Subclonal diversification of primary breast cancer revealed by multiregion sequencing.
Lucy R YatesMoritz GerstungStian KnappskogChristine DesmedtGunes GundemPeter Van LooTurid AasLudmil B AlexandrovDenis LarsimontHelen DaviesYilong LiYoung Seok JuManasa RamakrishnaHans Kristian HauglandPeer Kaare LillengSerena Nik-ZainalStuart McLarenAdam ButlerSancha MartinDominic GlodzikAndrew MenziesKeiran M RaineJonathan HintonDavid JonesLaura J MudieBing JiangDelphine VincentApril Greene-ColozziPierre-Yves AdnetAquila FatimaMarion MaetensMichail IgnatiadisMichael R StrattonChristos SotiriouAndrea L RichardsonPer Eystein LønningDavid C WedgePeter J CampbellPublished in: Nature medicine (2015)
The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.
Keyphrases
- single cell
- clinical trial
- end stage renal disease
- small cell lung cancer
- squamous cell carcinoma
- breast cancer risk
- newly diagnosed
- randomized controlled trial
- dna methylation
- chronic kidney disease
- peritoneal dialysis
- transcription factor
- radiation therapy
- childhood cancer
- cross sectional
- young adults
- small molecule
- case report
- drug delivery
- phase ii
- squamous cell
- study protocol
- human health
- double blind
- phase iii