Novel genetic variants in HDAC2 and PPARGC1A of the CREB-binding protein pathway predict survival of non-small-cell lung cancer.


The CREB-binding protein (CBP) pathway plays an important role in transcription and activity of acetyltransferase that acetylates lysine residues of histones and nonhistone proteins. In the present study, we hypothesized that genetic variants in the CBP pathway genes played a role in survival of non-small-cell lung cancer (NSCLC). We tested this hypothesis using the genotyping data from the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In the single-locus analysis, we evaluated associations between 13 176 (1107 genotyped and 12 069 imputed) single-nucleotide polymorphisms (SNPs) in 72 genes and survival of 1185 patients with NSCLC. The identified 106 significant SNPs in the discovery were further validated in additional genotyping data from another GWAS dataset of 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study. The combined results of two datasets showed that two independent, potentially functional SNPs (i.e., HDAC2 rs13213007G>A and PPARGC1A rs60571065T>A) were significantly associated with NSCLC overall survival, with a combined hazards ratio (HR) of 1.26 (95% confidence interval (CI), 1.09-1.45; P = .002) and 1.23 (1.04-1.47; P = .017), respectively. Furthermore, we performed an expression quantitative trait loci analysis and found that the survival-associated HDAC2 rs13213007A allele (GA+AA), but not PPARGC1A rs60571065A allele (TA+AA), was significantly associated with increased messenger RNA expression levels of HDAC2 in 373 lymphoblastoid cell lines. These results indicate that the HDAC2 rs13213007A allele is a potential predictor of NSCLC survival, likely by altering the HDAC2 expression.





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Publication Info

Tang, Dongfang, Yu Chen Zhao, Danwen Qian, Hongliang Liu, Sheng Luo, Edward F Patz, Patricia G Moorman, Li Su, et al. (2019). Novel genetic variants in HDAC2 and PPARGC1A of the CREB-binding protein pathway predict survival of non-small-cell lung cancer. Molecular carcinogenesis. 10.1002/mc.23132 Retrieved from

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Sheng Luo

Professor of Biostatistics & Bioinformatics

Carolyn Glass

Associate Professor of Pathology

Cardiothoracic Pathologist and Physician-Scientist
Division Chief, Cardiovascular Pathology 
Co-Director, Division of Artificial Intelligence and Computational Pathology
Director, Duke University Hospital Autopsy Service 
Associate Director, Residency Program  

Dr. Glass completed medical residency in Anatomic Pathology at the Brigham and Women’s Hospital/Harvard Medical School followed by fellowships in Cardiothoracic Pathology also at Brigham and Women’s Hospital/Harvard Medical School and Pulmonary/Cardiac Transplant Pathology at the University of Texas Southwestern Medical Center. Dr. Glass initially trained as a vascular surgeon with a focus on endovascular/interventional procedures through the 0+5 Integrated Vascular Surgery Program at the University of Rochester Medical Center from 2007-2011.  As a recipient of the NIH National Lung Blood Institute T32 Ruth Kirschstein National Service Research Award, she completed a Ph.D with a concentration in Genomics and Epigenetics in 2014.

Dr. Glass was awarded a five-year $3.2 million NIH grant to serve as P.I. of the Pathology Core as part of a larger U54 NIH grant ($13.5 million along with Duke Department of Medicine) to establish a Senescent Cell Human Tissue Mapping Center as part of the NIH Cellular Senescence Network. As a thoracic pathologist, Dr. Glass also has a special interest in identifying new epigenetic biomarkers that may predict response or resistance to conventional, targeted and immune therapy using computational techniques. She works closely with the Duke Thoracic Oncology Group, DCI Center for Cancer Immunotherapy, Duke Division of Cardiovascular Medicine and Cardiothoracic Surgery and Pratt School of Biomedical Engineering. 

Dr. Glass is the recipient of the Society of Cardiovascular Pathology (SCVP) Young Investigator’s Award, the William von Liebig Vascular Biology Research Fellowship at the Harvard Institutes of Medicine, the Duke Pathology Salvatore V. Pizzo Faculty Research Mentor Award, the Duke Department of Pathology Early Career Research Achievement Award and is author of over 90 publications (including book chapters in the recent W.H.O. Classification Tumours of the Lung, Pleura, Thymus and Heart) and 50 national presentations in cardiovascular disease, thoracic malignancies, surgery and machine learning. 

In addition to her clinical and research activities, Dr. Glass serves on the Executive/National Committees for the Society of Cardiovascular Pathology, College of American Pathology Artificial Intelligence Committee and the Duke School of Medicine Executive Admissions Committee. 

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