Oncotarget

Research Papers:

Putative effectors for prognosis in lung adenocarcinoma are ethnic and gender specific

Andrew Woolston _, Nardnisa Sintupisut, Tzu-Pin Lu, Liang-Chuan Lai, Mong-Hsun Tsai, Eric Y. Chuang and Chen-Hsiang Yeang

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Oncotarget. 2015; 6:19483-19499. https://doi.org/10.18632/oncotarget.4287

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Abstract

Andrew Woolston1, Nardnisa Sintupisut1, Tzu-Pin Lu2, Liang-Chuan Lai3, Mong-Hsun Tsai4, Eric Y. Chuang5, Chen-Hsiang Yeang1

1Institute of Statistical Science, Academia Sinica, Taipei, Taiwan

2Department of Public Health, National Taiwan University, Taipei, Taiwan

3Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan

4Institute of Biotechnology, National Taiwan University, Taipei, Taiwan

5Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan

Correspondence to:

Chen-Hsiang Yeang, e-mail: chyeang@stat.sinica.edu.tw

Keywords: lung adenocarcinoma, association module, ethnic specific, gender specific, east asian

Received: May 15, 2015     Accepted: June 09, 2015     Published: June 22, 2015

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.


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