One Less Thing to Worry About: The Shrinking Spectrum of Tumors in BRCA Founder Mutation Carriers

Extract

Defining the spectrum of disease associated with germline mutations in cancer susceptibility genes can be a difficult business. Many of the multiple cancer syndromes were defined clinically long ago, generally when astute clinicians and epidemiologists recognized that rare tumors, sometimes associated with congenital anomalies, clustered in families, and that survivors of certain neoplasms often developed other rare malignancies. The development of the Knudson–Strong hypothesis (1) provided a framework on which to place these observations, particularly when the cancers developed at earlier ages than are typical of the general population. Evidence that these rare tumors occurred more often than chance would dictate was relatively easy to gather, because the infrequency of the tumor made it possible to demonstrate statistically significant differences from population-based figures with relatively small numbers of study subjects. Examples of these syndromes include multiple endocrine neoplasias type 2A (2), Li–Fraumeni syndrome (3), and osteo- and soft tissue sarcomas associated with retinoblastoma (4).