title: Putative effectors for prognosis in lung adenocarcinoma are ethnic and gender specific.
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.
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Andrew
authors.initials: A
authors.lastname: Woolston
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Nardnisa
authors.initials: N
authors.lastname: Sintupisut
authors.affiliation: Department of Public Health, National Taiwan University, Taipei, Taiwan.
authors.forename: Tzu-Pin
authors.initials: TP
authors.lastname: Lu
authors.affiliation: Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan.
authors.forename: Liang-Chuan
authors.initials: LC
authors.lastname: Lai
authors.affiliation: Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.
authors.forename: Mong-Hsun
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Chuang
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Chen-Hsiang
authors.initials: CH
authors.lastname: Yeang
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000208:ethnology* / Q000235:genetics* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D044466:Asian People / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D019295:Computational Biology; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D030541:Databases, Genetic; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000175:diagnosis / Q000208:ethnology* / Q000235:genetics* / Q000401:mortality; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D056910:Republic of Korea / Q000453:epidemiology; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013624:Taiwan / Q000453:epidemiology; D013997:Time Factors; D044465:White People / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger
keywords: East Asian; association module; ethnic specific; gender specific; lung adenocarcinoma