This month's April 2011 Journal of Thoracic Oncology has an interesting paper by Xu and colleagues (abstract) that examines Wnt1 expression in non-small cell lung cancer (NSCLC) in relation to downstream Wnt signaling molecules, including beta-catenin, and correlates different marker expression with traditional clinicopathological parameters.
This is an immunohistochemical study of a tissue microarray composed of 262 NSCLC resected specimens. The authors define aberrant beta-catenin expression as: 1) decreased membranous pattern in less than 70% of tumor cells, 2) cytoplasmic pattern of expression, or 3) nuclear pattern of expression. As expected, the majority of patients are stage 1 or 2 but nearly 36% of the study population are never-smokers--over 50% in the adenocarcinoma histology group (!). The authors found that Wnt1 overexpression was significantly associated with never-smoker status and ADC histology; aberrant beta-catenin expression was associated with SQC histology. While each Wnt1 overexpression and aberrant beta-catenin expression were independently associated with decreased OS regardless of TNM stage, patients that demonstrated both had worse OS than other combinations of Wnt1/beta-catenin expression. Further, Wnt1/beta-catenin expression was also an independent factor adjusted by stage, pleural invasion, lymphatic invasion, ECOG PS or stage, age, gender, histology, and p53 expression.
A few comments about this paper. One significant caveat to the findings is the over-representation of never smokers (35%) in this Asian study population, especially nearly 54% of never smokers in the ADC group, compared to a more typical American population in a community hospital setting (about 10%). Overexpression of Wnt1 was significantly associated with never-smoking and as well as ADC histology, but, somewhat paradoxically, Wnt1 overexpression was associated with significantly shorter overall survival. Unfortunately, the authors do not break this further down into Wnt1 overexpression and OS with respect to histological type--perhaps some SQCs showing Wnt1 overexpression and dismal OS are skewing the data here since one would expect never-smokers with ADC to have a better prognosis in general. Another is the usual issues with using TMAs to represent complex heterogenous tumors. The authors do not sufficiently describe from where they target obtaining cores for constructing the TMA--are they targeting the invasive margin, the central tumor, wherever? what about mixed histology tumors? These are critical methodological issues--especially when extrapolating the data concerning marker expression. One admirable feature of this paper is the clear definition, supported by appropriate photomicrographs, of "aberrant" beta-catenin expression. As I am currently working on projects that are similarly assessing beta-catenin expression in NSCLC, I found this very helpful in assessing this paper's findings.