J Cancer 2019; 10(8):1862-1869. doi:10.7150/jca.28379 This issue
1. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
2. Zhejiang Provincial Office for Cancer Prevention and Control, Zhejiang Cancer Center/Zhejiang Cancer Hospital, Hangzhou 310004, China.
3. National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
4. Department of Thoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
5. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center of Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
*Y.W. and C.Z. contributed equally to this work.
Genome-wide association studies (GWASs) have consistently identified chromosome 3q28 as a lung cancer susceptibility region. To further characterize the potential genetic mechanism of the variants in this region, we conducted a fine-mapping study on chromosome 3q28 region. We performed a target resequencing in 200 lung cancer cases and 300 controls in the screening and followed by validation in multi-ethnic lung cancer GWASs with 12,843 cases and 12,639 controls. For our identified novel variants, we conducted expression quantitative trait loci (eQTL) analysis to reveal the potential target genes. Two susceptibility variants were identified (rs4396880: G>A, OR = 0.35, 95%CI: 0.20-0.62, P = 3.01×10-4; and rs3856776: C>T, OR = 2.05, 95%CI: 1.32-3.18, P = 1.49×10-3) and further supported in Asian population (rs4396880: OR = 0.88, P = 7.43×10-6; and rs3856776: OR =1.17, P = 1.64×10-4). The eQTL analysis showed the A allele of rs4396880 was significantly associated with higher mRNA expression of TP63 (P = 1.70×10-4) in lung tissues, while rs3856776 showed significant association with the expression of LEPREL1-AS1 (P = 6.90×10-3), which was the antisense RNA of LEPREL1 and could suppress the translation of LEPREL1. Notably, LEPREL1 was aberrantly downregulated (P = 2.54×10-18) in lung tumor tissues based on TCGA database. In conclusion, this is the first fine-mapping analysis of 3q28 region in Han Chinese, and we found two variants associated with lung cancer susceptibility in Asian population. What's more, rs3856776 was newly identified and might modulate lung cancer susceptibility by suppressing the function of LEPREL1.
Keywords: lung cancer, chromosome 3q28, fine mapping, susceptibility loci, Chinese population