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. 2015 Aug 14;6(23):19483-99.
doi: 10.18632/oncotarget.4287.

Putative Effectors for Prognosis in Lung Adenocarcinoma Are Ethnic and Gender Specific

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Free PMC article

Putative Effectors for Prognosis in Lung Adenocarcinoma Are Ethnic and Gender Specific

Andrew Woolston et al. Oncotarget. .
Free PMC article

Abstract

Lung adenocarcinoma possesses distinct patterns of EGFR/KRAS mutations between East Asian and Western, male and female patients. However, beyond the well-known EGFR/KRAS distinction, gender and ethnic specific molecular aberrations and their effects on prognosis remain largely unexplored. Association modules capture the dependency of an effector molecular aberration and target gene expressions. We established association modules from the copy number variation (CNV), DNA methylation and mRNA expression data of a Taiwanese female cohort. The inferred modules were validated in four external datasets of East Asian and Caucasian patients by examining the coherence of the target gene expressions and their associations with prognostic outcomes. Modules 1 (cis-acting effects with chromosome 7 CNV) and 3 (DNA methylations of UBIAD1 and VAV1) possessed significantly negative associations with survival times among two East Asian patient cohorts. Module 2 (cis-acting effects with chromosome 18 CNV) possessed significantly negative associations with survival times among the East Asian female subpopulation alone. By examining the genomic locations and functions of the target genes, we identified several putative effectors of the two cis-acting CNV modules: RAC1, EGFR, CDK5 and RALBP1. Furthermore, module 3 targets were enriched with genes involved in cell proliferation and division and hence were consistent with the negative associations with survival times. We demonstrated that association modules in lung adenocarcinoma with significant links of prognostic outcomes were ethnic and/or gender specific. This discovery has profound implications in diagnosis and treatment of lung adenocarcinoma and echoes the fundamental principles of the personalized medicine paradigm.

Keywords: East Asian; association module; ethnic specific; gender specific; lung adenocarcinoma.

Figures

Figure 1
Figure 1. Three types of association module
a. Cis-acting effects with CNVs of chromosomes, b. Trans-acting effects with CNVs of chromosomes; and c. Effects with DNA methylations. Solid lines: information flows following the central dogma (DNA → mRNA → protein). Dotted lines: regulatory links from regulators to their targets on other chromosomal locations. Dashed lines: associations between observed aberrations and mRNA gene expressions. Arrowheads indicate positive associations and bar-ends indicate negative associations. The figure is adapted from [42].
Figure 2
Figure 2. Validation tests to examine the target gene coherence of genes and prognostic power of the modules
a. Heatmaps illustrating the distributions of correlation coefficients among target gene expressions of female East Asian datasets. b. Heatmaps illustrating the distributions of Cox coefficients of target genes for female East Asian datasets. A distribution of all genes within the external data is included to provide a background comparison to compute the Kolmogorov-Smirnov statistic.
Figure 3
Figure 3. Kaplan-Meier curves of modules 1 and 3
Kaplan-Meier survival curves of patients divided by median gene expression amongst target genes in inferred modules. A red line indicates the survival curve of the patient group with high median expression levels in the target genes. A blue line indicates the survival curve of the patient group with low median expression levels in the target genes. Tick marks indicate censored data points; p-values are determined by log-rank tests. The size of each patient group and the log-rank p-value are reported.
Figure 4
Figure 4. Kaplan-Meier curves of module 2
The legend follows Fig. 3.
Figure 5
Figure 5. Partial least squares to investigate an association between modules in the Taiwan data
a. A correlation circle displaying the first two component loadings for two sets of randomly selected genes b. A correlation circle displaying the first two component loadings for target genes in modules 1 (shown in red) and 3 (shown in blue), c. A correlation circle displaying the first two component loadings for target genes in modules 2 (shown in red) and 3 (shown in blue). d. Distributions of correlation coefficients between module effectors and target genes. Solid red line: correlation coefficients between module 1 effector of chromosome 7p CNV and module 3 target gene expressions. Solid green line: correlation coefficients between module 1 effector of chromosome 7q CNV and module 3 target gene expressions. Dashed red line: correlation coefficients between module 2 effector of chromosome 18p CNV and module 3 target gene expressions. Dashed green line: correlation coefficients between module 2 effector of chromosome 18q CNV and module 3 target gene expressions.
Figure 6
Figure 6. Cox regression coefficients of target genes within selected cis-acting CNV modules mapped by the relative locations on the chromosome
The average of the standardized Cox coefficients for the two East Asian female datasets is shown by the black line, with a confidence interval for the two datasets shown by the blue band. Each target gene in the association module is flagged by a hollow red dot. The names of genes with high-ranking PubMed citations to lung cancer key terms are highlighted (see Materials and Methods), with the mean Cox coefficient shown with a solid red dot. The p and q arms of each chromosome are separated by blank columns; a. shows the gene locations for cis-acting CNV on chromosome 7; b. shows the gene locations for cis-acting CNV on chromosome 18.

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