Endometrial and Colorectal Tumors from Patients with Hereditary Nonpolyposis Colon Cancer Display Different Patterns of Microsatellite Instability

• Published in: The American journal of pathology Vol. 160; no. 6; pp. 1953 - 1958
• Main Authors: Kuismanen, Shannon A., Moisio, Anu-Liisa, Schweizer, Pascal, Truninger, Kaspar, Salovaara, Reijo, Arola, Johanna, Butzow, Ralf, Jiricny, Josef, Nyström-Lahti, Minna, Peltomäki, Päivi
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.06.2002; ASIP; American Society for Investigative Pathology
• Subjects: Adaptor Proteins, Signal Transducing; Alleles; Biological and medical sciences; Carrier Proteins; Colorectal Neoplasms - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - complications; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Dinucleotide Repeats - genetics; DNA-Binding Proteins; Endometrial Neoplasms - genetics; Female; Female genital diseases; Gastroenterology. Liver. Pancreas. Abdomen; Germ-Line Mutation; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Microsatellite Repeats; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplasm Proteins - genetics; Nuclear Proteins; Phosphoric Monoester Hydrolases - genetics; Proto-Oncogene Proteins - genetics; PTEN Phosphohydrolase; Short Communications; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Trinucleotide Repeat Expansion; Tumor Suppressor Proteins - genetics; Tumors; Human; Rectal disease; Carcinoma; Malignant tumor; Female genital diseases; Colonic disease; Microsatellite DNA; Rectum; Uterine diseases; Cytogenetics; Digestive diseases; Intestinal disease; Familial cancer; Female; Instability; Colon; Molecular biology; Endometrium; Comparative study
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)61144-3

The colorectum and uterine endometrium are the two most commonly affected organs in hereditary nonpolyposis colon cancer (HNPCC), but the genetic basis of organ selection is poorly understood. As tumorigenesis in HNPCC is driven by deficient DNA mismatch repair (MMR), we compared its typical consequence, instability at microsatellite sequences, in colorectal and endometrial cancers from patients with identical predisposing mutations in the MMR genes MLH1 or MSH2 . Analysis of non-coding (BAT25, BAT26, and BAT40) and coding mononucleotide repeats ( MSH6 , MSH3 , MLH3 , BAX , IGF2R , TGFβRII , and PTEN ), as well as MLH1 - and MSH2 -linked dinucleotide repeats (D3S1611 and CA7) revealed significant differences, both quantitative and qualitative, between the two tumor types. Whereas colorectal cancers displayed a predominant pattern consisting of instability at the BAT loci (in 89% of tumors), TGFβRII (73%), dinucleotide repeats (70%), MSH3 (43%), and BAX (30%), no such single pattern was discernible in endometrial cancers. Instead, the pattern was more heterogeneous and involved a lower proportion of unstable markers per tumor (mean 0.27 for endometrial cancers versus 0.45 for colorectal cancers, P < 0.001) and shorter allelic shifts for BAT markers (average 5.1 bp for unstable endometrial cancers versus 9.3 bp for colorectal cancers, P < 0.001). Among the individual putative “target” loci, PTEN instability was associated with endometrial cancers and TGFβRII instability with colon cancers. The different instability profiles in endometrial and colorectal cancers despite identical genetic predisposition underlines organ-specific differences that may be important determinants of the HNPCC tumor spectrum.