Genomics

Dataset Information

76

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


ABSTRACT: Primary triple negative breast cancers (TNBC) represent approximately 16% of all breast cancers 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 TNBC exhibiting more variation than non-basal TNBC. Although p53 and 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.

ORGANISM(S): Homo sapiens  

PROVIDER: EGAS00001000132 | EGA |

REPOSITORIES: EGA

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Publications

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

Shah Sohrab P SP   Roth Andrew A   Goya Rodrigo R   Oloumi Arusha A   Ha Gavin G   Zhao Yongjun Y   Turashvili Gulisa G   Ding Jiarui J   Tse Kane K   Haffari Gholamreza G   Bashashati Ali A   Prentice Leah M LM   Khattra Jaswinder J   Burleigh Angela A   Yap Damian D   Bernard Virginie V   McPherson Andrew A   Shumansky Karey K   Crisan Anamaria A   Giuliany Ryan R   Heravi-Moussavi Alireza A   Rosner Jamie J   Lai Daniel D   Birol Inanc I   Varhol Richard R   Tam Angela A   Dhalla Noreen N   Zeng Thomas T   Ma Kevin K   Chan Simon K SK   Griffith Malachi M   Moradian Annie A   Cheng S-W Grace SW   Morin Gregg B GB   Watson Peter P   Gelmon Karen K   Chia Stephen S   Chin Suet-Feung SF   Curtis Christina C   Rueda Oscar M OM   Pharoah Paul D PD   Damaraju Sambasivarao S   Mackey John J   Hoon Kelly K   Harkins Timothy T   Tadigotla Vasisht V   Sigaroudinia Mahvash M   Gascard Philippe P   Tlsty Thea T   Costello Joseph F JF   Meyer Irmtraud M IM   Eaves Connie J CJ   Wasserman Wyeth W WW   Jones Steven S   Huntsman David D   Hirst Martin M   Caldas Carlos C   Marra Marco A MA   Aparicio Samuel S  

Nature 20120404 7403


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 RN  ...[more]

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