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SUMMARY:The life histories of 21 breast cancers - Peter van Loo (Sanger In
 stitute)
DTSTART:20120625T150000Z
DTEND:20120625T160000Z
UID:TALK34788@talks.cam.ac.uk
CONTACT:Florian Markowetz
DESCRIPTION:*Introduction*\nCancer genomes contain a plethora of informati
 on about the complex processes of mutation and selection that formed them.
  Genomic changes conferring a selective advantage to developing cancer cel
 ls 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 canc
 er is currently lacking.\n\n*Materials and methods*\nWe developed multiple
  bioinformatic algorithms to characterize the subclonal architecture of ca
 ncers from their whole-genome sequences\, and apply these to 21 breast can
 cers which we have sequenced to 30- to 40-fold coverage (20 cases) or 188-
 fold coverage (one case).\n\n*Results and discussion*\nWe find that mutati
 onal processes evolve across the lifespan of a breast tumor\, with cancer-
 specific signatures of point mutations and chromosomal instability often e
 merging late but contributing extensive genetic variation. Subclonal diver
 sification is prominent\, providing insight into the dynamics of clonal ex
 pansion in breast cancer. Most point mutations are found in just a fractio
 n 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 chrom
 osomal copy number that complements the image emerging from point mutation
 s. Every tumor studied here has a dominant subclonal lineage\, representin
 g more than 50% of tumor cells. Minimal expansion of these subclones occur
 s until many hundreds to thousands of mutations have accumulated\, implyin
 g the existence of long-lived\, quiescent lineages of cells that are capab
 le of substantial proliferation upon acquisition of enabling genomic chang
 es. Expansion of the dominant subclone to an appreciable mass may therefor
 e represent the final rate-limiting step in a breast cancer’s developmen
 t\, triggering diagnosis.\n\n*Conclusion*\nThe interplay of point mutation
 s\, 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 h
 istory\, painting a dynamic picture of on-going evolution and clonal expan
 sion in breast carcinoma.\n
LOCATION:Cancer Research UK Cambridge Research Institute\, Lecture Theatre
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