Correspondence

Molecular Diagnosis of Hereditary Nonpolyposis Colon Cancer

N Engl J Med 1998; 339:924-925September 24, 1998

Article

To the Editor:

Although I agree with Aaltonen et al. (May 21 issue)1 that there is a need for a reliable diagnostic test for hereditary nonpolyposis colorectal cancer, I am concerned about their recommendations. To propose testing for replication errors (and if positive, subsequent testing for mutations of DNA mismatch-repair genes) in all patients with colorectal cancer who meet specific criteria may be premature and perhaps appropriate only as part of a research protocol.

The authors cite the conclusion by Vasen et al.2 — “carriers of mismatch-repair gene mutations have a greater than 80 percent risk of cancer by the age of 75” — as the fundamental reason for devising efficient and cost-effective ways of detecting hereditary nonpolyposis colorectal cancer. However, it is important to recognize that in that study, the families selected for analysis for DNA mismatch-repair gene mutations were those that met the Amsterdam criteria: a finding of colorectal cancer in at least three family members in at least two successive generations, with at least one of the cancers diagnosed before the age of 50 years. The natural history of patients with colorectal cancer (as well as asymptomatic carriers) with DNA mismatch-repair gene mutations whose families do not meet the Amsterdam criteria is currently not fully appreciated. Therefore, the implementation of the recommendations of Aaltonen et al. may lead to the identification of patients with colorectal cancer and, ultimately, family members with DNA mismatch-repair gene mutations in whom the clinical significance and the appropriate management of these mutations is unknown.

Future studies are obviously needed in well-characterized and carefully followed heterogeneous populations in order to determine the clinical significance of these mutations in patients with colorectal cancer or unaffected family members whose families may not meet the Amsterdam criteria.

José G. Guillem, M.D., M.P.H.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021

2 References

1. 1

   Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998;338:1481-1487
   Full Text | Web of Science | Medline

2. 2

   Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996;110:1020-1027[Erratum, Gastroenterology 1996;111:1402.]
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Dr. Guillem is concerned that our recommendations “may lead to the identification of patients with colorectal cancer and, ultimately, family members with DNA mismatch-repair gene mutations in whom the clinical significance and the appropriate management of these mutations is unknown.” In other words, Dr. Guillem is concerned that the mutations identified by our procedure might have a relatively low penetrance. We fully agree that few studies have evaluated the risk conferred by the mismatch-repair gene mutations, outside the setting of selected, familial cases. Our study is one of the first to address this question. Among 509 unselected patients, we found 10 with a mismatch-repair gene mutation in the germ line. Since all these patients had multiple primary tumors, an early age at onset, or a family history of colorectal cancer, we had no reason to doubt the clinical significance of the mutations.

The predictive value of missense mutations (ones that alter only an amino acid) can sometimes be difficult to assess, but truncating mutations are known to cause disease. In our study, 9 of the 10 germ-line mutations were truncating. Although only 4 of the 10 patients had a family history that met the Amsterdam criteria, a further 3 patients could be genealogically connected with larger pedigrees that met the criteria. Moreover, 9 of the 10 patients had at least one first-degree relative with colorectal or endometrial cancer. These facts suggest that the penetrance of the mismatch-repair gene mutations that we found is just as high as that found in a study of large, previously identified families with hereditary nonpolyposis colorectal cancer that met the Amsterdam criteria.1 Moreover, available data do not indicate that the character or penetrance of the mutations differs between families that meet the Amsterdam criteria and those that do not meet the criteria.2,3

Our study provides evidence that in a group of unselected patients, analysis for replication errors followed by analysis for mismatch-repair gene mutations identifies features found in known cases of familial colon cancer. There are likely to be a small number of problematic cases in genetic tests for any hereditary disease, but this should not prevent the use of novel molecular methods to diagnose hereditary nonpolyposis colorectal cancer, since the benefits to the patient are considerable.4

Lauri A. Aaltonen, M.D.
University of Helsinki, FIN 00014 Helsinki, Finland

Jukka-Pekka Mecklin, M.D.
Jyväskylä Central Hospital, 40620 Jyväskylä, Finland

Albert de la Chapelle, M.D.
Ohio State University, Columbus, OH 43210

4 References

1. 1

   Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996;110:1020-1027[Erratum, Gastroenterology 1996;111:1402.]
   CrossRef | Web of Science | Medline

2. 2

   Wijnen JT, Vasen HFA, Khan PM, et al. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998;339:511-518
   Full Text | Web of Science | Medline

3. 3

   Nystrom-Lahti M, Wu Y, Moisio A-L, et al. DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 1996;5:763-769
   CrossRef | Web of Science | Medline

4. 4

   Jarvinen HJ, Mecklin J-P, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1995;108:1405-1411
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   José G. Guillem, Andrew J. Smith, Jorge Puig-La Calle, Leyo Ruo. (1999) Gastrointestinal polyposis syndromes. Current Problems in Surgery 36:4, 217-323
   CrossRef