A 10-gene progenitor cell signature predicts poor prognosis in lung adenocarcinoma

Abstract

Background: One aspect of the cancer stem cell hypothesis is that patients with tumors that exhibit stem-like phenotypes have poor prognoses. Distal epithelial progenitors from lungs early in development demonstrate both self-renewal and potential to differentiate into all bronchial and alveolar epithelial cell types. By contrast, late progenitors are only able to produce alveolar cells. We sought to create a lung-specific progenitor cell signature for possible prognosis prediction in human lung cancer.

Methods: A transgenic mouse was created in which embryonic distal epithelial progenitor cells express green fluorescent protein when tamoxifen is administered. Lung progenitor cells were harvested after tamoxifen injection at either embryonic day 11.5 (E11.5) or 17.5 (E17.5). The RNA extracted from these cells was hybridized to Affymetrix 430.2 mouse chips (Affymetrix, Santa Clara, CA). A genomic signature was created by comparing the cell types using L1 logistic regression and applied to transcriptome datasets of resected patients from our tumor bank and the National Institutes of Health Director's Challenge Consortium.

Results: When a 10-gene genomic signature was applied to resected human adenocarcinoma datasets, tumors that were transcriptionally similar to the early progenitors had a significantly worse prognosis than those similar to the late progenitors. Using a Cox model in which age and stage were included, the predicted score from the logistic regression model was an independent predictor of survival.

Conclusions: A lung progenitor cell signature predicts poor prognosis in lung adenocarcinoma. Modulation of these genes or their signaling pathways may be effective therapeutic strategies in the future.