How useful are hereditary cancer susceptibility syndromes for modeling sporadic cancers? If the biology of cancers developing within hereditary syndromes follows the same pathways to malignancy as does a substantial proportion of sporadic cancers, then prevention trials focused on hereditary high-risk individuals can lead to important gains in the sporadic setting. McKusick struggled with this fundamental issue of genetics in his classic 1969 article “On lumpers and splitters, or the nosology of genetic disease” (1).

One of the first large studies to compare BRCA1/2-associated with sporadic breast cancers was reported by Lakhani et al. on behalf of the Breast Cancer Linkage Consortium. In univariate analyses, they found relatively less ductal carcinoma in situ (DCIS), a common precursor of sporadic invasive ductal cancers, and less lobular carcinoma in situ (LCIS), a histologic marker of increased breast cancer risk, in association with invasive breast cancer in BRCA1...

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