Human Molecular Genetics, 2002, Vol. 11, No. 4 445-450
© 2002 Oxford University Press
Distinct PTEN mutational spectra in hereditary non-polyposis colon cancer syndrome-related endometrial carcinomas compared to sporadic microsatellite unstable tumors
1Clinical Cancer Genetics Program and 2Human Cancer Genetics Program, Comprehensive Cancer Center and 3Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA, 4Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland, 5Department of Biosciences, University of Helsinki, Finland and 6Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, Cambridge, UK
Germline PTEN mutations cause Cowden syndrome (CS) and Bannayan–Riley–Ruvalcaba syndrome (BRR), two hamartoma-tumor syndromes with an increased risk of breast, thyroid and endometrial cancers. Somatic genetic and epigenetic inactivation of PTEN is involved in as high as 93% of sporadic endometrial carcinomas (EC), irrespective of microsatellite status, and can occur in the earliest precancers. EC is the most frequent extra-colonic cancer in patients with hereditary non-polyposis colon cancer syndrome (HNPCC), characterized by germline mutations in the mismatch repair (MMR) genes and by microsatellite instability (MSI) in component tumors. To determine whether PTEN is involved in the pathogenesis of EC arising in HNPCC cases, and whether PTEN inactivation precedes MMR deficiency, we obtained 41 ECs from 29 MLH1 or MSH2 mutation positive HNPCC families and subjected them to PTEN expression and mutation analysis. Immunohistochemical analysis revealed 68% (28/41) of the HNPCC-related ECs with absent or weak PTEN expression. The remaining 27% (11/41) of tumors had normal expression and 5% (2/41) with mixed populations showing weak/absent as well as normal expression. Mutation analysis of 20 aberrant PTEN-expressing tumors revealed that 17 (85%) harbored 18 somatic PTEN mutations. All mutations were frameshift, 10 (56%) of which involved the 6(A) tracts in exon 7 or 8. These results suggest that PTEN plays a significant pathogenic role in both HNPCC and sporadic endometrial carcinogenesis, unlike the scenarios for colorectal cancer. Furthermore, we have shown that somatic PTEN mutation, especially frameshift, is a consequence of profound MMR deficiency in HNPCC-related ECs. In contrast, among 60 previously reported MSI+ sporadic ECs with 70 somatic mutations in PTEN, 39 (56%) were frameshift, of which only eight (21%) were affecting the 6(A) tracts in exon 7 or 8 (P = 0.01), suggesting that PTEN mutations may precede MMR deficiency.
+ To whom correspondence should be addressed at: Human Cancer Genetics Program, The Ohio State University, 420 West 12th Avenue, Suite 690 TMRF, Columbus, OH 43210, USA. Tel: +1 614 292 2347; Fax: +1 614 688 3582; Email: eng-1@medctr.osu.edu
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