A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
A recurrent mutation in PALB2 in Finnish cancer families
Tekijät: Erkko H, Xia B, Nikkilae J, Schleutker J, Syrjaekoski K, Mannermaa A, Kallioniemi A, Pylkas K, Karppinen SM, Rapakko K, Miron A, Sheng Q, Li GL, Mattila H, Bell DW, Haber DA, Grip M, Reiman M, Jukkola-Vuorinen A, Mustonen A, Kere J, Aaltonen LA, Kosma VM, Kataja V, Soini Y, Drapkin RI, Livingston DM, Winqvist R
Kustantaja: NATURE PUBLISHING GROUP
Julkaisuvuosi: 2007
Journal: Nature
Tietokannassa oleva lehden nimi: NATURE
Lehden akronyymi: NATURE
Vuosikerta: 446
Numero: 7133
Aloitussivu: 316
Lopetussivu: 319
Sivujen määrä: 4
ISSN: 0028-0836
DOI: https://doi.org/10.1038/nature05609
Tiivistelmä
BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer(1-3). Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified(4). The BRCA2-PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity(4). 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.
BRCA1, BRCA2 and other known susceptibility genes account for less than half of the detectable hereditary predisposition to breast cancer(1-3). Other relevant genes therefore remain to be discovered. Recently a new BRCA2-binding protein, PALB2, was identified(4). The BRCA2-PALB2 interaction is crucial for certain key BRCA2 DNA damage response functions as well as its tumour suppression activity(4). 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.
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