Involvement of PTEN mutations in the genetic pathways of colorectal cancerogenesis

• Published in: Human molecular genetics Vol. 9; no. 2; pp. 283 - 287
• Main Authors: GUANTI, G, RESTA, N, SIMONE, C, CARIOLA, F, DEMMA, I, FIORENTE, P, GENTILE, M
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 22.01.2000
• Subjects: APC gene; BAX gene; Biological and medical sciences; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Colorectal Neoplasms - etiology; Colorectal Neoplasms - genetics; Female; Frameshift Mutation; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Genes, Tumor Suppressor - genetics; hMSH3 gene; hMSH6 gene; Humans; IGFIIR gene; Male; Medical sciences; Molecular and cellular biology; Phosphoric Monoester Hydrolases - genetics; Precancerous Conditions - genetics; PTEN gene; PTEN Phosphohydrolase; Repetitive Sequences, Nucleic Acid - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; TGFbRII gene; Tumor Suppressor Proteins; Tumors; Colonic disease; Case study; Human; Rectal disease; Rectum; Digestive diseases; Genetics; Tumor; Colon; Mutation; Carcinogenesis; Tumor suppressor gene
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/9.2.283

So far, somatic mutations of the PTEN gene have been found in several different neoplasms but not in colorectal tumours. As exons 7 and 8 of the PTEN coding sequence contain an (A)(6)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 whether PTEN gene repeats are frequently mutated in MI(+)colorectal cancers. Of 32 cases studied, seven mutations were found in six (18.75%) patients, as a PTEN biallelic frameshift mutation was observed in one case, with consequent loss of function of the gene. Loss of heterozygosity, evaluated in the remaining five cases using the microsatellite marker D10S541, was detected in two of three informative samples. To further address the role of the PTEN 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 TGFbRII gene only were present, indicating that PTEN may have a role in the mutator pathway of colorectal tumorigenesis. Overall, these results indicate that PTEN mutations are selected for during tumorigenesis in MI(+)colorectal tumours. The mutation of both PTEN alleles and evidence that the PTEN protein is expressed in normal colon suggest that loss of function of this gene could play a direct role in tumorigenesis.