Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair.
Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis. Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent oncogenic consequence of BRCA1-dependent dysfunction in DNA repair and provide insight into the pathogenesis of BBC with therapeutic implications. These findings also argue that obtaining an accurate census of genes mutated in cancer will require a systematic examination for gross gene rearrangements, particularly in tumors with deficient DSB repair.
Saal
Lao H
LH
Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.
Gruvberger-Saal
Sofia K
SK
Persson
Camilla
C
Lövgren
Kristina
K
Jumppanen
Mervi
M
Staaf
Johan
J
Jönsson
Göran
G
Pires
Maira M
MM
Maurer
Matthew
M
Holm
Karolina
K
Koujak
Susan
S
Subramaniyam
Shivakumar
S
Vallon-Christersson
Johan
J
Olsson
Håkan
H
Su
Tao
T
Memeo
Lorenzo
L
Ludwig
Thomas
T
Ethier
Stephen P
SP
Krogh
Morten
M
Szabolcs
Matthias
M
Murty
Vundavalli V V S
VV
Isola
Jorma
J
Hibshoosh
Hanina
H
Parsons
Ramon
R
Borg
Ake
A
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D004260:DNA Repair; D005260:Female; D019398:Genes, BRCA1; D016147:Genes, Tumor Suppressor; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics*; D051379:Mice; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*
D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human