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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.

PROVIDER: EGAS00001000132 | EGA |

REPOSITORIES: EGA

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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]

PMID: 22495314

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Project description:Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer with high intra-tumoral heterogeneity, frequently resistant to treatment and no known targeted therapy available to improve patient outcomes. It has been hypothesized that the genomic architecture of a TNBC tumour evolves over time, both before, and during therapy, leading to therapy resistance and a high propensity to relapse. Whether this is an inherent property of the tumour or acquired over time is not well characterized. Despite this important clinical implication, limited studies have been carried out to unravel temporal evolution of TNBC over time. Herein, we report an OMICS based analysis of three TNBC patients who were longitudinally sampled during their treatment at different times of relapse. We recruited three TNBC patients at the time of their first relapse who were then followed-up through the course of their treatment. We obtained retrospective samples (tumour samples) from patient tumours at diagnosis (before neo-adjuvant chemotherapy - NACT) at surgery (post NACT) and prospectively sampled them at each subsequent relapse (tumour, blood plasma, and buffy coat) as determined by RECIST criteria. Tumor and buffy coat DNA were subjected to whole exome sequencing (WES) at 200x, and SNP arrays for copy number variation (CNV) analysis. RNA from tumour samples at relapse was subjected to whole transcriptome sequencing. Pathogenic germline BRCA1 variants identified in WES were validated using Sanger sequencing. 1084 somatic mutations identified in whole exome sequencing of all tumour tissues (n=13) from three patients, were subjected to a custom amplicon ultra-deep sequencing assay at 30,000X in their germline DNA (n=3), tumour DNA (n=10), and cfDNA from plasma samples at relapse (n=8). Copy number corrected allele frequencies, tumour ploidy, tumour purity, and ultra-deep sequencing assay derived variant allele frequencies were used to infer clonal and phylogenetic architecture of each patient as it evolved under selective pressure of therapy over time. Clonality analysis incorporating allele fractions from ultra-deep sequencing identified clones comprising of mutations that are present throughout the course of therapy which we term as founding clones and stem mutations respectively. Such founding clones comprising of stem mutations in all 3 patients were present throughout the course of treatment, irrespective of change in treatment modalities. These stem clones included well characterized cancer related genes like PDGFRB & ARID2 (Patient 02), TP53, BRAF & CSF3R (Patient 04) and ESR1, APC, EZH2 & TP53 (Patient 07). Such branching evolution is seen in all three patients wherein the dominant clone (stem clone) acquires additional mutations to form sub-clones, while persisting over time. These sub-clones may be chemo and radio resistant, while also providing for organ specific metastatic potential. Allele fractions of expressed variants inferred from RNA-Seq data co-related with allele fractions from WES data indicating that all somatic.

Dataset Information

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

Publications

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

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