Letter abstract


Nature Genetics 40, 102 - 107 (2008)
Published online: 9 December 2007 | doi:10.1038/ng.2007.39

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

Lao H Saal1,2, Sofia K Gruvberger-Saal1, Camilla Persson3, Kristina Lövgren3, Mervi Jumppanen4,5, Johan Staaf3, Göran Jönsson3, Maira M Pires6, Matthew Maurer1,7, Karolina Holm3, Susan Koujak1, Shivakumar Subramaniyam8, Johan Vallon-Christersson3, Håkan Olsson3, Tao Su9, Lorenzo Memeo10, Thomas Ludwig1,8, Stephen P Ethier11, Morten Krogh12, Matthias Szabolcs8, Vundavalli VVS Murty1,8, Jorma Isola5, Hanina Hibshoosh8,9, Ramon Parsons1,7,8,9,14 & Åke Borg3,13,14

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Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis1, 2, 3. 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 subtype3, 4, 5; 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.

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  1. Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.
  2. College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
  3. Division of Oncology, Department of Clinical Sciences, Lund University, 22185 Lund, Sweden.
  4. Department of Pathology, Seinäjoki Central Hospital, 60220 Seinäjoki, Finland.
  5. Institute of Medical Technology, University of Tampere, 33014 Tampere, Finland.
  6. Department of Biochemistry, Columbia University, New York, New York 10032, USA.
  7. Department of Medicine, Columbia University, New York, New York 10032, USA.
  8. Department of Pathology, Columbia University, New York, New York 10032, USA.
  9. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.
  10. Pathology Unit, Mediterranean Institute of Oncology, 95029 Catania, Italy.
  11. Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
  12. Computational Biology and Biological Physics, Department of Theoretical Physics, Lund University, 22362 Lund, Sweden.
  13. Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University, 22185 Lund, Sweden.
  14. These authors contributed equally to this work.

Correspondence to: Ramon Parsons1,7,8,9,14 e-mail: rep15@columbia.edu



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