Transcriptomic Meta-Analysis Identifies Upregulated Clotting and Fibrinolysis Pathways in Colorectal Cancer Tumors Containing Hereditary PMS2 Mismatch Repair Deficiency

TL;DR

This study finds that tumors with hereditary PMS2 deficiency show increased clotting and fibrinolysis activity, which may influence cancer growth and spread.

Contribution

The study identifies unique transcriptional profiles in PMS2-deficient colorectal tumors, highlighting clotting-related pathways as novel features.

Findings

PMS2-deficient tumors show upregulated prothrombin activation pathways.

Fibrinolysis and uPA/uPAR signaling are enriched in PMS2-mutated tumors.

These pathways are linked to tumor invasiveness and metastasis.

Abstract

Lynch Syndrome is characterized by deficient mismatch repair (dMMR) components. We performed a meta-analysis of multiple RNA-sequencing datasets from patients with different dMMR variants (PMS2, MLH1, and MSH2) to better characterize the unique transcriptional profiles. Our results reveal enriched signaling pathways from tumor samples with germline mutations in the PMS2 gene including upregulation in pathways related to intrinsic and extrinsic prothrombin activation, fibrinolysis, and uPA/uPAR-mediated signaling. These pathways have been associated with tumor growth, invasiveness, and metastasis. This work provides support for further exploration into the role of PMS2 in tumor development, and as a potential therapeutic mechanism.

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