title: A recurrent mutation in PALB2 in Finnish cancer families.
abstract: 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.
authors.affiliation: Department of Clinical Genetics, University of Oulu and Oulu University Hospital, FIN-90029 OYS, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Erkko
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.forename: Jenni
authors.initials: J
authors.lastname: Nikkilä
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleutker
authors.forename: Kirsi
authors.initials: K
authors.lastname: Syrjäkoski
authors.forename: Arto
authors.initials: A
authors.lastname: Mannermaa
authors.forename: Anne
authors.initials: A
authors.lastname: Kallioniemi
authors.forename: Katri
authors.initials: K
authors.lastname: Pylkäs
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Karppinen
authors.forename: Katrin
authors.initials: K
authors.lastname: Rapakko
authors.forename: Alexander
authors.initials: A
authors.lastname: Miron
authors.forename: Qing
authors.initials: Q
authors.lastname: Sheng
authors.forename: Guilan
authors.initials: G
authors.lastname: Li
authors.forename: Henna
authors.initials: H
authors.lastname: Mattila
authors.forename: Daphne W
authors.initials: DW
authors.lastname: Bell
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Mervi
authors.initials: M
authors.lastname: Grip
authors.forename: Mervi
authors.initials: M
authors.lastname: Reiman
authors.forename: Arja
authors.initials: A
authors.lastname: Jukkola-Vuorinen
authors.forename: Aki
authors.initials: A
authors.lastname: Mustonen
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Kosma
authors.forename: Vesa
authors.initials: V
authors.lastname: Kataja
authors.forename: Ylermi
authors.initials: Y
authors.lastname: Soini
authors.forename: Ronny I
authors.initials: RI
authors.lastname: Drapkin
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
authors.forename: Robert
authors.initials: R
authors.lastname: Winqvist
mesh_terms: 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
chemical_list: D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins