The major thrust of this study is to identify new germline polymorphisms in micro-RNAs (miRs) that are associated with increased risk of developing lung cancer (LC) or provide LC prognostic information. Such loci will be important in early cancer detection and patient management. In addition, we want to determine if miRs provide a blood biomarker for LC detection and if certain miR biomarkers also play a functional role in LC pathogenesis. miRNAs are a class of small non-coding endogenous RNAs capable of regulating an estimated third of human genes. miRNAs can function as oncogenes or tumor suppressor genes depending on the cellular context. In cancer, dysregulation of tumor suppressive or oncogenic miRNAs could have profound effects on various cellular processes including proliferation, differentiation, and cell death. miRNA relevant genomic variations may have regulatory effects on gene expression and cellular processing by altering gene splicing, modulating miRNA-target interaction, and disrupting miRNA biogenesis. However, no studies have systematically screened and validated SNPs in miRNA pathways as modulators of LC risk and outcomes. One of the added advantages of miRNA and miR pathway targeted study of SNPs (miR-SNPs) is that most miR-SNPs are not covered by current GWAS chips. Therefore, we propose to conduct a systematic analysis of SNPs in miRs and miR pathway(s) as susceptibility factors for NSCLC risk and clinical outcome, incorporating germline miR-SNP genotyping, somatic miRNA profiling, circulating miRNA detection, and functional characterization. This proposal builds upon a rich specimen repository, well annotated with comprehensive epidemiologic, clinical and genetic data, from one of the largest LC studies in the U. S., MD Anderson LC Study, along with the Harvard LC study. The four specific aims are:
Aim 1) To screen and validate a custom array of ~6,000 miR-SNPs as predictors of NSCLC risk using a three-stage design (discovery, internal and external validation) in a total of 4,800 Caucasian cases and 4,800 matched controls, as well as 1,600 pairs of African American cases and controls;
Aim 2) To screen and validate the above 6,000 miR-SNPs as predictors of NSCLC recurrence in the subset of surgically resected early stage NSCLC patients using a similar three-stage design;
Aim 3) To identify circulating miRNAs as predictors for recurrence in early stage NSCLC using a testing and validation design;
Aim 4) To determine the functional impact on lung cancer of significant miR-SNPs and miRNAs identified from the above aims.

Public Health Relevance

Primary lung cancer (LC) is the most common cancer and the leading cause of cancer death and non-small cell lung cancer (NSCLC) accounts for over 80% of LC cases. This project aims to identify genetic miR variants for NSCLC risk and recurrence and circulating miR biomarkers for recurrence in early stage patients. The identified biomarkers may be incorporated into risk prediction models to improve risk stratification for cost-effective surveillance, screening, detection, and personalized management of early stage lung cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
United States
Zip Code
Wang, Jacqueline F; Pu, Xingxiang; Zhang, Xiaoshan et al. (2018) Variants with a low allele frequency detected in genomic DNA affect the accuracy of mutation detection in cell-free DNA by next-generation sequencing. Cancer 124:1061-1069
Pierzynski, Jeanne A; Ye, Yuanqing; Lippman, Scott M et al. (2018) Socio-demographic, Clinical, and Genetic Determinants of Quality of Life in Lung Cancer Patients. Sci Rep 8:10640
Rashdan, Sawsan; Minna, John D; Gerber, David E (2018) Diagnosis and management of pulmonary toxicity associated with cancer immunotherapy. Lancet Respir Med 6:472-478
Zhang, Wei; Girard, Luc; Zhang, Yu-An et al. (2018) Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res 7:32-49
Akbay, Esra A; Kim, James (2018) Autochthonous murine models for the study of smoker and never-smoker associated lung cancers. Transl Lung Cancer Res 7:464-486
McMillan, Elizabeth A; Ryu, Myung-Jeom; Diep, Caroline H et al. (2018) Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer. Cell 173:864-878.e29
Tan, Xiaochao; Banerjee, Priyam; Liu, Xin et al. (2018) The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network. J Clin Invest 128:1267-1282
Skoulidis, Ferdinandos; Goldberg, Michael E; Greenawalt, Danielle M et al. (2018) STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov 8:822-835
Walser, Tonya C; Jing, Zhe; Tran, Linh M et al. (2018) Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells. Cancer Res 78:1986-1999
Ferdosi, Shadi; Rehder, Douglas S; Maranian, Paul et al. (2018) Stage Dependence, Cell-Origin Independence, and Prognostic Capacity of Serum Glycan Fucosylation, ?1-4 Branching, ?1-6 Branching, and ?2-6 Sialylation in Cancer. J Proteome Res 17:543-558

Showing the most recent 10 out of 1059 publications