Evaluation of RAD50 in familial breast cancer predisposition.
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.
Tommiska
Johanna
J
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
Seal
Sheila
S
Renwick
Anthony
A
Barfoot
Rita
R
Baskcomb
Linda
L
Jayatilake
Hiran
H
Bartkova
Jirina
J
Tallila
Jonna
J
Kaare
Milja
M
Tamminen
Anitta
A
Heikkilä
Päivi
P
Evans
D Gareth
DG
Eccles
Diana
D
Aittomäki
Kristiina
K
Blomqvist
Carl
C
Bartek
Jiri
J
Stratton
Michael R
MR
Nevanlinna
Heli
H
Rahman
Nazneen
N
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
D004268:DNA-Binding Proteins; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes