Title |
The clonal and mutational evolution spectrum of primary triple-negative breast cancers
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Published in |
Nature, April 2012
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DOI | 10.1038/nature10933 |
Pubmed ID | |
Authors |
Sohrab P. Shah, Andrew Roth, Rodrigo Goya, Arusha Oloumi, Gavin Ha, Yongjun Zhao, Gulisa Turashvili, Jiarui Ding, Kane Tse, Gholamreza Haffari, Ali Bashashati, Leah M. Prentice, Jaswinder Khattra, Angela Burleigh, Damian Yap, Virginie Bernard, Andrew McPherson, Karey Shumansky, Anamaria Crisan, Ryan Giuliany, Alireza Heravi-Moussavi, Jamie Rosner, Daniel Lai, Inanc Birol, Richard Varhol, Angela Tam, Noreen Dhalla, Thomas Zeng, Kevin Ma, Simon K. Chan, Malachi Griffith, Annie Moradian, S.-W. Grace Cheng, Gregg B. Morin, Peter Watson, Karen Gelmon, Stephen Chia, Suet-Feung Chin, Christina Curtis, Oscar M. Rueda, Paul D. Pharoah, Sambasivarao Damaraju, John Mackey, Kelly Hoon, Timothy Harkins, Vasisht Tadigotla, Mahvash Sigaroudinia, Philippe Gascard, Thea Tlsty, Joseph F. Costello, Irmtraud M. Meyer, Connie J. Eaves, Wyeth W. Wasserman, Steven Jones, David Huntsman, Martin Hirst, Carlos Caldas, Marco A. Marra, Samuel Aparicio |
Abstract |
Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 11 | 28% |
Canada | 8 | 21% |
United Kingdom | 3 | 8% |
Japan | 1 | 3% |
Ecuador | 1 | 3% |
Singapore | 1 | 3% |
Switzerland | 1 | 3% |
Australia | 1 | 3% |
France | 1 | 3% |
Other | 0 | 0% |
Unknown | 11 | 28% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 18 | 46% |
Scientists | 14 | 36% |
Practitioners (doctors, other healthcare professionals) | 4 | 10% |
Science communicators (journalists, bloggers, editors) | 3 | 8% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 34 | 2% |
United Kingdom | 13 | <1% |
Canada | 10 | <1% |
France | 6 | <1% |
Spain | 6 | <1% |
Netherlands | 6 | <1% |
Denmark | 4 | <1% |
Japan | 4 | <1% |
Germany | 3 | <1% |
Other | 33 | 2% |
Unknown | 1731 | 94% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 456 | 25% |
Researcher | 431 | 23% |
Student > Master | 174 | 9% |
Student > Bachelor | 124 | 7% |
Other | 89 | 5% |
Other | 302 | 16% |
Unknown | 274 | 15% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 627 | 34% |
Biochemistry, Genetics and Molecular Biology | 391 | 21% |
Medicine and Dentistry | 272 | 15% |
Computer Science | 62 | 3% |
Pharmacology, Toxicology and Pharmaceutical Science | 33 | 2% |
Other | 154 | 8% |
Unknown | 311 | 17% |