Article Text


Microsatellite unstable colorectal cancer
  1. J R Jass
  1. Department of Pathology, University of Queensland, School of medicine, Herston, Queensland 4006, Australia j.jass{at}
    1. K Shitoh,
    2. F Konishi,
    3. T Furukawa,
    4. H Nagai,
    5. M Miyaki,
    6. T Iijima,
    7. T Tsukamoto
    1. Department of Surgery, Jichi Medical School, 3311–1Yakushiji, Minamikawachimachi, Tochigi, Japan
    2. Tokyo Metropolitan Komagome Hospital, 3–18–22 Honkomagome, Bunkyo-ku, Tokyo, Japan
    3. Department of Pharmacology, Kitasato University, 5–9–1 Shirogane, Minato-ku, Tokyo, Japan

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      The paper by Shitoh et al on the pathogenesis of non-familial colorectal carcinomas with high microsatellite instability (MSI) indicates little clinicopathological distinction from microsatellite stable cancers and a similar distribution of mutation in the adenomatous polyposis coli (APC) and TP53 genes, and loss of heterozygosity (LOH) at 17p.1 The authors claim that their data fit with some earlier studies, but several of the pioneering studies do not distinguish clearly between MSI low (MSI-L) and MSI high (MSI-H) cancers. Their findings are very different from multiple studies that adequately distinguish between sporadic MSI-H and MSI-L cancers.

      By way of explanation, the authors suggest that other studies may include hereditary non-polyposis colorectal carcinoma (HNPCC) cases. It is more likely that their own series includes HNPCC cases, because a lack of a family history does not exclude this diagnosis. Given that somatic mutations of hMSH2 and hMLH1 are described in six of their MSI-H cases, these could be examples of HNPCC because methylation of the promoter region of hMLH1 is regarded as the usual pathogenetic basis for non-familial examples of MSI-H colorectal cancer. Again, the failure to identify a germline mutation in these six cases does not exclude HNPCC: polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) is not a very sensitive technique for detecting germline mutations in HNPCC.

      It is interesting that of the six MSI-H cases with mutation of TP53, three show somatic mutation of hMSH2 or hMLH1. Of four MSI-H cases with LOH at 17p, three show somatic mutation of hMSH2 or hMLH1. Three of the 11 MSI-H cancers with mutation of APC also show somatic mutation of hMSH2 or hMLH1. The finding of APC mutation is expected in HNPCC cancers because these are associated with traditional adenomas.2 The relatively low mean age at onset of their MSI-H cases (67.5 years) also suggests the inclusion of some HNPCC cases because sporadic MSI-H cancer is age related. In HNPCC cancers identified in the course of population based surveys, distinguishing clinicopathological features—notably site and mucinous differentness—are not as obvious as they are in large kindreds ascertained through cancer family clinics.3 This would explain an earlier report by the same group that fails to associate mucinous differentiation with the MSI-H phenotype.4

      Given the origin of at least a subset of sporadic MSI-H cancers within serrated polyps (hyperplastic polyps, mixed polyps, and serrated adenomas),5 it is important to distinguish between sporadic and HNPCC cancers and not to assume that the underlying mechanisms are the same. If a considerable proportion of the cancers in the series by Shitoh and colleagues1 is HNPCC related, one may surmise that sporadic MSI-H cancers are relatively under represented in comparison with reports from the West. It would be interesting to relate this observation to underlying environmental differences. Nevertheless, the interesting possibility that two pathways might lead to sporadic MSI-H cancer, one via serrated polyps and one via flat adenoma, remains a valid hypothesis for further testing. The possibility that geographical factors could explain different pathogenetic pathways in the East and West would again be worth investigating.


      The authors reply

      We thank Professor Jass for having read our article1 carefully and for his comments. When investigating non-familial colorectal carcinoma cases, the criteria for defining these are very important. We guess that the non-familial colorectal carcinomas excluded familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal carcinoma (HNPCC) in most reports from Western countries. Viewing the criteria of non-familial colorectal carcinoma, our criteria were supposed to be stringent. In fact, a lack of a family history does not exclude HNPCC as Professor Jass mentioned. However, stringent criteria for a family history should be applied when evaluating the non-familal colorectal carcinoma cases. In addition, the characteristics of our microsatellite instability high (MSI-H) cases were different from those of HNPCC, as reported previously.

      We detected normal bands in polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) analysis of the matched normal tissue DNA from all six cases of hMSH2 or hMLH1 mutation. We agree that PCR-SSCP is not a very sensitive technique for detecting gemline mutation in HNPCC, as mentioned by Professor Jass, because the alternative splicing cases could not be detected by this method. However, we do not think that we missed the germline mutations in these six cases because of the existence of normal bands in normal tissues. We believe that all these six mutations were somatic.

      Jass mentioned that the finding of adenomatous polyposis coli (APC) gene mutation is expected in HNPCC; however, we think that mutations in the gene encoding β catenin mainly contribute to HNPCC colorectal carcinogenesis, as reported previously,2 and that the frequency of APC mutation is lower (∼ 20%) in these cancers. The frequency of APC mutation in our MSI-H non-familial colorectal cancers was higher than in HNPCC cancers. Interestingly the β catenin–Tcf signalling pathway, through either β catenin or APC mutation, frequently contributes to carcinogenesis of MSI-H non-familial cancers, similarly to HNPCC cancers.3 We think that most MSI-H cancers (both HNPCC and non-familal colorectal cancers) are associated with traditional adenomas. In HNPCC cancers identified in the course of population based surveys, mucinous-type tumours were three times more likely to occur in HNPCC kindreds than in the non-HNPCC familial group, and no HNPCC cases were detected in the over 65 years age group.4 We believe that these data support the notion that most of our cases were non-HNPCC cancers.

      We think that the two pathways (one via serrated polyp and one via flat adenoma ) are very interesting, as Professor Jass mentioned. We hope that we will be able to verify this pathway in the near future and we believe that the β catenin–Tcf signalling pathway may be a key factor in the carcinogenesis of MSI-H cancers.


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