Public Release: 

Genetic manifestation of melanoma linked to geographic location

Journal of the National Cancer Institute

Geographic location appears to influence the probability of whether a person carrying a specific genetic mutation will develop melanoma, suggests new research published in the June 19 issue of the Journal of the National Cancer Institute.

Mutations in the CDKN2A gene are the main cause of inherited susceptibility to melanoma. Roughly 20% of tested melanoma families--or families that have multiple cases of melanoma--have this mutation. It is unclear, however, whether penetrance of this gene mutation (the likelihood people with a CDKN2A mutation will develop melanoma) is influenced by environmental factors found in different geographic regions, or other factors, such as gender and alterations to the CDKN2A gene product, the p14ARF protein.

To answer this question, D. Timothy Bishop, Ph.D., of Cancer Research U.K. in Leeds, his colleagues at the Melanoma Genetics Consortium examined the penetrance of CDKN2A mutations in 80 families in Europe, Australia, and the Unites States. The families all had documented CDKN2A mutations and at least two cases of cutaneous malignant melanoma.

The authors found that, overall, CDKN2A mutation penetrance reached 30% by age 50, and 67% by age 80. Gender and p14ARF protein alterations did not appear to influence penetrance. However, there was a statistically significant association with residing in a place with a high incidence of melanoma.

Carriers of CDKN2A mutations who lived in Australia had an estimated 32% risk of developing melanoma by age 50, compared with an estimated 50% likelihood for those living in the Unites States and an estimated 13% likelihood for those living in Europe (namely, England, France, Italy, and the Netherlands). By age 80, that risk increased to an estimated 91%, 76%, and 58%, in these regions, respectively.

Bishop and his colleagues note that the proportionate increase in penetrance in CDKN2A mutation carriers between high and low baseline incidence locations is similar in magnitude to the increase in risk of melanoma among the general population. The authors conclude that "the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance."

In a related editorial, Gloria M. Petersen, Ph.D., and Celine M. Vachon, Ph.D., of the Mayo Clinic in Rochester, Minn., say that, "this finding is at first glance puzzling, because the long-held belief in the field is that the phenotype [physical manifestations] of hereditary cancer gene mutations should not be tied to the environment."

The authors raise the issue of why and how factors that affect geographic incidence rates of melanoma also affect the expression of melanoma among mutation carriers. They say that future investigations should examine whether environment (such as differing UV radiation levels between countries), genetic predisposition (such as presence of dysplastic nevi or modifier genes), or both underlie the variation seen in penetrance estimates.


Contact: Ruth Francis, Cancer Research U.K., +44 020 7317 5026; fax: +44 020 7935 1546,

Editorial: Mary Lawson, Mayo Clinic, (507) 266-0810; fax: (507) 284-8713,

Bishop T, Demenais F, Goldstein A, Bergman W, Bishop J, Bressac-de Paillerets B, et al. Geographic variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst 2002;94:894-903.

Editorial: Petersen G, Vachon C. Genetic epidemiology of melanoma: of consortia and conundrums. J Natl Cancer Inst 2002;94:872-3.

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