# Urothelium marker UPK2 identifies aggressive colorectal cancers with distinct molecular and histological features

## TL;DR

UPK2 identifies a subset of aggressive colorectal cancers with unique features and poor outcomes, suggesting potential for targeted treatments.

## Contribution

Identification of UPK2 as a marker for aggressive CRCs with distinct molecular and histological features.

## Key findings

- UPK2-positive CRCs are associated with advanced stage, lymphovascular invasion, and poor survival.
- UPK2 marks tumors with reduced immune infiltration and molecular features like TP53 mutation and CMS4 subtype.
- UPK2-positive tumors show keratinization and squamous differentiation markers like KRT17 and DSG3.

## Abstract

Uroplakin-2 (UPK2) is a relatively specific marker for urothelial cancer, often used in the differential diagnosis of tumors of unknown origin. UPK2 expression has been observed in colorectal cancers (CRCs), prompting further investigation.

UPK2 expression was analyzed in two independent CRC cohorts (N = 1851) and The Cancer Genome Atlas (N = 467). We investigated the histopathological, immunological, molecular, and clinical characteristics of UPK2-positive CRCs.

UPK2 was expressed in 12% of CRCs and associated with adverse features including advanced stage, lymphovascular invasion, tumor budding, and micropapillary growth (p < 0.01). UPK2 positivity correlated with higher CRC-specific mortality in both cohorts (Cohort 1: HR 1.97, 95% CI 1.00–3.88; Cohort 2: HR 3.33, 95% CI 2.15–5.16). In the larger cohort, this association remained independent of other prognostic parameters (HR 2.31, 95% CI 1.46–3.65). UPK2-positive tumors showed reduced infiltration of CD3 + T cells, B cells, plasma cells, and M2-like macrophages. Molecularly, these tumors were associated with TP53 mutation, CMS4 subtype, and upregulation of genes linked to keratinization and squamous differentiation, such as KRT17 and DSG3 (p < 0.01).

UPK2 marks a distinct subset of CRCs with poor prognosis, epithelial-mesenchymal transition, micropapillary growth, and squamous differentiation. These findings may affect the development of targeted therapies in precision medicine.