title: Assessment of SLX4 Mutations in Hereditary Breast Cancers.
abstract: 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.
  
  
  
  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.
  
  
  
  Loss-of-function mutations in SLX4 may contribute to the development of breast cancer in very rare cases.
authors.affiliation: Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Sohela
authors.initials: S
authors.lastname: Shah
authors.forename: Yonghwan
authors.initials: Y
authors.lastname: Kim
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.forename: Rajmohan
authors.initials: R
authors.lastname: Murali
authors.forename: Kasmintan A
authors.initials: KA
authors.lastname: Schrader
authors.forename: Francis P
authors.initials: FP
authors.lastname: Lach
authors.forename: Kara
authors.initials: K
authors.lastname: Sarrel
authors.forename: Rohini
authors.initials: R
authors.lastname: Rau-Murthy
authors.forename: Nichole
authors.initials: N
authors.lastname: Hansen
authors.forename: Liyng
authors.initials: L
authors.lastname: Zhang
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhoff
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Stadler
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
authors.forename: Joseph
authors.initials: J
authors.lastname: Vijai
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Agata
authors.initials: A
authors.lastname: Smogorzewska
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D002460:Cell Line; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D045522:Recombinases / Q000235:genetics*; D055815:Young Adult
chemical_list: D045522:Recombinases; C542319:SLX4 protein, human