Publication Date:
2012-04-13
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863681/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863681/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Sohrab P -- Roth, Andrew -- Goya, Rodrigo -- Oloumi, Arusha -- Ha, Gavin -- Zhao, Yongjun -- Turashvili, Gulisa -- Ding, Jiarui -- Tse, Kane -- Haffari, Gholamreza -- Bashashati, Ali -- Prentice, Leah M -- Khattra, Jaswinder -- Burleigh, Angela -- Yap, Damian -- Bernard, Virginie -- McPherson, Andrew -- Shumansky, Karey -- Crisan, Anamaria -- Giuliany, Ryan -- Heravi-Moussavi, Alireza -- Rosner, Jamie -- Lai, Daniel -- Birol, Inanc -- Varhol, Richard -- Tam, Angela -- Dhalla, Noreen -- Zeng, Thomas -- Ma, Kevin -- Chan, Simon K -- Griffith, Malachi -- Moradian, Annie -- Cheng, S-W Grace -- Morin, Gregg B -- Watson, Peter -- Gelmon, Karen -- Chia, Stephen -- Chin, Suet-Feung -- Curtis, Christina -- Rueda, Oscar M -- Pharoah, Paul D -- Damaraju, Sambasivarao -- Mackey, John -- Hoon, Kelly -- Harkins, Timothy -- Tadigotla, Vasisht -- Sigaroudinia, Mahvash -- Gascard, Philippe -- Tlsty, Thea -- Costello, Joseph F -- Meyer, Irmtraud M -- Eaves, Connie J -- Wasserman, Wyeth W -- Jones, Steven -- Huntsman, David -- Hirst, Martin -- Caldas, Carlos -- Marra, Marco A -- Aparicio, Samuel -- 5U01ES017154-02/ES/NIEHS NIH HHS/ -- R01 GM084875/GM/NIGMS NIH HHS/ -- R01GM084875/GM/NIGMS NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Apr 4;486(7403):395-9. doi: 10.1038/nature10933.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada. sshah@bccrc.ca〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22495314" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Breast Neoplasms/diagnosis/*genetics/*pathology
;
Clone Cells/metabolism/pathology
;
DNA Copy Number Variations/genetics
;
DNA Mutational Analysis
;
Disease Progression
;
*Evolution, Molecular
;
Female
;
Gene Expression Profiling
;
Gene Expression Regulation, Neoplastic/genetics
;
Genotype
;
High-Throughput Nucleotide Sequencing
;
Humans
;
INDEL Mutation/genetics
;
Mutation/*genetics
;
Point Mutation/genetics
;
Precision Medicine
;
Reproducibility of Results
;
Sequence Analysis, RNA
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
