Genetic anticipation and breast cancer: a prospective follow-up study

Genetic anticipation is characterized by an earlier age of disease onset, i ncreased severity, and a greater proportion of affected individuals in succ eeding generations. The discovery of trinucleotide repeat expansion (TRE) m utations as the molecular correlate of anticipation in a number of rare Men delian neurodegenerative disorders has led to a resurgence of interest in t his phenomenon. Because of the difficulties presented to traditional geneti cs by complex diseases, the testing for genetic anticipation coupled with T RE detection has been proposed as a strategy for expediting the identificat ion of susceptibility genes for complex disorders. In the case of breast ca ncer, a number of previous studies found evidence consistent with genetic a nticipation. It is known that a proportion of such families are linked to e ither BRCA1 or BRCA2, but no TRE mutations have been identified. It has bee n shown that the typical ascertainment employed in studies purporting to de monstrate genetic anticipation combined with unadjusted statistical analysi s can dramatically elevate the type I error. We re-examine the evidence for anticipation in breast cancer by applying a new statistical approach that appears to have validity in the analysis of anticipation to data ascertaine d from a recent follow-up of a large prospective cohort family study of bre ast cancer. Using this approach, we find no statistically significant evide nce for genetic anticipation in familial breast cancer. We discuss the limi tations of our analysis, including the problem of adequate sample size for this new statistical test.