Article Text

  1. J. K. Lee,
  2. S. C. Huang,
  3. J. M. Carethers
  1. University of California, San Diego


Purpose Microsatellite unstable-high (MSI-H) colorectal cancers account for 15% of sporadic colorectal cancers and indicate genomic instability at microsatellite sequences. Many MSI mutations occur in targeted genes important for regulation of growth suppression. The tumor 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 contains two coding hexadenine microsatellites that often change in length within cancers of the breast, endometrium, prostate, and reportedly colon cancers, and is thought to play a role in its pathogenesis. Here, we analyzed MSI-H sporadic colorectal cancers to determine if PTEN microsatellite frameshifts occur and whether somatic inactivation of PTEN occurs in the tumors with PTEN frameshift mutations.

Methods 91 MSI-H sporadic colon cancers from a total cohort of 710 sporadic colon cancers were analyzed for mutations in two hexadenine tracts (exons 7 and 8) of PTEN. PTEN expression was determined by immunohistochemistry using an antibody targeting an epitope beyond the predicted truncated protein.

Results 9/91 MSI-H cancers (10%) demonstrated frameshifts in exon 8 while 2/62 demonstrated frameshifts in exon 7 (3%). Of tumors with mutant PTEN, all demonstrated down regulation or complete loss of PTEN in the epithelium.

Conclusions PTEN frameshifts occur at a greater rate in exon 8 than exon 7 in MSI-H sporadic colorectal cancers. PTEN frameshift mutations are associated with down-regulation or inactivation of PTEN in MSI-H sporadic colorectal cancers. Loss of this function may contribute to the pathogenesis of colon cancers.

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