Assessment of SLX4 Mutations in Hereditary Breast Cancersopen access
- Authors
- Shah S.; Kim Y.; Ostrovnaya I.; Murali R.; Schrader K.A.; Lach F.P.; Sarrel K.; Rau-Murthy R.; Hansen N.; Zhang L.; Kirchhoff T.; Stadler Z.; Robson M.; Vijai J.; Offit K.; Smogorzewska A.
- Issue Date
- Jun-2013
- Publisher
- Public Library of Science
- Citation
- PLoS ONE, v.8, no.6
- Journal Title
- PLoS ONE
- Volume
- 8
- Number
- 6
- URI
- https://scholarworks.sookmyung.ac.kr/handle/2020.sw.sookmyung/6380
- DOI
- 10.1371/journal.pone.0066961
- ISSN
- 1932-6203
- Abstract
- Background:SLX4 encodes a DNA repair protein that regulates three structure-specific endonucleases and is necessary for resistance to DNA crosslinking agents, topoisomerase I and poly (ADP-ribose) polymerase (PARP) inhibitors. Recent studies have reported mutations in SLX4 in a new subtype of Fanconi anemia (FA), FA-P. Monoallelic defects in several FA genes are known to confer susceptibility to breast and ovarian cancers.Methods and Results:To determine if SLX4 is involved in breast cancer susceptibility, we sequenced the entire SLX4 coding region in 738 (270 Jewish and 468 non-Jewish) breast cancer patients with 2 or more family members affected by breast cancer and no known BRCA1 or BRCA2 mutations. We found a novel nonsense (c.2469G>A, p.W823*) mutation in one patient. In addition, we also found 51 missense variants [13 novel, 23 rare (MAF<0.1%), and 15 common (MAF>1%)], of which 22 (5 novel and 17 rare) were predicted to be damaging by Polyphen2 (score = 0.65-1). We performed functional complementation studies using p.W823* and 5 SLX4 variants (4 novel and 1 rare) cDNAs in a human SLX4-null fibroblast cell line, RA3331. While wild type SLX4 and all the other variants fully rescued the sensitivity to mitomycin C (MMC), campthothecin (CPT), and PARP inhibitor (Olaparib) the p.W823* SLX4 mutant failed to do so.Conclusion:Loss-of-function mutations in SLX4 may contribute to the development of breast cancer in very rare cases. © 2013 Shah et al.
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