Spatial genomic heterogeneity within localized, multifocal prostate cancer.
Paul C BoutrosMichael FraserNicholas J HardingRichard J de BorjaDominique TrudelEmilie LalondeAlice MengPablo H Hennings-YeomansAndrew W McPhersonVeronica Y SabelnykovaAmin ZiaNatalie S FoxJulie LivingstoneYu-Jia ShiahJianxin WangTimothy A BeckCherry L HaveTaryne ChongMichelle SamJeremy JohnsLee TimmsNicholas BuchnerAda WongJohn D WatsonTrent T SimmonsChristine P'ngGaetano ZafaranaFrancis NguyenXuemei LuoKenneth C ChuStephenie D ProkopecJenna SykesAlan Dal PraAlejandro BerlinAndrew BrownMichelle A Chan-Seng-YueFouad YousifRobert E DenrocheLauren C ChongGregory M ChenEsther JungClement FungMaud H W StarmansHanbo ChenShaylan K GovindJames HawleyAlister D'CostaMelania PintilieDaryl WaggottFaraz HachPhilippe LambinLakshmi B MuthuswamyColin CooperRosalind EelesDavid NealBernard TetuCenk SahinalpLincoln D SteinNeil FleshnerSohrab P ShahColin C CollinsThomas J HudsonJohn D McPhersonTheodorus van der KwastRobert G BristowPublished in: Nature genetics (2015)
Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.
Keyphrases
- copy number
- prostate cancer
- mitochondrial dna
- single cell
- radical prostatectomy
- dna damage
- genome wide
- dna methylation
- end stage renal disease
- ejection fraction
- gene expression
- newly diagnosed
- oxidative stress
- single molecule
- chronic kidney disease
- transcription factor
- papillary thyroid
- electronic health record
- dna repair
- young adults
- squamous cell
- deep learning
- lymph node metastasis
- ultrasound guided