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The clonal and mutational evolution spectrum of primary triple-negative breast cancers

Authors :
Jiarui Ding
Philippe Gascard
Samuel Aparicio
Mahvash Sigaroudinia
Annie Moradian
Gavin Ha
Angela Burleigh
Oscar M. Rueda
Sambasivarao Damaraju
Paul D.P. Pharoah
Christina Curtis
Leah M Prentice
Peter H. Watson
Damian Yap
Suet-Feung Chin
Rodrigo Goya
Kelly Hoon
Inanc Birol
Sohrab P. Shah
Connie J. Eaves
Karen A. Gelmon
Steven J.M. Jones
Noreen Dhalla
Gulisa Turashvili
Andrew Roth
Yongjun Zhao
Alireza Heravi-Moussavi
Irmtraud M. Meyer
Gregg B. Morin
Ali Bashashati
Anamaria Crisan
Richard Varhol
John R. Mackey
Joseph F. Costello
Carlos Caldas
Jaswinder Khattra
S.-W. Grace Cheng
Timothy T. Harkins
Simon K. Chan
Jamie Rosner
Daniel Lai
Arusha Oloumi
Kane Tse
David G. Huntsman
Malachi Griffith
Vasisht Tadigotla
Stephen Chia
Ryan Giuliany
Virginie Bernard
Kevin C. Ma
Thea D. Tlsty
Martin Hirst
Karey Shumansky
Andrew McPherson
Thomas Zeng
Wyeth W. Wasserman
Angela Tam
Gholamreza Haffari
Marco A. Marra
Source :
Nature, vol 486, iss 7403, Breast Cancer Research : BCR
Publication Year :
2012
Publisher :
eScholarship, University of California, 2012.

Abstract

Primary triple negative breast cancers (TNBC) represent approximately 16% of all breast cancers1 and are a tumour type defined by exclusion, for which comprehensive landscapes of somatic mutation have not been determined. Here we show in 104 early TNBC cases, that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some exhibiting only a handful of somatic aberrations in a few pathways, whereas others contain hundreds of somatic events and multiple pathways implicated. Integration with matched whole transcriptome sequence data revealed that only ~36% of mutations are expressed. By examining single nucleotide variant (SNV) allelic abundance derived from deep re-sequencing (median >20,000 fold) measurements in 2414 somatic mutations, we determine for the first time in an epithelial tumour, the relative abundance of clonal genotypes among cases in the population. We show that TNBC vary widely and continuously in their clonal frequencies at the time of diagnosis, with basal subtype TNBC2,3 exhibiting more variation than non-basal TNBC. Although p53 and PIK3CA/PTEN somatic mutations appear clonally dominant compared with other pathways, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal and cell shape/motility proteins occurred at lower clonal frequencies, suggesting they occurred later during tumour progression. Taken together our results show that future attempts to dissect the biology and therapeutic responses of TNBC will require the determination of individual tumour clonal genotypes.

Details

Database :
OpenAIRE
Journal :
Nature, vol 486, iss 7403, Breast Cancer Research : BCR
Accession number :
edsair.doi.dedup.....4bbcc35bb7ac9493fde0c36676387dda