-8041

Publication Date

October 1, 2019

Volume

30

Issue

10

Start / End Page

1622 / 1629

Location

England

Related Subject Headings

  • Young Adult
  • Tumor Microenvironment
  • Transcriptome
  • Survival Rate
  • Retrospective Studies
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Mutation
  • Middle Aged
 

Citation

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Dienstmann, R., Villacampa, G., Sveen, A., Mason, M. J., Niedzwiecki, D., Nesbakken, A., … Guinney, J. (2019). Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer. Ann Oncol, 30(10), 1622–1629. https://doi.org/10.1093/annonc/mdz287
Dienstmann, R., G. Villacampa, A. Sveen, M. J. Mason, D. Niedzwiecki, A. Nesbakken, V. Moreno, R. S. Warren, R. A. Lothe, and J. Guinney. “Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer.Ann Oncol 30, no. 10 (October 1, 2019): 1622–29. https://doi.org/10.1093/annonc/mdz287.
Dienstmann R, Villacampa G, Sveen A, Mason MJ, Niedzwiecki D, Nesbakken A, Moreno V, Warren RS, Lothe RA, Guinney J. Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer. Ann Oncol. 2019 Oct 1;30(10):1622–1629.
Journal cover image

Published In

Ann Oncol

DOI

EISSN

1569-8041

Publication Date

October 1, 2019

Volume

30

Issue

10

Start / End Page

1622 / 1629

Location

England

Related Subject Headings

  • Young Adult
  • Tumor Microenvironment
  • Transcriptome
  • Survival Rate
  • Retrospective Studies
  • Prognosis
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Mutation
  • Middle Aged