Cancer-like mutations in non-cancer tissue: towards a better understanding of multistep carcinogenesis

Using Duplex Sequencing, the most accurate sequencing technology currently available, we recently reported the novel finding that mutations in TP53, the most commonly mutated gene in cancer, are present at a very low frequency in non-cancerous tissues of women with and without ovarian cancer (1). These mutations were mostly non-synonymous, clustered in common TP53 cancer-associated hotspot codons and frequently led to an inactive protein. Thus, the mutations were not simply random, but appeared to have arisen through positive selection, akin to that occurring in tumors, yet in normal tissue. In most patients, multiple “biological background” mutations were simultaneously present, and mutation abundance increased with patient age. Taken together, our observations support the striking conclusion that clonal evolutionary processes typically thought of as operative only in neoplasia are, in fact, a ubiquitous part of normal aging.