Genetic variants of genes in the NER pathway associated with risk of breast cancer: A large-scale analysis of 14 published GWAS datasets in the DRIVE study.

Ge, Jie

Liu, Hongliang

Qian, Danwen

Wang, Xiaomeng

Moorman, Patricia G

Luo, Sheng

Hwang, Shelley

Wei, Qingyi

2019-08-01T21:14:03Z

2019-08-01T21:14:03Z

2019-09

2019-08-01T21:13:58Z

A recent hypothesis-free pathway-level analysis of genome-wide association study (GWAS) datasets suggested that the overall genetic variation measured by single nucleotide polymorphisms (SNPs) in the nucleotide excision repair (NER) pathway genes was associated with breast cancer (BC) risk, but no detailed SNP information was provided. To substantiate this finding, we performed a larger meta-analysis of 14 previously published GWAS datasets in the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) study with 53,107 subjects of European descent. Using a hypothesis-driven approach, we selected 138 candidate genes from the NER pathway using the "Molecular Signatures Database (MsigDB)" and "PathCards". All SNPs were imputed using IMPUTE2 with the 1000 Genomes Project Phase 3. Logistic regression was used to estimate BC risk, and pooled ORs for each SNP were obtained from the meta-analysis using the false discovery rate for multiple test correction. RegulomeDB, HaploReg, SNPinfo and expression quantitative trait loci (eQTL) analysis were used to assess the SNP functionality. We identified four independent SNPs associated with BC risk, BIVM-ERCC5 rs1323697_C (OR = 1.06, 95% CI = 1.03-1.10), GTF2H4 rs1264308_T (OR = 0.93, 95% CI = 0.89-0.97), COPS2 rs141308737_C deletion (OR = 1.06, 95% CI = 1.03-1.09) and ELL rs1469412_C (OR = 0.93, 95% CI = 0.90-0.96). Their combined genetic score was also associated with BC risk (OR = 1.12, 95% CI = 1.08-1.16, ptrend < 0.0001). The eQTL analysis revealed that BIVM-ERCC5 rs1323697 C and ELL rs1469412 C alleles were correlated with increased mRNA expression levels of their genes in 373 lymphoblastoid cell lines (p = 0.022 and 2.67 × 10-22 , respectively). These SNPs might have roles in the BC etiology, likely through modulating their corresponding gene expression.

0020-7136

1097-0215

https://hdl.handle.net/10161/19156

eng

Wiley

International journal of cancer

10.1002/ijc.32371

DNA repair

breast cancer susceptibility

expression quantitative trait loci analysis

single nucleotide polymorphism

Genetic variants of genes in the NER pathway associated with risk of breast cancer: A large-scale analysis of 14 published GWAS datasets in the DRIVE study.

Journal article

Moorman, Patricia G|0000-0002-2978-6495

Luo, Sheng|0000-0003-4214-5809

Wei, Qingyi|0000-0002-3845-9445|0000-0003-4115-4439

1270

1279

5

School of Medicine

Duke

Duke Cancer Institute

Institutes and Centers

Population Health Sciences

Basic Science Departments

Medicine, Medical Oncology

Medicine

Clinical Science Departments

Duke Clinical Research Institute

Biostatistics & Bioinformatics

Family Medicine and Community Health, Prevention Research

Family Medicine and Community Health

Accepted

145