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Deep sequencing of 234 tiny biopsies of normal eyelid skin from four people found thousands of clones carrying cancer driver mutations, with about a fifth to a third of cells carrying NOTCH1 mutations, showing that driver mutations are common in healthy tissue.
The Sanger Institute group sequenced 74 cancer genes at high depth in 234 punch biopsies (each about 1 mm2) of physiologically normal eyelid skin removed during blepharoplasty from four individuals aged 55-73.
Normal skin carried 2-6 mutations per megabase per cell, a burden comparable to many cancers, dominated by ultraviolet signatures. Positive selection was evident for NOTCH1, NOTCH2, FAT1 and TP53 mutations; clones with NOTCH1 mutations occupied around 20% of the skin surface, and an estimated 140 driver mutations were present per square centimetre. Yet none of the tissue was cancerous.
The paper began the field of somatic mutation in normal tissues, later extended to oesophagus, colon, bladder, lung, liver and blood, and forced a rethink of what a driver mutation means for cancer risk and for the specificity of mutation-based early detection tests.
Carrying a cancer mutation is normal; most mutant clones never become cancer. This means blood or tissue tests that look for driver mutations alone will produce false positives, and that the question of what tips a mutant clone into cancer (tissue environment, further hits, immune surveillance) is as important as the mutation itself.
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