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| WNT Pathway Activation Predicts Increased Risk of Tumor Recurrence in Patients with Stage I Non-Small Cell Lung Cancer |
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Mark Shapiro1, Gal Akiri3, Cynthia S. Chin2, Juan P. Wisnivesky4, Todd S. Weiser2, Scott J. Swanson5, Stuart A. Aaronson3; 1Surgery, The Mount Sinai Medical Center, New York, NY; 2Cardiothoracic Surgery, The Mount Sinai Medical Center, New York, NY; 3Oncological Sciences, The Mount Sinai Medical Center, New York, NY; 4Medicine, The Mount Sinai Medical Center, New York, NY; 5Cardiothoracic Surgery, Brigham and Women's Hospital, Boston, MA Objective: Aberrant Wnt signaling activation by genetic alterations of components of this pathway plays an important role in the development of a wide variety of tumor types. Recent studies have shown that Wnt pathway activation in several tumor types including non-small cell lung cancer (NSCLC) cell lines occurs at high frequency by an autocrine mechanism. There have been reports that, due to increased Wnt signaling, primary NSCLCs can exhibit increased levels of cytosolic or nuclear β-catenin as visualized by increased immunostaining of tumor tissues. We developed a quantitative means of identifying Wnt activated primary tumors and utilized this biochemical approach to determine the frequency of Wnt pathway activation in patients with stage I NSCLC and assess its effect on lung cancer recurrence. Methods: 57 patients treated with surgical resection for stage I NSCLC between June 2006 and May 2008 were selected from an IRB-approved database linked to the cancer tissue biorepository containing fresh frozen tumor as well as a normal lung tissue specimens linked to each patient. A glutathione-S-transferase (GST) pull-down assay combined with immunoblot analysis was used to assess the levels of uncomplexed and total β-catenin in tissues. The β-catenin gene was tested for oncogenic mutations in tumors with activated Wnt signaling, and we compared cancer recurrence rates in Wnt pathway positive and negative tumors. Results: 38.6% (n=22) of tumors were scored as Wnt positive with only one exhibiting a β-catenin oncogenic mutation. Thus, the great majority of Wnt activated primary tumors, as with NSCLC tumor lines, likely exhibit Wnt autocrine activation. Patients with Wnt positive tumors experienced a significantly higher rate of cancer recurrence than those whose tumors were Wnt negative (27.3%, n=6 vs. 5.7%, n=2) (Figure). Moreover, there were 5 patients with distal tumor recurrence in the Wnt positive group compared to 1 in the other group (22.7% vs. 2.9%, p = 0.036). Conclusion: Our study establishes a role for Wnt pathway activation in a substantial fraction of primary human NSCLCs. Moreover, increased levels of Wnt pathway activation were associated with a higher rate of cancer recurrence in patients with Stage I NSCLC. These findings suggest that Wnt activation reflects a more aggressive tumor phenotype and identifies patients who may benefit from more aggressive therapy in addition to resection.  Disease-free survival according to Wnt pathway activation in tumors of patients with pathologic stage I NSCLC. Back to 2010 Annual Meeting Back to Program Outline Back to Main Program |
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