Apparent anticipation in familial melanoma.

Genetic anticipation refers to progressively earlier age at diagnosis (AAD) and/or increasing severity of a disorder in successive generations. Previous examination of 23 familial melanoma kindreds revealed evidence for a dramatic reduction in AAD in successive generations. To further evaluate evidence for anticipation, we examined the AAD, number of tumours, and tumour thickness in affected parent-offspring (P-O) pairs from these 23 kindreds. Number of tumours and tumour thickness were also evaluated by generation. There were statistically significant intergenerational differences for AAD and number of tumours in the 47 affected P-O pairs. Median AAD decreased from 48 years to 28 years. The median AAD in the offspring (AADo) of a parent with CMM (median 28, mean 29.3 +/- 10.1 years, n = 51) was significantly different from the median AADo of a parent without CMM (42, 42.3 +/- 13.9 years, n = 55) (P < 0.001). In addition, parents with AAD less than the median of 48 years had offspring with a median AAD (26, 25.8 +/- 8.5 years, n = 21) significantly different from those of parents with AAD > or = 48 years (32, 34.5 +/- 10.2 years, n = 26) (P = 0.005). Ninety-four percent (44/47) of the P-O pairs showed positive anticipation, with 62% showing anticipation of > 15 years. There was little difference based on the affected parent's sex. In the 106 CMM cases there were no significant differences in tumour number (P = 0.08) or tumour thickness (P = 0.85) by generation. Number of tumours was however significantly different in cases with AAD < 34 years (n = 52, median 1.5, mean 2.3 +/- 2.4) vs cases with AAD > or = 34 years (n = 54, 1.0, 1.6 +/- 1.7) (P < 0.001). Thus these 23 familial melanoma kindreds showed evidence for anticipation as defined by a decrease in AAD in successive generations. Although increased surveillance may partly explain the results, additional studies should evaluate melanoma risk factors, genetic and/or environmental, across generations to examine the reasons for the apparent anticipation.