Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis

So far, somatic mutations of the PTEN gene have been found in several diffe rent neoplasms but not in colorectal tumours, As exons 7 and 8 of the PTEN coding sequence contain an (A), repeat and mononucleotide repeat sequences are targets for mutations in tumours with microsatellite instability (MI), we screened a panel of sporadic colorectal tumours exhibiting MI to test wh ether PTEN gene repeats are frequently mutated in MI+ colorectal cancers. O f 32 cases studied, seven mutations were found in six (18.75%) patients, as a PTEN biallelic frameshift mutation was observed in one case, with conseq uent loss of function of the gene. Loss of heterozygosity, evaluated in the remaining five cases using the microsatellite marker D105541, was detected in two of three informative samples, To further address the role of the PT EN gene in MI+ colorectal cancer, in the six patients with mutated PTEN, we analysed the mononucleotide repeats of six other genes: BAX, hMSH3, hMSH6, TGFbRII, IGFIIR and APC, In two of these six patients, mutations of the TG FbRII gene only were present, indicating that PTEN may have a role in the m utator pathway of colorectal tumorigenesis. Overall, these results indicate that PTEN mutations are selected for during tumorigenesis in MI+ colorecta l tumours, The mutation of both PTEN alleles and evidence that the PTEN pro tein is expressed in normal colon suggest that loss of function of this gen e could play a direct role in tumorigenesis.