Affiliations of authors: Gastroenterology (LL, PB, AM) and Pathology (MR), Istituto Clinico Humanitas, Milan, Italy
Correspondence to: Luigi Laghi, MD, PhD, Istituto Clinico Humanitas Gastroenterology, via Manzoni, 56 Rozzano, Milan 20089, Italy (e-mail: luigi.laghi{at}humanitas.it)
We read with interest the "Revised Bethesda Guidelines for Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability" article recently published in the Journal (1). We would like to comment on the discrepancies that exist between the guidelines for identifying hereditary nonpolyposis colorectal cancer (HNPCC) and the molecular tools recommended to detect microsatellite instability (MSI). We think that to identify HNPCC, practitioners with cancer patients need an anamnestic test to uncover a hereditary predisposition to cancer. To detect MSI, recommendations are made regarding panels to evaluate MSI, taking both MSI-high and MSI-low into account. Currently, the recognition of MSI-low colorectal cancers, if they really exist (2), is inconsequential in clinical practice. This fact should be clearly pointed out, so the reader not involved with research issues can avoid the complication of one additional pool of MSI tumors with clinical, pathologic, and biologic significance not fully determined. Furthermore, if the aim of the Guidelines is to identify the colorectal cancers with the highest chances of being HNPCC, should recommendation for MSI evaluation also apply to colorectal cancers in the general population? We believe that screening all colorectal cancers for MSI is feasible (3), but not by using the five-marker panel suggested in the Guidelines to test both normal and matched cancer tissue, which is a costly and time-consuming effort. Instead, we suggest that a single, sensitive and specific marker, BAT26, be used. This marker is 100% sensitive and 100% specific in colorectal cancers of patients of Caucasian ancestry and has yielded prevalence of the MSI phenotype between 8% and 12% (3,4). The only known false-negative example is the MSI cell line LoVo, which has a bi-allelic deletion of hMSH2 (5).
We have assessed MSI at BAT26 in a consecutive series of 740 unselected, colorectal cancers that were surgically resected at the same institution since 1997, and we have identified MSI in 60 (8%) of the tumors. Even though we have not completed the reappraisal of their family histories, we have identified 10 patients younger than age 50 years with MSI who represent 1.35% of all case patients and 16% of MSI patients. The prevalence of HNPCC in the above series of MSI cancers might increase after we merge the data concerning personal and family history with sequencing data from mismatch repair genes. Furthermore, we are collecting data on the clinical behavior of MSI colorectal cancer that might be different from that of colorectal cancer without this molecular defect (6). Thus, it is possible that, in referral centers, the analysis of one robust marker of MSI would become the core for the evaluation of mismatch repair defects in colorectal cancers and of their hereditary basis. Having a single reliable marker would allow clinicians to screen for HNPCC in all patients with colorectal cancer and might also speed up HNPCC diagnosis. The results of the screening could be used by clinicians, in conjunction with other specific criteria, to help identify patients and their relatives with HNPCC (7). As MSI-low colorectal cancer is currently a matter of investigation, multi-marker panels are likely best suited for a research context rather than for molecular analysis relevant to the clinical practice.
REFERENCES
1 Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:2618.
2 Laiho P, Launonen V, Lahermo P, Esteller M, Guo M, Herman JG, et al. Low-level microsatellite instability in most colorectal carcinomas. Cancer Res 2002;62:116670.
3 Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomaki P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998;338:14817.
4 Elsaleh H, Joseph D, Grieu F, Zeps N, Spry N, Iacopetta B. Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000;355:174550.[CrossRef][ISI][Medline]
5 Suraweera N, Duval A, Reperant M, Vaury C, Furlan D, Leroy K, et al. Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology 2002;123:180411.[CrossRef][ISI][Medline]
6 Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:24757.
7 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;116:14536.[Medline]
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