CORRESPONDENCE

Re: Characterization of Hereditary Nonpolyposis Colorectal Cancer Families From a Population-Based Series of Cases

D. Gareth Evans, Chu Lee Wu, Shelia Walsh, Isobel Hansen, Loreena Verma, Charmaine Robinson, Reginald Kingston, Eamonn R. Maher

Affiliations of authors: D. G. Evans, Department of Medical Genetics, St. Mary's Hospital, and Centre for Cancer Epidemiology, Christie Hospital, Manchester, U.K.; C.-L. Wu, I. Hansen, Department of Medical Genetics, St. Mary's Hospital; S. Walsh, C. Robinson, R. Kingston, Department of Clinical Studies, Trafford General Hospital, Manchester; L. Verma, E. R. Maher, Section of Medical and Molecular Genetics, University of Birmingham, The Medical School, Edgbaston, U.K.

Correspondence to: Professor D. Gareth Evans, St. Mary's Hospital, Regional Genetic Service, Hathersage Rd., Manchester, M130JH, U.K. (e-mail: gevans{at}central.cmht.nwcst.nhs.uk).

Peel et al. (1) have reported a low frequency of mismatch repair (MMR) gene defects in a population-based series of colorectal cancers. Previously, we determined the incidence of hereditary nonpolyposis colorectal cancer (HNPCC) by family history of colorectal cancer in a population-based series of colorectal cancers (2).

We now describe a molecular study to estimate the incidence of MMR mutations in an extended series of 1329 patients. Since 1981, all patients with colorectal cancer (n = 1329) presenting to the referring hospital have been asked about a family history of cancer in first- or second-degree relatives. The family trees were classified as HNPCC according to the strict Amsterdam criteria (3), the Amsterdam II criteria, the modified Amsterdam criteria, or the Bethesda criteria (4).

Case patients classified by the Amsterdam criteria were analyzed for MLH1 and MSH2 mutations by single-strand conformation polymorphism analysis. Individuals fulfilling other criteria were investigated for tumor microsatellite instability (MSI) (5) and for MLH1/MSH2 immunostaining in most cases. Germline MSH2 and MLH1 mutations were sought in case patients with MSI or abnormal immunostaining.

A family history of colorectal cancer in first-degree relatives was present in 134 (10%) of 1329 patients, although only three (0.2%) case patients had a family history of colorectal cancer consistent with the strict Amsterdam criteria (3). A further 16 case patients had two or more first-degree relatives with colorectal or other HNPCC cancers (Amsterdam II criteria), and another 17 case patients had at least one affected first-degree relative where the index case patient or the relative was diagnosed with colorectal cancer at age less than 55 years (the modified Amsterdam criteria). There were 29 patients with colorectal cancer that was diagnosed at age less than 45 years; of these patients, five (17%) had an affected first-degree relative (which included two of the three HNPCC families). Two patients had double primary tumors that involved the colon and another HNPCC cancer but did not fulfill any HNPCC criteria. Germline DNA was available for two of three HNPCC patients eligible for mutation analysis, and 62 patients were eligible for tumor studies. Germline mutations were identified in both HNPCC patients (Table 1Go). Tumor DNA was available for 49 of 62 case patients eligible for tumor studies, and three of these case patients demonstrated MSI. One of these patients (patient 2, Table 1Go) fulfilled Bethesda and Amsterdam II criteria, and mutational analysis revealed a truncating mutation in exon 15 of MSH2. The remaining two patients aged less than 45 years (patients 1 and 3 in Table 1Go) and a further patient with low-level MSI and absent MLH1 tumor immunostaining did not have a detectable mutation. Thus, MSI was identified in five (10%) of 51 tumors [four (16%) of 24 of those patients diagnosed at age <45 years] analyzed, and three of these patients had a germline MLH1 or MSH2 mutation.


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Table 1. Patients with mutations in MLH1 and MSH2, of 1329 patients with colorectal cancer
 
We observed a very low frequency (0.2%) of HNPCC by strict Amsterdam criteria. It is recognized that the Amsterdam criteria are relatively specific but have only moderate sensitivity for HNPCC diagnosis (4). Germline mutations in MSH2 and MLH1 account for most HNPCC gene mutations, and only a small proportion of patients with germline MMR mutations will have negative tumor MSI studies. We detected germline MLH1 or MSH2 mutations in only three case patients; a further case patient satisfied the Amsterdam criteria, but no DNA was available for analysis. Only three of 48 early-onset or familial case patients with available tumor DNA had tumor MSI, and one of these had a germline mutation. Even if we allow for the various causes of false-negative results, our data further support the concept that non-HNPCC familial aggregations of colorectal cancer are unlikely to have an MMR mutation and the frequency of HNPCC in colorectal cancer case patients outside founder populations is approximately 1% (1,6,7).

REFERENCES

1 Peel DJ, Ziogas A, Fox EA, Gildea M, Laham B, Clements E, et al. Characterization of hereditary nonpolyposis colorectal cancer families from a population-based series of cases. J Natl Cancer Inst 2000;92:1517–22.[Abstract/Free Full Text]

2 Evans DG, Walsh S, Jeacock J, Robinson C, Hadfield L, Davies DR, et al. Incidence of hereditary non-polyposis colorectal cancer in a population-based study of 1137 consecutive cases of colorectal cancer. Br J Surg 1997;84:1281–5.[Medline]

3 Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 1999;36:801–18[Abstract/Free Full Text]

4 Syngal 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;37:641–5.[Abstract/Free Full Text]

5 Verma L, Kane MF, Brassett C, Schmeits J, Evans DG, Kolodner RD, et al. Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer. J Med Genet 1999;36:678–82.[Abstract/Free Full Text]

6 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;338:1481–7.[Abstract/Free Full Text]

7 Ravnik-Glavac M, Potocnik U, Glavac D. Incidence of germline mutations in hMLH1 and hMSH2 mutations (HNPCC patients) among newly diagnosed colorectal cancers in a Slovenian population. J Med Genet 2000;37:533–6.[Free Full Text]



             
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