title: Uncovering synthetic lethal interactions for therapeutic targets and predictive markers in lung adenocarcinoma.
abstract: Two genes are called synthetic lethal (SL) if their simultaneous mutation leads to cell death, but mutation of either individual does not. Targeting SL partners of mutated cancer genes can selectively kill cancer cells, but leave normal cells intact. We present an integrated approach to uncover SL gene pairs as novel therapeutic targets of lung adenocarcinoma (LADC). Of 24 predicted SL pairs, PARP1-TP53 was validated by RNAi knockdown to have synergistic toxicity in H1975 and invasive CL1-5 LADC cells; additionally FEN1-RAD54B, BRCA1-TP53, BRCA2-TP53 and RB1-TP53 were consistent with the literature. While metastasis remains a bottleneck in cancer treatment and inhibitors of PARP1 have been developed, this result may have therapeutic potential for LADC, in which TP53 is commonly mutated. We also demonstrated that silencing PARP1 enhanced the cell death induced by the platinum-based chemotherapy drug carboplatin in lung cancer cells (CL1-5 and H1975). IHC of RAD54B↑, BRCA1↓-RAD54B↑, FEN1(N)↑-RAD54B↑ and PARP1↑-RAD54B↑ were shown to be prognostic markers for 131 Asian LADC patients, and all markers except BRCA1↓-RAD54B↑ were further confirmed by three independent gene expression data sets (a total of 426 patients) including The Cancer Genome Atlas (TCGA) cohort of LADC. Importantly, we identified POLB-TP53 and POLB as predictive markers for the TCGA cohort (230 subjects), independent of age and stage. Thus, POLB and POLB-TP53 may be used to stratify future non-Asian LADC patients for therapeutic strategies.
authors.affiliation: Department of Laboratory Medicine and Epigenome Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Jan-Gowth
authors.initials: JG
authors.lastname: Chang
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yi-Ying
authors.initials: YY
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Ting-Fang
authors.initials: TF
authors.lastname: Che
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Yi-Syuan
authors.initials: YS
authors.lastname: Huang
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.|Department of Pathology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Kun-Tu
authors.initials: KT
authors.lastname: Yeh
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.|Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan.|Genome and Systems Biology Degree Program, Academia Sinica and National Taiwan University, Taipei, Taiwan.
authors.forename: Grace S
authors.initials: GS
authors.lastname: Shieh
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D014408:Biomarkers, Tumor; D002470:Cell Survival / Q000235:genetics; D004843:Epistasis, Genetic; D015870:Gene Expression; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D034622:RNA Interference; D015203:Reproducibility of Results; D000072020:Synthetic Lethal Mutations
chemical_list: D014408:Biomarkers, Tumor; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: TP53; gene expression data; lung adenocarcinoma; prognosis marker; synthetic lethal