Gene Expression Profiling in Human Lung Development: An Abundant Resource for Lung Adenocarcinoma Prognosis

<div><p>A tumor can be viewed as a special “organ” that undergoes aberrant and poorly regulated organogenesis. Progress in cancer prognosis and therapy might be facilitated by re-examining distinctive processes that operate during normal development, to elucidate the intrinsic features of cancer that are significantly obscured by its heterogeneity. The global gene expression signatures of 44 human lung tissues at four development stages from Asian descent and 69 lung adenocarcinoma (ADC) tissue samples from ethnic Chinese patients were profiled using microarrays. All of the genes were classified into 27 distinct groups based on their expression patterns (named as PTN1 to PTN27) during the developmental process. In lung ADC, genes whose expression levels decreased steadily during lung development (genes in PTN1) generally had their expression reactivated, while those with uniformly increasing expression levels (genes in PTN27) had their expression suppressed. The genes in PTN1 contain many n-gene signatures that are of prognostic value for lung ADC. The prognostic relevance of a 12-gene demonstrator for patient survival was characterized in five cohorts of healthy and ADC patients [ADC_CICAMS (n = 69, p = 0.007), ADC_PNAS (n = 125, p = 0.0063), ADC_GSE13213 (n = 117, p = 0.0027), ADC_GSE8894 (n = 62, p = 0.01), and ADC_NCI (n = 282, p = 0.045)] and in four groups of stage I patients [ADC_CICAMS (n = 22, p = 0.017), ADC_PNAS (n = 76, p = 0.018), ADC_GSE13213 (n = 79, p = 0.02), and ADC_qPCR (n = 62, p = 0.006)]. In conclusion, by comparison of gene expression profiles during human lung developmental process and lung ADC progression, we revealed that the genes with a uniformly decreasing expression pattern during lung development are of enormous prognostic value for lung ADC.</p></div

The most significantly enriched functional categories and GO terms of genes in each vPTN with corresponding enrichment score (ES).

<p>The most significantly enriched functional categories and GO terms of genes in each vPTN with corresponding enrichment score (ES).</p

Global gene classification and functional annotation.

<p>(<b>A</b>) The genes were classified into 27 PTNs according to their expression dynamics throughout the lung development process. The time points during development were plotted on the x-axis, and the normalized gene expression level in every panel was plotted on the y-axis. Each gene is depicted with a line colored according to its relative expression level at the corresponding time points. (<b>B</b>) The results of the gene set enrichment analysis of vPTNs and ES-related gene lists are indicated by the color of the corresponding box, with red representing significant enrichment (the number in the red box indicates the negative log10 of the enrichment p value) and black representing the absence of enrichment. (<b>C</b>) The rose diagram displays the distribution of lung ADC-related genes in 26 vPTNs. The proportions of lung ADC-related genes in vPTNs are represented by the length of the petals, with red and blue indicating up- and downregulated genes, respectively. The rose petals corresponding to vPTNs significantly enriched with genes that were up- and downregulated in ADC are highlighted by colored outlines while those corresponding to vPTNs without enrichment are outlined in white.</p

Morphological and transcriptomic features of human lung during development.

<p>(<b>A</b>–<b>C</b>), (<b>D</b>–<b>F</b>), (<b>G</b>–<b>I</b>) & (<b>J</b>–<b>L</b>), Morphological images for the four types of human developmental lung samples, i.e., WholeE, EarlyL, MiddleL & MatureL. (<b>M</b>) Cladogram was created with the whole expression profiles obtained for the developmental lung samples and shows the phylogenetic relationships among the developmental lung samples. (<b>N</b>) Hierarchical clustering analysis of top 4000 most divergent genes. For each gene, we calculated its coefficient of variation (CV) based on its expression values across all developmental samples. The genes were then ranked based on their CV values. The heatmap was generated by hierarchical clustering of the top 4000 genes with largest CV values. The colored matrix indicated the relative expression levels of genes (red for higher expression, green for lower). The distribution of samples from each developmental stage was shown above the heatmap. (<b>O</b>) Developmental samples were projected onto the two-dimensional space captured by PCA with the stages of each sample indicated by color.</p

The antagonistic relationship of genes in the PTN1 and PTN27 group.

<p>(<b>A</b>) Genes in PTN1 and PTN27 were represented by lines as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105639#pone-0105639-g003" target="_blank">Figure 3A</a>, except for the right-most section which is the extension of the corresponding gene’s expression level in lung ADC. The average expression level of each gene of the pattern is represented by a thick red line for PTN1 and a blue line for PTN27. (<b>B</b>) Hierarchical clustering of genes in PTN1 and PTN27 from the ADC_CICAMS dataset. The expression levels of PTN1 and PTN27 genes are illustrated as a color spectrum, with red, black and green representing high, medium and low expression, respectively, in a matrix indexed by genes in rows and samples in columns. The genes were specified on the left side of the matrix by short lines colored orange for PTN1 or blue for PTN27.</p