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The life histories of 21 breast cancers

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If you have a question about this talk, please contact Florian Markowetz.

Introduction Cancer genomes contain a plethora of information about the complex processes of mutation and selection that formed them. Genomic changes conferring a selective advantage to developing cancer cells drive successive waves of clonal expansion, shaping new cancer clones or subclones. While the existence of genetic heterogeneity within cancers is recognized, systematic insight into the subclonal architecture of cancer is currently lacking.

Materials and methods We developed multiple bioinformatic algorithms to characterize the subclonal architecture of cancers from their whole-genome sequences, and apply these to 21 breast cancers which we have sequenced to 30- to 40-fold coverage (20 cases) or 188-fold coverage (one case).

Results and discussion We find that mutational processes evolve across the lifespan of a breast tumor, with cancer-specific signatures of point mutations and chromosomal instability often emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, providing insight into the dynamics of clonal expansion in breast cancer. Most point mutations are found in just a fraction of tumor cells, and often occur in several distinct clusters resulting from specific clonal expansions. We observe both large and small subclonal copy number changes, painting a picture of frequent variegation in chromosomal copy number that complements the image emerging from point mutations. Every tumor studied here has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent lineages of cells that are capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer’s development, triggering diagnosis.

Conclusion The interplay of point mutations, chromosomal gains and losses and clonal expansions, leave a record of the life history of a cancer inscribed in its genome. Using whole-genome sequencing and novel bioinfomatic methods, we can reconstruct this life history, painting a dynamic picture of on-going evolution and clonal expansion in breast carcinoma.

This talk is part of the Seminars on Quantitative Biology @ CRUK Cambridge Institute series.

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