Assessment of <i>SLX4</i> Mutations in Hereditary Breast Cancers

<div><p>Background</p><p><i>SLX4</i> 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 <i>SLX4</i> 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.</p><p>Methods and Results</p><p>To determine if <i>SLX4</i> is involved in breast cancer susceptibility, we sequenced the entire <i>SLX4</i> 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 <i>BRCA1</i> or <i>BRCA2</i> 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 <i>SLX4</i> variants (4 novel and 1 rare) cDNAs in a human <i>SLX4</i>-null fibroblast cell line, RA3331. While wild type <i>SLX4</i> and all the other variants fully rescued the sensitivity to mitomycin C (MMC), campthothecin (CPT), and PARP inhibitor (Olaparib) the p.W823* <i>SLX4</i> mutant failed to do so.</p><p>Conclusion</p><p>Loss-of-function mutations in <i>SLX4</i> may contribute to the development of breast cancer in very rare cases.</p>