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Replication error phenotype in colorectal cancer
  1. J R JASS
  1. Department of Pathology, University Queensland
  2. Medical School, Herston Qld 4006, Australia
  3. Email: j.jass{at}mailbox.uq.edu.au
    1. B CURRAN,
    2. K LENEHAN,
    3. H MULCAHY,
    4. O TIGHE,
    5. M A BENNETT,
    6. E W KAY,
    7. D P O'DONOGHUE,
    8. M LEADER,
    9. D T CROKE
    1. Departments of Pathology and Biochemistry
    2. Royal College of Surgeons in Ireland
    3. 123 St Stephen's Green, Dublin, Republic of Ireland
    1. Dr D T Croke. Email:dtcroke{at}rcsi.ie

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    Editor,—The results presented in the article by Curran et al (

    ) may have been different if the authors had classified DNA microsatellite instability status as stable (MSS), low (MSI-L) or high (MSI-H), as recommended by a National Cancer Institute sponsored workshop.1 Their “RER+” group included both MSI-H and MSI-L cancers. The finding of bandshifts in two of eight dinucleotide markers is not specific for MSI-H cancers and will pick up a proportion of MSI-L cases.2 3 Two of the three RER+ cancers with a K-ras mutation (study Nos 52 and 129) showed bandshifts at only two loci, were left sided, and were positive for nuclear p53. It would be interesting to know if these cancers are characterised by bandshifts at the mononucleotide markers BAT25, BAT26, or BAT40 (specific and sensitive for MSI-H) and/or show loss of expression of hMLH1.4 I expect these (and other cancers) will be found to be MSI-L. This would also explain the high frequency of p53 positivity, not seen by others.5 Their conclusions with respect to RER+ cancers regarding molecular profiles and prognostic significance only compound the confusion generated by earlier studies that failed to draw the fundamental distinction between MSI-L and MSI-H.

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    Reply

    Editor,—Jass has pointed out that the criteria we used to define microsatellite instability (MSI) status are not in accordance with the recommendations produced by the National Cancer Institute workshop on microsatellite instability.1-1 We would point out that the conclusion of our study and submission of our manuscript were contemporaneous with the publication of these recommendations. It is clear that the criteria we used may have resulted in some MSI-L cases being included in the RER+ cohort for the purpose of the analysis. Clearly, the best way to address this issue would be to reassess our RER+ cohort using a mononucleotide repeat marker, BAT-25 or BAT-261-2 1-3; however, sufficient clinical material is no longer available to us.

    We based our analysis on eight dinucleotide repeat markers and defined tumours as RER+ if two or more markers (that is, 25%) exhibited allelic shifts.1-4 1-5 This analysis categorised 14% of tumours (22 of 159) as RER+. The NCI recommendations for analyses involving greater than five markers were that MSI-H would be defined as having allelic shifts in >30–40% of markers.1-1 This would suggest that our RER+ cohort must contain a number of MSI-L tumours but that, by the NCI criterion, the majority are likely to have been MSI-H. Therefore, while we readily concede that our study included a number of MSI-L tumours in the RER+ category, we believe that this number was small (in the context of a total patient cohort of 159) and does not completely invalidate our conclusions. Furthermore, as we have pointed out in our paper, we believe that our decision to include only patients who underwent potentially curative surgery for cancers which had penetrated beyond the bowel wall but which had not breached the peritoneal surface, spread to other organs or metastasised to lymph nodes or distant sites at the time of operation (T3, N0, M0), lends significant strength to our study in avoiding potentially confounding effects of tumour stage on microsatellite instability or other parameters.

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