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Summary
Cancer evolves dyna
mically as clonal expansions supersede one another driven by shifting selective pressures,
mutational processes, and disrupted cancer genes. These processes
mark the geno
me, such that a cancer's life history is encrypted in the so
matic
mutations present. We developed algorith
ms to decipher this narrative and applied the
m to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with
many e
merging late but contributing extensive genetic variation. Subclonal diversification is pro
minent, and
most
mutations are found in just a fraction of tu
mor cells. Every tu
mor has a do
minant subclonal lineage, representing
more than 50 % of tu
mor cells. Mini
mal expansion of these subclones occurs until
many hundreds to thousands of
mutations have accu
mulated, i
mplying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling geno
mic changes. Expansion of the do
minant subclone to an appreciable
mass
may therefore represent the final rate-li
miting step in a breast cancer's develop
ment, triggering diagnosis.
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