Correspondence
Microsatellite Instability in Colorectal Cancer
N Engl J Med 2000; 342:1607-1608May 25, 2000
- Article
To the Editor:
Gryfe et al. (Jan. 13 issue)1 report that microsatellite instability in colorectal cancer is independently predictive of a favorable outcome. We have some concern about this conclusion, since the tumors with microsatellite instability were more frequently localized (59 percent, vs. 38 percent of those with microsatellite stability) and since the 10-year survival at each Dukes' stage did not differ significantly between patients with microsatellite instability and those with microsatellite stability (Figure 2B, 2C, 2D, and 2E in the article). The authors state that in a multivariate analysis, microsatellite status was found to be “significantly and independently” associated with survival. In our opinion, however, we still need clear evidence in a univariate analysis of a survival advantage at each Dukes' stage.
1 ReferencesMaurizio Ponz de Leon, M.D.
Luca Roncucci, M.D.
Università di Modena Policlinico, 41100 Modena, Italy1
Gryfe R ,Kim H ,Hsieh ETK , et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000;342:69-77
Full Text | Web of Science | Medline
To the Editor:
In contrast with the results of other studies,1,2 which indicated that 15 to 20 percent of colorectal cancers had low-frequency microsatellite instability, the percentage of tumors with low-frequency microsatellite instability detected by Gryfe et al. was surprisingly low (3 percent). We believe that this underestimation could result from the fact that only tumors showing one unstable microsatellite locus (of an initial set of five loci) were further analyzed in order to distinguish between cancers with low-frequency and high-frequency microsatellite instability. Since tumors without an unstable locus were not included in the second test series, no distinction between cancers with low-frequency microsatellite instability and those with microsatellite stability could be made. Thus, a considerable proportion of patients (10 to 15 percent) may have been falsely characterized as having microsatellite stability. Because all the patients who had colorectal cancer with low-frequency microsatellite instability were subsequently excluded from further statistical analysis, information bias may have been introduced, distorting the findings with respect to clinical outcome among patients whose cancer had high-frequency microsatellite instability as compared with microsatellite stability.
Among the 84 patients who had colorectal cancer with high-frequency microsatellite instability for whom information on family history was available, 13 were found to fulfill the classic Amsterdam criteria for hereditary nonpolyposis colorectal cancer. However, no information is given on how many patients met the recently revised criteria of the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (the Amsterdam II criteria),3 which also include extracolonic tumors associated with hereditary nonpolyposis colorectal cancer, or the more clinically oriented Bethesda guidelines.4
In view of the diagnostic importance of testing for microsatellite instability in hereditary nonpolyposis colorectal cancer, immunohistochemical and mutational analysis of the mismatch-repair genes, at least in this group of patients, would be essential for a better understanding of the biologic relevance of microsatellite instability in colorectal carcinogenesis.
4 ReferencesKarl Heinimann, M.D., Ph.D.
Hansjakob Müller, M.D.
Zuzana Dobbie, Ph.D.
