Reply to Vasen et al.

Abstract

To the Editor: Hereditary nonpolyposis colorectal cancer (HNPCC) is associated, at least in part, with germline mutations in genes involved in DNA mismatch repair. Two genes, termed “hMSH2” and “hMLH1,” account for HNPCC in ∼60% of families whose symptoms adhere to the Amsterdam Criteria (Syngal et al. Syngal et al., 2000Syngal S Fox EA Eng C Kolodner RD Garber JE Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1.J Med Genet. 2000; 37: 641-645Crossref PubMed Scopus (230) Google Scholar). Three other genes—hPMS1, hPMS2, and hMSH6—account for an additional 5%–10%, the exact percentage not being known at this time. There remains a significant proportion of families, ∼30%, in which HNPCC does not appear to be accounted for by these genes, suggesting that additional genes, which may or may not have anything to do with DNA mismatch repair, are involved. Given that errors in DNA mismatch repair result in the characteristic signature of microsatellite instability (MSI), it should be relatively straightforward to determine whether families whose symptoms adhere to the Amsterdam Criteria but who do not harbor changes in known DNA mismatch-repair genes display MSI. To our knowledge, little information exists that indicates which of these two scenarios is most likely. The letter by Vasen et al. (Vasen et al., 2001Vasen HFA Morreau H Nortier JWR Is breast cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer?.Am J Hum Genet. 2001; 68 (in this issue): 1533-1534Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar) questions the association between mutations in the DNA mismatch-repair gene hMLH1 and breast cancer, which we identified in a report published at the beginning of this year (Scott et al. Scott et al., 2001Scott RJ McPhillips M Meldrum CJ Fitzgerald PE Adams K Spigelman AD du Sart D Tucker K Kirk J the Hunter Family Cancer Service Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative families.Am J Hum Genet. 2001; 68: 118-127Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar). In our report, we presented data that indicated a statistically significant difference between the likelihood of developing breast cancer in the hMLH1 mutation–positive group and the mutation-negative group compared with the likelihood in hMSH2 mutation–positive families. One of the reasons we focused on breast cancer was precisely because there was little or no agreement as to whether it was part of the disease spectrum of HNPCC. Furthermore, there were sufficient anecdotal reports of breast cancer occurring at an earlier age within the context of HNPCC to suggest that it is part of the disease spectrum. The results that were obtained reflect breast cancer incidence observed in our population. We cannot explain why the findings for our population differ from those observed in the Dutch families with HNPCC or those reported by Watson et al. (Watson and Lynch, 1993Watson P Lynch HT Extracolonic cancer in hereditary nonpolyposis colorectal cancer.Cancer. 1993; 71: 677-685Crossref PubMed Scopus (651) Google Scholar) or Aarnio et al. (Aarnio et al., 1999Aarnio M Sankila R Pukkala E Salovaara R Aaltonen LA de la Chapelle A Peltomaki P Mecklin J-P Jarvinen HJ Cancer risk in mutation carriers of DNA-mismatch-repair genes.Int J Cancer. 1999; 81: 214-218Crossref PubMed Google Scholar), who showed that there was no increased risk of breast cancer in HNPCC. In the analysis of Dutch families with HNPCC, either no association or indeed a slight protective effect of DNA mismatch-repair errors was reported. There are several interesting differences between our population and the Dutch population. The most interesting is the relative percentage of families with linkage to hMSH2 and hMLH1. In Holland, the ratio of hMSH2 to hMLH1 mutation carriers is ∼1:1, compared with our findings, which suggest a 1:2 ratio of hMSH2 to hMLH1 mutations. This difference does not account for the discrepancy seen between our population and the Dutch population, but it does suggests that there are significant differences between the two. We are currently accumulating more HNPCC families (>230) and will re-analyze the data when mutation analysis is complete, to determine whether the results of our initial analysis of the first 95 families hold true or were a result of a bias within our population. Finally, we agree with the notion put forward by Vasen et al. (Vasen et al., 2001Vasen HFA Morreau H Nortier JWR Is breast cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer?.Am J Hum Genet. 2001; 68 (in this issue): 1533-1534Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar) that breast cancer development may be accelerated in persons who are deficient in DNA mismatch repair.