Urothelium marker UPK2 identifies aggressive colorectal cancers with distinct molecular and histological features
Ville K Äijälä1, Jouni Härkönen2,3, Päivi Sirniö1
1Translational Medicine Research Unit, University of Oulu, and Medical Research Center Oulu, Oulu University Hospital, Oulu, Finland.
Background:
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.
Methods:
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.
Results:
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).
Conclusions:
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.