University Clinics of Basel, CH-4031 Basel, Switzerland1
Thibodeau SN ,French AJ ,Cunningham JM , et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 1998;58:1713-1718
Web of Science | Medline2
Boland CR ,Thibodeau SN ,Hamilton SR , et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58:5248-5257
Web of Science | Medline3
Rodriguez-Bigas MA ,Boland CR ,Hamilton SR , et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997;89:1758-1762
CrossRef | Web of Science | Medline4
Vasen HF ,Watson P ,Mecklin JP ,Lynch HT . New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453-1456
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Using a multivariate analysis with the Cox proportional-hazards model to study a population-based group of young patients with colorectal cancer, we found that high-frequency microsatellite instability was a significant predictor of improved survival. Similar estimates of this survival benefit were evident with use of two different multivariate models, and both models included cancer stage. The inclusion of patients with all stages of disease demonstrates the proportionality of this survival advantage. Ponz de Leon and Roncucci would like to see definitive evidence of a survival advantage at each stage, but for the statistical power required to estimate significant survival benefits at each stage, we would need far more patients than the 607 we studied. The inclusion of patients with all stages of disease allowed us to demonstrate that cancers with high-frequency microsatellite instability have a lower chance of metastasizing to regional lymph nodes or distant organs. Had we restricted our study to patients with only a single stage of cancer, this observation could not have been made. Moreover, it is worth pointing out that others have reported a significant survival advantage for stage III colorectal cancers with high-frequency microsatellite instability.1
In response to Heinimann et al.: we used National Cancer Institute criteria to define low-frequency microsatellite instability.2 Although they were not included in our survival analyses, patients who had cancer with low-frequency microsatellite instability were clinically indistinguishable from patients with microsatellite stability (unpublished data), a finding consistent with others' results.2 It is therefore unlikely that the inclusion of patients who had tumors with low-frequency microsatellite instability would have affected the survival analyses. The genetic basis of low-frequency microsatellite instability is unknown, and it remains controversial whether these tumors should be distinguished from those with microsatellite stability.2
In another report, 68 of 102 patients (67 percent) who had a tumor with high-frequency microsatellite instability fulfilled at least one of the Bethesda criteria.3 However, 31 of these patients qualified only because they were less than 45 years old at diagnosis. The Bethesda guidelines were developed to guide testing for microsatellite instability rather than to designate a specific test for hereditary nonpolyposis colorectal cancer. Comparison of the patients with high-frequency microsatellite instability who fulfilled the Bethesda criteria with those who did not revealed no significant difference in five-year survival (76±5 and 76±7 percent, respectively; P=0.8). Use of newly revised criteria of the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (the Amsterdam II criteria)4 identified no additional cases of hereditary nonpolyposis colorectal cancer in our series.
We agree that mutational analyses of mismatch-repair genes would further contribute to the biologic importance of testing for microsatellite instability in both hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer, and we are currently undertaking these studies.
4 ReferencesRobert Gryfe, M.D.
Mark Redston, M.D.
Steven Gallinger, M.D.
Samuel Lunenfeld Research Institute, Toronto, ON M5G 1X5, Canada1
Halling KC ,French AJ ,McDonnell SK , et al. Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers. J Natl Cancer Inst 1999;91:1295-1303
CrossRef | Web of Science | Medline2
Boland CR ,Thibodeau SN ,Hamilton SR , et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58:5248-5257
Web of Science | Medline3
Rodriguez-Bigas MA ,Boland CR ,Hamilton SR , et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997;89:1758-1762
CrossRef | Web of Science | Medline4
Vasen HF ,Watson P ,Mecklin JP ,Lynch HT . New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453-1456
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Laurent Poincloux, Xavier Durando, Jean François Seitz, Emilie Thivat, Valérie-Jeanne Bardou, Marie-Hélène Giovannini, Danièle Parriaux, Nicolas Barriere, Marc Giovannini, Jean-Robert Delpero, Geneviève Monges. (2009) Loss of Bcl-2 expression in colon cancer: A prognostic factor for recurrence in stage II colon cancer. Surgical Oncology 18:4, 357-365
CrossRef2
Alessandro Lugli, Alexandar Tzankov, Inti Zlobec, Luigi Maria Terracciano. (2008) Differential diagnostic and functional role of the multi-marker phenotype CDX2/CK20/CK7 in colorectal cancer stratified by mismatch repair status. Modern Pathology 21:11, 1403-1412
CrossRef3
Martha L. Slattery, Karen Curtin, Donna Schaffer, Kristen Anderson, Wade Samowitz. (2002) Associations between family history of colorectal cancer and genetic alterations in tumors. International Journal of Cancer 97:6, 823-827
CrossRef4
A. ??rbo, K. Eklo, M. Kopp. (2002) A Semiautomated Test for Microsatellite Instability and its Significance for the Prognosis of Sporadic Endometrial Cancer in Northern Norway. International Journal of Gynecological Pathology 21:1, 27-33
CrossRef
