Abstract LB-334: Functional polymorphisms in the stem-cell related pathway affect susceptibility to non-small cell lung cancer: a finding from Texas lung cancer genome-wide association study

Abstract

Abstract Cancer stem cells (CSCs) are the putative origin of cancer developing from normal cells. Wnt, Notch, Hedgehog (Hh, including sonic Hedgehog pathway) are those signaling pathways that are shared by both normal stem cells and CSCs, and regulate and maintain the ability to self-renew, form differentiated progeny, develop resistance to therapy. Previous studies showed that chromosome 4q31 locus (Hedgehog-interacting protein (HHIP) /glycophorin A (GYPA)) in chronic obstructive pulmonary disease are associated with lung cancer, while HHIP is an important gene in the Hh pathway. We hypothesized that CSCs evolve into cells with metastatic potential through accumulated mutations in stem cells and that genetic variants in Wnt, Notch, and Hh pathways (stem cell-related pathways) may modulate phenotypes of stem cell, hence affecting susceptibility to cancer (including non-small cell lung cancer). Published genome-wide association studies (GWAS) have identified few variants in known biological pathways involved in lung cancer etiology. To mine the additional causal single nucleotide polymorphisms (SNPs), we explored tagSNPs in the stem cell-related pathways from our published GWAS dataset for 1154 lung cancer cases and 1137 cancer-free controls. In an initial association analysis of 2685 tagSNPs in 196 stem cell-related pathway genes, the p values for the most significant tagSNPs (rs1828591, rs720485, rs6845536) also located in chromosome 4q31 (HHIP/GYPA) were 8.21×10−5, 3.19×10−5, and 7.15×10−5, respectively. However, these tagSNPs are neither functional SNPs themselves nor tagged other predicted functional but untyped SNPs. Additional 16 tagSNPs that either are functional SNPs themselves or tagged other predicted functional but untyped SNPs associated with lung cancer risk only had a p value of <0.05. We imputed (NCBI35/hg17) 18072 tagSNPs in the same 196 genes, and identified an additional 39 tagSNPs associated with lung cancer risk with a p value <0.05, but the total number was reduced to 41 after taking into account LD among all SNPs with a p value <0.05 (ranging from 3.81×10−4 to 4.96×10−2). The most significant SNP rs2229263 in LRP2 had a p value of 3.81×10−4. The genes with top significant P values (<10−3) were located in Hh and Notch pathways. When we used Ingenuity Systems pathway analysis (IPA), we found that Hh and Notch signaling pathways were the most significant pathways (p-values were 1.31×10−10, 5.48×10−10, respectively), and the top transcription regulators in the signaling pathway were Gli, SMAD4, GLI3, Notch, and GLI2, with the p value 4.42×10−5, 7.43×10−4, 8.91E×10−4, 1.13×10−3, 3.34×10−3. Our findings suggest that functional SNPs in the Hh and Notch pathways genes may affect susceptibility to non-small cell lung cancer. Further replication and functional studies are warranted to confirm these findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-334. doi:1538-7445.AM2012-LB-334