Oncogenomics

Oncogene (2004) 23, 617–628. doi:10.1038/sj.onc.1207059

PTEN mutations are common in sporadic microsatellite stable colorectal cancer

Najah T Nassif1,9, Glenn P Lobo1,9, Xiaojuan Wu2, Christopher JA Henderson2, Carl D Morrison3,4, Charis Eng3,5,6,7, Bin Jalaludin8 and Eva Segelov1

  1. 1Cancer Research Laboratories, South West Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool, NSW 2170, Australia
  2. 2Department of Anatomical Pathology, South Western Area Pathology Service, Liverpool Hospital, Liverpool, NSW 2170, Australia
  3. 3Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
  4. 4Department of Pathology, The Ohio State University, Columbus, OH 43210, USA
  5. 5Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
  6. 6Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA
  7. 7Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, Cambridge CB2 2XZ, UK
  8. 8Epidemiology Unit, School of Public Health and Community Medicine, University of New South Wales, Liverpool Hospital, Liverpool, NSW 2170, Australia

Correspondence: N Nassif, Department of Cell and Molecular Biology, University of Technology Sydney, St Leonards Campus, Cnr Pacific Hwy and Westbourne St, Gore Hill, NSW 2065, Australia. E-mail: Najah.Nassif@uts.edu.au; E Segelov, Cancer Research Laboratories, South West Sydney Clinical School, University of NSW, Locked Bag 7103, Liverpool BC, NSW 1871, Australia. E-mail: e.segelov@unsw.edu.au

9These authors contributed equally to this work.

Received 20 June 2003; Revised 28 July 2003; Accepted 31 July 2003.

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Abstract

The tumour suppressor gene PTEN, located at chromosome sub-band 10q23.3, encodes a dual-specificity phosphatase that negatively regulates the phosphatidylinositol 3'-kinase (PI3 K)/Akt-dependent cellular survival pathway. PTEN is frequently inactivated in many tumour types including glioblastoma, prostate and endometrial cancers. While initial studies reported that PTEN gene mutations were rare in colorectal cancer, more recent reports have shown an approximate 18% incidence of somatic PTEN mutations in colorectal tumours exhibiting microsatellite instability (MSI+). To verify the role of this gene in colorectal tumorigenesis, we analysed paired normal and tumour DNA from 41 unselected primary sporadic colorectal cancers for PTEN inactivation by mutation and/or allelic loss. We now report PTEN gene mutations in 19.5% (8/41) of tumours and allele loss, including all or part of the PTEN gene, in a further 17% (7/41) of the cases. Both PTEN alleles were affected in over half (9/15) of these cases showing PTEN genetic abnormalities. Using immunohistochemistry, we have further shown that all tumours harbouring PTEN alterations have either reduced or absent PTEN expression and this correlated strongly with later clinical stage of tumour at presentation (P=0.02). In contrast to previous reports, all but one of the tumours with PTEN gene mutations were microsatellite stable (MSI-), suggesting that PTEN is involved in a distinct pathway of colorectal tumorigenesis that is separate from the pathway of mismatch repair deficiency. This work therefore establishes the importance of PTEN in primary sporadic colorectal cancer.

Keywords:

PTEN, sporadic colorectal cancer, mutation, microsatellite instability, loss of heterozygosity, immunohistochemistry

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