Wnt Pathway Activation Predicts Increased Risk of Tumor Recurrence in Patients With Stage I Nonsmall Cell Lung Cancer

Objective: To determine the incidence of Wnt pathway activation in patients with stage I NSCLC and its influence on lung cancer recurrence. Background: Despite resection, the 5-year recurrence with localized stage I nonsmall cell lung cancer (NSCLC) is 18.4%-24%. Aberrant Wnt signaling activation plays an important role in a wide variety of tumor types. However, there is not much known about the role the Wnt pathway plays in patients with stage I lung cancer. Methods: Tumor and normal lung tissues from 55 patients following resection for stage I NSCLC were subjected to glutathione S-transferase (GST) E-cadherin pulldown and immunoblot analysis to assess levels of uncomplexed beta-catenin, a reliable measure of Wnt signaling activation. The beta-catenin gene was also screened for oncogenic mutations in tumors with activated Wnt signaling. Cancer recurrence rates were correlated in a blinded manner in patients with Wnt pathway-positive and -negative tumors. Results: Tumors in 20 patients (36.4%) scored as Wnt positive, with only 1 exhibiting a beta-catenin oncogenic mutation. Patients with Wnt-positive tumors experienced a significantly higher rate of overall cancer recurrence than those with Wnt-negative tumors (30.0% vs. 5.7%, P = 0.02), with 25.0% exhibiting distal tumor recurrence compared with 2.9% in the Wnt-negative group (P = 0.02). Conclusions: Wnt pathway activation occurred in a substantial fraction of Stage I NSCLCs, which was rarely due to mutations. Moreover, Wnt pathway activation was associated with a significantly higher rate of tumor recurrence. These findings suggest that Wnt pathway activation reflects a more aggressive tumor phenotype and identifies patients who may benefit from more aggressive therapy in addition to resection.