Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation

Abstract

Although it has been hypothesized that some of the somatic mutations found in tumors may occur before tumor initiation, there is little experimental or conceptual data on this topic. To gain insights into this fundamental issue, we formulated a mathematical model for the evolution of somatic mutations in which all relevant phases of a tissue's history are considered. The model makes the prediction, validated by our empirical findings, that the number of somatic mutations in tumors of self-renewing tissues is positively correlated with the age of the patient at diagnosis. Importantly, our analysis indicates that half or more of the somatic mutations in certain tumors of self-renewing tissues occur before the onset of neoplasia. The model also provides a unique way to estimate the in vivo tissue-specific somatic mutation rates in normal tissues directly from the sequencing data of tumors. Our results have substantial implications for the interpretation of the large number of genome-wide cancer studies now being undertaken.

Fig. 1.

The “Fish,” a schematic representation of the different phases in which somatic mutations occur in a tissue giving rise to a cancer. Starting from a single precursor cell, a tissue is created via clonal expansion (head of the fish). The tissue is then subjected to periodic self-renewals (body of the fish). During development and tissue renewal, passenger mutations occur randomly, undergo clonal expansions (various brown clones), and either go extinct or expand as successive passenger mutations accumulate. A driver gene mutation can initiate a tumor cell clone, which then can expand through subsequent driver mutations, eventually yielding a clinically detectable tumor mass (fish’s tail, where each clonal expansion driver by a new driver mutation is indicated by a different color). Passenger mutations occur during this phase as well.

Fig. 2.

Relationship between the number of somatic mutations and the age of diagnosis in four types of cancer: chronic lymphocitic leukemia (A), uterine cancer (B), colorectal cancer (C), and pancreatic cancer (D).