Implications of CLSPN Variants in Cellular Function and Susceptibility to Cancer

Cancers

EricW. -F. Lam¹  MariaC. Lopes²  Diana Azenha²  Alexandra Martins³  TeresaC. Martins⁴  MartaS. Viegas⁴  Santiago Hernandez-Perez⁵  Yuse Martin⁵  Raimundo Freire⁵ 

[1] Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London W12 0NN, UK;Faculdade de Farmácia da Universidade de Coimbra, 3000-548 Coimbra, Portugal;Inserm U1245, UNIROUEN, Normandie Univ, Normandy Centre for Genomic and Personalized Medicine, 76183 Rouen, France;New preventive and therapeutic strategies, Centro de Neurociências e Biologia Celular, Universidade de Coimbra, 3004-504 Coimbra, Portugal;Unidad de Investigación, Hospital Universitario de Canarias, 38320 Tenerife, Spain;

关键词: Claspin;    genetic changes;    cancer;    breast cancer;    glioma;   

DOI  :  10.3390/cancers12092396

来源: DOAJ

【 摘 要 】

Claspin is a multifunctional protein that participates in physiological processes essential for cell homeostasis that are often defective in cancer, namely due to genetic changes. It is conceivable that Claspin gene (CLSPN) alterations may contribute to cancer development. Therefore, CLSPN germline alterations were characterized in sporadic and familial breast cancer and glioma samples, as well as in six cancer cell lines. Their association to cancer susceptibility and functional impact were investigated. Eight variants were identified (c.-68C>T, c.17G>A, c.1574A>G, c.2230T>C, c.2028+16G>A, c.3595-3597del, and c.3839C>T). CLSPN c.1574A>G (p.Asn525Ser) was significantly associated with breast cancer and was shown to cause partial exon skipping and decreased Claspin expression and Chk1 activation in a minigene splicing assay and in signalling experiments, respectively. CLSPN c.2028+16G>A was significantly associated with familial breast cancer and glioma, whereas c.2230T>C (p.Ser744Pro), was exclusively detected in breast cancer and glioma patients, but not in healthy controls. The remaining variants lacked a significant association with cancer. Nevertheless, the c.-68C>T promoter variant increased transcriptional activity in a luciferase assay. In conclusion, some of the CLSPN variants identified in the present study appear to modulate Claspin’s function by altering CLSPN transcription and RNA processing, as well as Chk1 activation.

【 授权许可】

Unknown