A Clinically Applicable Gene-Expression Classifier Reveals Intrinsic and Extrinsic Contributions to Consensus Molecular Subtypes in Primary and Metastatic Colon Cancer.

Abstract

PURPOSE:

Four consensus molecular subtypes (CMS1-4) of colorectal cancer were identified in primary tumors and found to be associated with distinctive biological features and clinical outcomes. Given that distant metastasis largely accounts for colorectal cancer-related mortality, we examined the molecular and clinical attributes of CMS in metastatic colorectal cancer (mCRC).

EXPERIMENTAL DESIGN:

We developed a colorectal cancer-focused NanoString-based CMS classifier that is ideally suited to interrogate archival tissues. We successfully used this panel in the CMS classification of formalin-fixed paraffin-embedded (FFPE) tissues from mCRC cohorts, one of which is composed of paired primary tumors and metastases. Finally, we developed novel mouse implantation models to enable modeling of colorectal cancer in vivo at relevant sites.

RESULTS:

Using our classifier, we find that the biological hallmarks of mCRC, including CMS, are in general highly similar to those observed in nonmetastatic early-stage disease. Importantly, our data demonstrate that CMS1 has the worst outcome in relapsed disease, compared with other CMS. Assigning CMS to primary tumors and their matched metastases reveals mostly concordant subtypes between primary and metastasis. Molecular analysis of matched discordant pairs reveals differences in stromal composition at each site. The development of two novel in vivo orthotopic implantation models further reinforces the notion that extrinsic factors may impact on CMS identification in matched primary and metastatic colorectal cancer.

CONCLUSIONS:

We describe the utility of a NanoString panel for CMS classification of FFPE clinical samples. Our work reveals the impact of intrinsic and extrinsic factors on colorectal cancer heterogeneity during disease progression.

• Authors: Robert Piskol, Ling Huw, Ismail Sergin, Christiaan Kljin, Zora Modrusan, Doris Kim, Noelyn Kljavin, Rachel Tam, Rajesh Patel, Jeremy Burton, Elicia Penuel, Xueping Qu, Hartmut Koeppen, Teiko Sumiyoshi, Frederic de Sauvage, Mark R Lackner, Felipe de Sousa E Melo, Omar Kabbarah
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 14 Pg. 4431-4442 (07 15 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 31004000 (Publication Type: Journal Article)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor

Topics

• Animals
• Biomarkers, Tumor (genetics)
• Clinical Trials, Phase II as Topic
• Clinical Trials, Phase III as Topic
• Cohort Studies
• Colorectal Neoplasms (classification, genetics, secondary)
• Female
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Inbred NOD
• Molecular Typing (methods)
• Mutation
• Neoplasm Metastasis
• Neoplasm Staging
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays