Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability - PubMed (original) (raw)

Endometrial and colorectal tumors from patients with hereditary nonpolyposis colon cancer display different patterns of microsatellite instability

Shannon A Kuismanen et al. Am J Pathol. 2002 Jun.

Abstract

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, TGF beta RII, 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), TGF beta RII (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 TGF beta RII 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.

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Figures

Figure 1.

Figure 1.

Comparison of the MSI profiles in colorectal (A) and endometrial (B) cancers originating from MLH1 or MSH2 mutation carriers. Mutations 1–8 affect MLH1 while mutation 9 affects MSH2. The expression patterns of the proteins corresponding to the genes mutated in the germline (MLH1 for cases with mutations 1–8, MSH2 for cases with mutation 9), as determined by immunohistochemistry (IHC), are shown on the right. Case F67:6 in A is a colorectal adenoma. Eight patients were diagnosed with both endometrial and colorectal cancer, and the identification numbers of these individuals are in italics. The tumors were grouped into four categories according to their BAT and coding region instability patterns (among colorectal cancers, there were no cases in the “coding region instability only” category). Among genes with coding repeats, MSH6, MSH3, and MLH3 are MMR genes, BAX is a proapoptotic gene, and IGF2R, TGFβRII, and PTEN are tumor suppressor genes. The percentage of (informative) tumors showing instability for each marker is indicated below the marker columns. MSI: black, unstable; white, stable; gray, not determined. IHC: diagonal stripes, not expressed; gray, not determined.

Figure 2.

Figure 2.

Distribution of allelic size shifts in colorectal versus endometrial tumors. The values on the x axis represent the means of size deviations at the BAT25, BAT26, and BAT40 loci from the length of the germline alleles, calculated for each tumor and plotted against the number of cases. All size shifts were deletions.

Figure 3.

Figure 3.

A: Autoradiographs of mononucleotide repeat instability analysis of the PTEN (exon 7), TGFβRII, and BAT26 loci in paired cases of colorectal (C) and endometrial (E) tumors from the same patients. These loci are essentially monomorphic, and the position of the normal-sized fragment can be determined from lanes N1 and N2 that represent normal DNA samples from control individuals. Arrowheads denote fragments of aberrant size resulting from gains (endometrial tumor from F19:48, TGFβRII) or losses of mononucleotides (all other unstable cases, PTEN and TGFβRII). Shortening of the A26 repeat within BAT26 gives rise to a ladder of extra fragments in the lower portion of the autoradiograph (+) that are absent in stable cases (−). B: Autoradiograph of BAT40 results, coded (+) or (−) as BAT26 above. Since BAT40 is polymorphic, the results from normal DNA of each individual (N) are shown adjacent to tumor lanes.

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