Correspondence

CDKN2A Mutations in Multiple Primary Melanomas

N Engl J Med 1998; 339:347-348July 30, 1998

Article

To the Editor:

The clinical relevance of the conclusion of Monzon et al. (March 26 issue)1 that patients with multiple melanomas have a germ-line mutation of the CDKN2A gene that predisposes them to melanoma is difficult to ascertain because no information is provided on the incidence of this mutation in patients who do not have multiple primary melanomas or in the normal population. Consequently, the possibility that this mutation is unrelated to the pathogenesis of melanoma has not been excluded.

In any case, the mutation appears to be of minor clinical relevance, even if it is associated with multiple melanomas, because it was present in only 15 percent of patients who had multiple primary melanomas, indicating that other factors are more important with respect to the multiple occurrences of this cancer in some patients.

Jean-Claude Bystryn, M.D.
New York University Medical Center, New York, NY 10016

1 References

1. 1

   Monzon J, Liu L, Brill H, et al. CDKN2A mutations in multiple primary melanomas. N Engl J Med 1998;338:879-887
   Full Text | Web of Science | Medline

To the Editor:

In their interesting paper, Monzon and his colleagues write, “Approximately 10 percent of patients with melanoma have family histories of the disease, suggesting a genetic susceptibility.” If the general risk of melanoma is 1 in 80, the chance of its presence in the lifetime of any group of 5 persons is 1–(79/80)⁵, or 6 percent, and of any group of 10 persons, 11.8 percent. Its presence in the propositus does not affect the odds. For a condition this common, its presence in a single relative may mean little.

T.H. Hughes-Davies, F.R.C.P.
Breamore Marsh, Fordingbridge, Hampshire SP6 2EJ, United Kingdom

Author/Editor Response

The authors reply:

To the Editor: In regard to Dr. Bystryn's comments: at the time our manuscript was submitted, the prevalence of germ-line CDKN2A mutations among normal persons had not been established. However, from available data, it appears that the frequency of germ-line CDKN2A mutations in the general population is very low. For example, in a recent study, Sun et al.1 screened affected members of 67 families with cancers at multiple sites for germ-line mutations in the CDKN2A gene. Only one subject had such a mutation. This subject had had two melanomas but no family history of melanoma. In the same study, the second exon of CDKN2A was also evaluated in 309 Canadian and Scottish controls. None had a mutation in this exon (which has been found to harbor the majority of CDKN2A mutations2,3).

We disagree with Dr. Bystryn's premise that the clinical relevance of a germ-line mutation is defined solely on the basis of its prevalence. Although we found CDKN2A mutations in only 15 percent of patients with multiple primary melanomas, the clinical relevance of this finding in these patients and their families, though currently undefined, may be considerable.

We agree, in part, with the comments of Dr. Hughes-Davies. However, the probabilities to which he refers are lifetime cumulative risks. Since most pedigrees contain multiple members who are middle-aged or younger, the risk of melanoma within a pedigree is considerably lower than the cumulative risk for the same number of people who live their full life expectancy. Nonetheless, in the absence of genetic testing, an inherited predisposition cannot be readily distinguished from a chance association in families that have only two members with melanoma. However, data from our laboratories and from other groups indicate that some of these families do, in fact, have germ-line CDKN2A mutations. As might be expected, families with three or more affected members have a higher likelihood of CDKN2A mutations than those with two or fewer affected members.

Other groups have recently reported similar trends. Soufir et al.4 found that the frequency of germ-line CDKN2A mutations in families with two affected members was relatively low (1 of 13, or 7.7 percent), but the frequency was much higher in families with at least one member with multiple melanomas and those with three members with melanoma. Similarly, Harland et al.5 found that only 1 of 12 families with two affected members had a germ-line CDKN2A mutation, but they identified 5 mutations among 12 families with three or more affected members.

Norman J. Lassam, M.D., Ph.D.
David Hogg, M.D.
John McLaughlin, Ph.D.
University of Toronto, Toronto, ON M5S 1A8, Canada

5 References

1. 1

   Sun S, Pollock PM, Liu L, et al. CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein. Int J Cancer 1997;73:531-536
   CrossRef | Web of Science | Medline

2. 2

   Smith-Sørensen B, Hovig E. A database of CDKN2A mutations. (See: http://129.240.38.133/cgi/NetFinder/NetFinder.acgi.)
   

3. 3

   Foulkes WD, Flanders TY, Pollock PM, Hayward NK. The CDKN2A (p16) gene and human cancer. Mol Med 1997;3:5-20
   Web of Science | Medline

4. 4

   Soufir N, Avril MF, Chompret A, et al. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. Hum Mol Genet 1998;7:209-216
   CrossRef | Web of Science | Medline

5. 5

   Harland M, Meloni R, Gruis N, et al. Germline mutations of the CDKN2 gene in UK melanoma families. Hum Mol Genet 1997;6:2061-2067
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   M.J Hicks, C.M Flaitz. (2000) Oral mucosal melanoma: epidemiology and pathobiology. Oral Oncology 36:2, 152-169
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