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

摘要

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.