Li-Fraumeni Syndrome is a hereditary disorder with predisposition to multiple forms of cancer throughout life and often associated with germline mutations of the TP53 tumor suppressor gene. It has been observed that the average age at onset of first cancer decreases with successive generations. Germline genome instability has been proposed as a mechanism for this observed genetic anticipation. We find no evidence for germline instability in two Li-Fraumeni families and a mouse model study. We propose an alternative model of genetic regression to explain the apparent genetic anticipation using the concept of regression to the mean.
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