Genome-Wide Cnv Study and Functional Evaluation Identified Ctdspl as Tumour Suppressor Gene for Cervical Cancer

Author(s): Dandan Zhang,Shuai Wang, Zhenli Li, Tao Cui5, Xiunian Chen, Jingwen Gong, Yatao Du, Yuexin Gan, Xiaoguang Ren, Jinyan Huang, Patrik KE Magnusson, Ping Zhang, Xingping Zhao, Dabao Xu, Wenqiang Yu, Huibo Wang, Gyllensten Ulf, Dan Chen

Background: Copy number variations (CNVs) may explain some of the missing heritability not identified in genome-wide association studies (GWASs).

Method: We performed the first genome-wide study of both common and rare germline CNVs in relation to cervical cancer by analyzing 731,422 single-nucleotide polymorphisms (SNPs) in 1,034 cervical cancer cases and 3,948 controls, followed by replication in 1,396 cases and 1,057 controls.

Results: We found that a 6367bp deletion in intron 1 of the CTD small phosphatase like gene (CTDSPL) was associated with 2.54- fold increased risk of cervical cancer (odds ratio = 2.54, 95% confidence interval =2.08-3.12, P = 2.0×10-19). This CNV is one of the strongest common genetic risk variants identified so far for cervical cancer. The deletion removes the binding sites of zinc finger protein 263 (ZNF263), binding protein 2 (GATA2) and interferon regulatory factor 1(IRF1), and hence downregulates the transcription of CTDSPL. HeLa cells expressing CTDSPL showed a significant decrease in colony- forming ability. Compared with control groups, mice injected with HeLa cells expressing CTDSPL exhibited a significant reduction in tumour volume. Furthermore, CTDSPL-depleted immortalized End1/E6E7 could form tumours in NOD- SCID mice.

Conclusion: These findings indicate that CTDSPL is a tumour suppressor gene for cervical cancer and the 6367bp deletion downregulates CTDSPL transcription by removing binding sites of ZNF263, GATA2 and IRF1.