Assessment of SLX4 Mutations in Hereditary Breast Cancers Journal Article
| 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. |
| Article Title: | Assessment of SLX4 Mutations in Hereditary Breast Cancers |
| 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. |
| Keywords: | adult; human tissue; aged; gene mutation; gene sequence; human cell; major clinical study; missense mutation; gene; cancer susceptibility; breast cancer; camptothecin; genetic variability; familial cancer; mitomycin; drug sensitivity; nonsense mutation; olaparib; slx4 gene |
| Journal Title: | PLoS ONE |
| Volume: | 8 |
| Issue: | 6 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2013-06-26 |
| Start Page: | e66961 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0066961 |
| PROVIDER: | scopus |
| PMCID: | PMC3694110 |
| PUBMED: | 23840564 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 August 2013" - "CODEN: POLNC" - "Source: Scopus" |
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