A recurrent mutation in PALB2 in Finnish cancer families.
BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer. Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified. The BRCA2-PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity. Here we show, by screening for PALB2 mutations in Finland that a frameshift mutation, c.1592delT, is present at significantly elevated frequency in familial breast cancer cases compared with ancestry-matched population controls. The truncated PALB2 protein caused by this mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair. Further screening of c.1592delT in unselected breast cancer individuals revealed a roughly fourfold enrichment of this mutation in patients compared with controls. Most of the mutation-positive unselected cases had a familial pattern of disease development. In addition, one multigenerational prostate cancer family that segregated the c.1592delT truncation allele was observed. These results indicate that PALB2 is a breast cancer susceptibility gene that, in a suitably mutant form, may also contribute to familial prostate cancer development.
Erkko
Hannele
H
Department of Clinical Genetics, University of Oulu and Oulu University Hospital, FIN-90029 OYS, Finland.
Xia
Bing
B
Nikkilä
Jenni
J
Schleutker
Johanna
J
Syrjäkoski
Kirsi
K
Mannermaa
Arto
A
Kallioniemi
Anne
A
Pylkäs
Katri
K
Karppinen
Sanna-Maria
SM
Rapakko
Katrin
K
Miron
Alexander
A
Sheng
Qing
Q
Li
Guilan
G
Mattila
Henna
H
Bell
Daphne W
DW
Haber
Daniel A
DA
Grip
Mervi
M
Reiman
Mervi
M
Jukkola-Vuorinen
Arja
A
Mustonen
Aki
A
Kere
Juha
J
Aaltonen
Lauri A
LA
Kosma
Veli-Matti
VM
Kataja
Vesa
V
Soini
Ylermi
Y
Drapkin
Ronny I
RI
Livingston
David M
DM
Winqvist
Robert
R
D000328:Adult; D000368:Aged; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011471:Prostatic Neoplasms / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins