Pan-cancer genomic amplifications underlie a WNT hyperactivation phenotype associated with stem cell-like features leading to poor prognosis.

Cancer stem cells pose significant obstacles to curative treatment contributing to tumor relapse and poor prognosis. They share many signaling pathways with normal stem cells that control cell proliferation, self-renewal, and cell fate determination. One of these pathways known as Wnt is frequently implicated in carcinogenesis where Wnt hyperactivation is seen in cancer stem cells. Yet, the role of conserved genomic alterations in Wnt genes driving tumor progression across multiple cancer types remains to be elucidated. In an integrated pan-cancer study involving 21 cancers and 18,484 patients, we identified a core Wnt signature of 16 genes that showed a high frequency of somatic amplifications linked to increased transcript expression. The signature successfully predicted overall survival rates in 6 cancer cohorts (n = 3050): bladder (P = 0.011), colon (P = 0.013), head and neck (P = 0.026), pan-kidney (P < 0.0001), clear cell renal cell (P < 0.0001), and stomach (P = 0.032). Receiver operating characteristic analyses revealed that the performance of the 16-Wnt-gene signature was superior to tumor staging benchmarks in all 6 cohorts and multivariate Cox regression analyses confirmed that the signature was an independent predictor of overall survival. In bladder and renal cancer, high-risk patients as predicted by the Wnt signature had more hypoxic tumors and a combined model uniting tumor hypoxia and Wnt hyperactivation resulted in further increased death risks. Patients with hyperactive Wnt signaling had molecular features associated with stemness and epithelial-to-mesenchymal transition. Our study confirmed that genomic amplification underpinning pan-cancer Wnt hyperactivation and transcriptional changes associated with molecular footprints of cancer stem cells lead to increased death risks.