| Figur
es/Tabl
esFigur
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es | Referenc
esReferenc
esSummary
Cancer evolv
es dynamically as clonal expansions supersede one another driven by shifting selective pr
essur
es, mutational proc
ess
es, and disrupted cancer gen
es. Th
ese proc
ess
es mark the genome, such that a cancer's life history is encrypted in the somatic mutations pr
esent. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational proc
ess
es evolve across a cancer's lif
espan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, repr
esenting more than 50%of tumor cells. Minimal expansion of th
ese subclon
es occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, qui
escent cell lineag
es capable of substantial proliferation upon acquisition of enabling genomic chang
es. Expansion of the dominant subclone to an appreciable mass may therefore repr
esent the final rate-limiting step in a breast cancer's development, triggering diagnosis.
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