Genetic Melanoma Manifestation Depends on Geography

Scientists investigating the factors that mediate manifestation of malignant melanoma in individuals carrying a mutant gene that increases susceptibility to the disease found that where the individual lives significantly influences the likelihood that melanoma will develop.

Mutations in the CDKN2A gene are the main cause of inherited susceptibility to melanoma. Approximately 20% of families with multiple cases of melanoma carry this mutation. It had not been known, however, what factors would trigger the appearance of melanoma in these individuals. This question of penetrance--the proportion of individuals of a particular genotype that express its phenotypic effect in a given environment--was investigated by scientists from the Cancer Research UK Clinical Center (Leeds, UK), and results of their study were published in the June 19, 2002, issue of the Journal of the National Cancer Institute.

A group of 80 families from Europe, Australia, and the US with documented CDKN2A mutations and at least two cases of cutaneous malignant melanoma took part in the study. The authors found that CDKN2A mutation penetrance reached 30% by age 50 and 67% by age 80. Neither gender nor expression of altered p14ARF protein produced by the mutant CDKND2A gene appeared 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 US 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. The proportionate increase in penetrance in CDKN2A mutation carriers between high and low baseline incidence locations was similar in magnitude to the increase in risk of melanoma among the general population. The authors concluded, "The same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.”

The next step will be to investigate whether environment (such as differing ultraviolet radiation levels between countries), genetic predisposition (such as presence of dysplastic nevi or modifier genes), or both underlie the variation seen in penetrance.



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