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
Notes: --- - "Export Date: 1 August 2013" - "CODEN: POLNC" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Kenneth Offit
    511 Offit
  2. Mark E Robson
    365 Robson
  3. Liying Zhang
    89 Zhang
  4. Zsofia Kinga Stadler
    148 Stadler
  5. Rajmohan Murali
    156 Murali
  6. Vijai Joseph
    117 Joseph
  7. Sohela Shah
    15 Shah
  8. Nichole Hansen
    9 Hansen
  9. Kara Lindsay Sarrel
    7 Sarrel