Chenchen Yang1,2,3, Theresa Ryan Stueve1,2,3,4, Chunli Yan1,2,3, Suhn K Rhie1,2,3, Daniel J Mullen1,2,3, Jiao Luo2,5, Beiyun Zhou3,5,6, Zea Borok2,3,5,6, Crystal N Marconett1,2,3, Ite A Offringa1,2,3. 1. Department of Surgery, University of Southern California, CA 90089, USA. 2. Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA. 3. Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA. 4. Department of Preventive Medicine, University of Southern California, CA 90089, USA. 5. Department of Medicine, Division of Pulmonary & Critical Care & Sleep Medicine, University of Southern California, CA 90089, USA. 6. Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, CA 90089, USA.
Abstract
AIM: To identify functional lung adenocarcinoma (LUAD) risk SNPs. MATERIALS & METHODS: Eighteen validated LUAD risk SNPs (p ≤ 5 × 10-8) and 930 SNPs in high linkage disequilibrium (r2 > 0.5) were integrated with epigenomic information from primary human alveolar epithelial cells. Enhancer-associated SNPs likely affecting transcription factor-binding sites were predicted. Three SNPs were functionally investigated using luciferase assays, expression quantitative trait loci and cancer-specific expression. RESULTS: Forty-seven SNPs mapped to putative enhancers; 11 located to open chromatin. Of these, seven altered predicted transcription factor-binding motifs. Rs6942067 showed allele-specific luciferase expression and expression quantitative trait loci analysis indicates that it influences expression of DCBLD1, a gene that encodes an unknown membrane protein and is overexpressed in LUAD. CONCLUSION: Integration of candidate LUAD risk SNPS with epigenomic marks from normal alveolar epithelium identified numerous candidate functional LUAD risk SNPs including rs6942067, which appears to affect DCBLD1 expression. Data deposition: Data are provided in GEO record GSE84273.
AIM: To identify functional lung adenocarcinoma (LUAD) risk SNPs. MATERIALS & METHODS: Eighteen validated LUAD risk SNPs (p ≤ 5 × 10-8) and 930 SNPs in high linkage disequilibrium (r2 > 0.5) were integrated with epigenomic information from primary human alveolar epithelial cells. Enhancer-associated SNPs likely affecting transcription factor-binding sites were predicted. Three SNPs were functionally investigated using luciferase assays, expression quantitative trait loci and cancer-specific expression. RESULTS: Forty-seven SNPs mapped to putative enhancers; 11 located to open chromatin. Of these, seven altered predicted transcription factor-binding motifs. Rs6942067 showed allele-specific luciferase expression and expression quantitative trait loci analysis indicates that it influences expression of DCBLD1, a gene that encodes an unknown membrane protein and is overexpressed in LUAD. CONCLUSION: Integration of candidate LUAD risk SNPS with epigenomic marks from normal alveolar epithelium identified numerous candidate functional LUAD risk SNPs including rs6942067, which appears to affect DCBLD1 expression. Data deposition: Data are provided in GEO record GSE84273.
Authors: I A Offringa; Z Borok; B Zhou; T R Stueve; E A Mihalakakos; L Miao; D Mullen; Y Wang; Y Liu; J Luo; E Tran; K D Siegmund; S K Lynch; A L Ryan; C N Marconett Journal: BMC Genomics Date: 2021-12-18 Impact factor: 3.969
Authors: Evelyn Tran; Tuo Shi; Xiuwen Li; Adnan Y Chowdhury; Du Jiang; Yixin Liu; Hongjun Wang; Chunli Yan; William D Wallace; Rong Lu; Amy L Ryan; Crystal N Marconett; Beiyun Zhou; Zea Borok; Ite A Offringa Journal: iScience Date: 2022-01-15
Authors: Ammar J Alsheikh; Sabrina Wollenhaupt; Emily A King; Jonas Reeb; Sujana Ghosh; Lindsay R Stolzenburg; Saleh Tamim; Jozef Lazar; J Wade Davis; Howard J Jacob Journal: BMC Med Genomics Date: 2022-04-01 Impact factor: 3.063