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Journal of Clinical Oncology, Vol 24, No 12 (April 20), 2006: pp. 1962-1963 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.8750
In Reply:Centre for Molecular, Environmental, Genetic Epidemiology, Department of Public Health, The University of Melbourne, Victoria, Australia; and International Agency for Research into Cancer, Lyon, France
Centre for Molecular, Environmental, Genetic Epidemiology, Department of Public Health, The University of Melbourne, Victoria, Australia
Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
Epidemiology Centre, The Cancer Council Victoria, Carlton, Victoria, Australia In a recent population-based study of colorectal cancer cases diagnosed before age 45 years,1 we showed that immunohistochemistry (IHC) testing of the tumor for mismatch repair (MMR) proteins MLH1, MSH2, MSH6 and PMS2 was sensitive and specific for having a germline mutation in MMR genes MLH1, MSH2, MSH6, and PMS2. Of equal sensitivity and specificity was microsatellite instability (MSI) defined as MSI high and MSI low combined, but IHC testing may be preferable because it indicates which gene(s) were likely to be mutated and was a technically simpler test. We found that both these molecular tests were more sensitive than the Amsterdam Criteria,2 which are based on family history (P = .003). In their letter regarding our article, Evans et al took the opportunity to present new data and concluded that, for cases of colorectal cancer seen in their hereditary non-polyposis colorectal cancer testing service, MSI-high status was less sensitive than Amsterdam Criteria for having a germline mutation in MLH1 or MSH2. Their conclusion, however, is not justified because they did not take into consideration the role of chance. We calculate their respective sensitivities to be 58% (17 of 29; 95% CI, 39% to 76%) for MSI high and 72% (21 of 29; 95% CI, 53% to 87%) for Amsterdam Criteria, which are not significantly different (P = .3). Evans et al defined MSI as MSI high only. We calculated from their data that if they had included MSI low the sensitivity would have increased from 58% to 69% (20 of 29; 95% CI, 49% to 85%). We found that including MSI-low tumors increased the sensitivity from 72% to 94% and concluded that MSI low was a useful screen for MMR mutations as, in our data, it was particularly specific for MSH6 mutations, and explained approximately 20% of MMR deficiency. Sensitivity of a test is not the only criteria that should be considered for a screening test. From Evans et al we calculated that the positive predictive value of Amsterdam Criteria for a MMR mutation was a modest 57% (21 of 37; 39% to 73%) indicating that even in a population enriched for carriers, Amsterdam Criteria were not specific. The results of Evans et al are only pertinent to cases attending family cancer clinics, the majority of whom have a strong family history. In contrast, our results demonstrated the utility of screening tests for early-onset colorectal cancer cases irrespective of family history and are relevant to the general population. Based on our findings, a recommendation has been made by the Victorian Cooperative Oncology Group of The Cancer Council Victoria, that IHC testing be routinely performed on colorectal cancer tissue surgically removed from patients younger than 50 years of age at diagnosis. The process from diagnosis to MMR testing is outlined in Figure 1. 3
Evans et al support their preference for Amsterdam Criteria over MSI by claiming that molecular testing requires "tumor sections to be cut by a trained pathologist." In our opinion, a pathologist would only need to oversee the process which can be adequately performed by a trained technician. In cases unselected for family history, which was the setting for our study, a family history of colorectal cancer is often under-recognized4 because taking an accurate and multigenerational family history of cancer is not straightforward, and perhaps no easier, or less technically difficult to get and confirm than the effort and cost required for molecular testing of the tumor. Surgeons and gastroenterologists not working in a family cancer clinic may not have the required skills required to take family history, may not be able to validate reports of caner in relatives, may not know the requirements of meeting Amsterdam Criteria, and may not have the time. In conclusion, we envisage a new paradigm for colorectal cancer genetic services (see Fig 1) whereby identification of mutation carriers is not reliant on referral to family cancer clinics, but instead the family cancer clinics play an essential role in providing genetic counseling and genetic testing for individuals who have developed colorectal cancer and have, through testing of their tumor, a high chance of being a mutation carrier. The role of taking a family history before testing, an expensive, inaccurate, and time-consuming process, may become redundant. More resources will be available to put into providing clinical management for mutation-carrying families. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Southey MC, Jenkins MA, Mead L, et al: Use of molecular tumor characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol 23:6524-6532, 2005 2. Vasen HF, Watson P, Mecklin JP, et al: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453-1456, 1999[CrossRef][Medline] 3. Hopper JL: Application of genetics to the prevention of colorectal cancer. Recent Results Cancer Res 166:17-33, 2005[Medline] 4. Grover S, Stoffel EM, Bussone L, et al: Physician assessment of family cancer history and referral for genetic evaluation in colorectal cancer patients. Clin Gastroenterol Hepatol 2:813-819, 2004[Medline]
Related Correspondence
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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