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Background <p>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.</p> Methods <p>UPK2 expression was analyzed in two independent CRC cohorts (<i>N</i> = 1851) and The Cancer Genome Atlas (<i>N</i> = 467). We investigated the histopathological, immunological, molecular, and clinical characteristics of UPK2-positive CRCs.</p> Results <p>UPK2 was expressed in 12% of CRCs and associated with adverse features including advanced stage, lymphovascular invasion, tumor budding, and micropapillary growth (<i>p</i> &lt; 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 <i>TP53</i> mutation, CMS4 subtype, and upregulation of genes linked to keratinization and squamous differentiation, such as <i>KRT17</i> and <i>DSG3</i> (<i>p</i> &lt; 0.01).</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月11日

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  • Ville K. Äijälä,
  • Jouni Härkönen,
  • Päivi Sirniö,
  • Tuomo Mantere,
  • Hanna Elomaa,
  • Onni Sirkiä,
  • Akseli Kehusmaa,
  • Henna Karjalainen,
  • Meeri Kastinen,
  • Vilja V. Tapiainen,
  • Maarit Ahtiainen,
  • Olli Helminen,
  • Erkki-Ville Wirta,
  • Jukka Rintala,
  • Sanna Meriläinen,
  • Juha Saarnio,
  • Tero Rautio,
  • Toni T. Seppälä,
  • Jan Böhm,
  • Jukka-Pekka Mecklin,
  • Anne Tuomisto,
  • Markus J. Mäkinen,
  • Juha P. Väyrynen

摘要

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.