title: Evaluation of RAD50 in familial breast cancer predisposition.
abstract: The genes predisposing to familial breast cancer are largely unknown, but 5 of the 6 known genes are involved in DNA damage repair. RAD50 is part of a highly conserved complex important in recognising, signalling and repairing DNA double-strand breaks. Recently, a truncating mutation in the RAD50 gene, 687delT, was identified in 2 Finnish breast cancer families. To evaluate the contribution of RAD50 to familial breast cancer, we screened the whole coding region for mutations in 435 UK and 46 Finnish familial breast cancer cases. We identified one truncating mutation, Q350X, in one UK family. We screened a further 544 Finnish familial breast cancer cases and 560 controls for the 687delT mutation, which was present in 3 cases (0.5%) and 1 control (0.2%). Neither Q350X nor 687delT segregated with cancer in the families in which they were identified. Functional analyses suggested that RAD50 687delT is a null allele as there was no detectable expression of the mutant protein. However, the wild-type allele was retained and expressed in breast tumors from mutation carriers. The abundance of the full-length RAD50 protein was reduced in carrier lymphoblastoid cells, suggesting a possible haploinsufficiency mechanism. These data indicate that RAD50 mutations are rare in familial breast cancer and either carry no, or a very small, increased risk of cancer. Altogether, these results suggest RAD50 can only be making a very minor contribution to familial breast cancer predisposition in UK and Finland.
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Tommiska
authors.forename: Sheila
authors.initials: S
authors.lastname: Seal
authors.forename: Anthony
authors.initials: A
authors.lastname: Renwick
authors.forename: Rita
authors.initials: R
authors.lastname: Barfoot
authors.forename: Linda
authors.initials: L
authors.lastname: Baskcomb
authors.forename: Hiran
authors.initials: H
authors.lastname: Jayatilake
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Jonna
authors.initials: J
authors.lastname: Tallila
authors.forename: Milja
authors.initials: M
authors.lastname: Kaare
authors.forename: Anitta
authors.initials: A
authors.lastname: Tamminen
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
mesh_terms: D017766:Acid Anhydride Hydrolases; D000368:Aged; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D006113:United Kingdom
chemical_list: D004268:DNA-Binding Proteins; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes