The Werner's syndrome 4330T>C (Cys1367Arg) gene variant does not affect the in vitro cytotoxicity of topoisomerase inhibitors and platinum compounds.
OBJECTIVE
Werner's syndrome (WS) is a recessive disorder of premature onset of processes associated with aging. Defective DNA repair has been reported after exposure of cells isolated from WS patients to DNA-damaging agents. The germline 4330T>C (Cys1367Arg) variant in the WS gene (WRN) has been associated with protection from age-related diseases, suggesting it has a functional role. We studied whether the 4330T>C variant confers altered drug sensitivity in vitro.


METHODS
4330T>C was genotyped in 372 human lymphoblastoid cell lines (LCLs) from unrelated healthy Caucasian individuals using a TaqMan-based method. The study was powered to detect the effect of the 4330T>C genotypes after exposure to camptothecin (based upon preliminary data). The effect of the 4330T>C variant on the cytotoxicity of etoposide, carboplatin, cisplatin and daunorubicin was also tested. WRN expression in 57 LCLs was measured by microarray.


RESULTS
No significant difference between the IC50 of the cells was observed among genotypes (P = 0.46) after exposure to camptothecin. No association was also observed for etoposide, carboplatin, cisplatin, and daunorubicin (ANOVA, P > 0.05). WRN expression also did not vary across genotypes (ANOVA, P = 0.37).


CONCLUSIONS
These results suggest that this nonsynonymous variant has relatively normal function at the cellular level.
Innocenti
Federico
F
Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637, USA. finnocen@medicine.bsd.uchicago.edu
Mirkov
Snezana
S
Nagasubramanian
Ramamoorthy
R
Ramírez
Jacqueline
J
Liu
Wanqing
W
Bleibel
Wasim K
WK
Shukla
Sunita J
SJ
Hennessy
Kathleen
K
Rosner
Gary L
GL
Cook
Edwin
E
Eileen Dolan
M
M
Ratain
Mark J
MJ
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology; D016190:Carboplatin / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005090:Exodeoxyribonucleases / Q000235:genetics*; D005838:Genotype; D006801:Humans; D017671:Platinum Compounds / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059003:Topoisomerase Inhibitors; D014898:Werner Syndrome / Q000235:genetics*; D000071657:Werner Syndrome Helicase
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D017671:Platinum Compounds; D012333:RNA, Messenger; D059003:Topoisomerase Inhibitors; D005047:Etoposide; D016190:Carboplatin; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D002945:Cisplatin; D002166:Camptothecin; D003630:Daunorubicin