title: Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution.
abstract: Recent advances in next generation sequencing have made it possible to precisely characterize all somatic coding mutations that occur during the development and progression of individual cancers. Here we used these approaches to sequence the genomes (>43-fold coverage) and transcriptomes of an oestrogen-receptor-alpha-positive metastatic lobular breast cancer at depth. We found 32 somatic non-synonymous coding mutations present in the metastasis, and measured the frequency of these somatic mutations in DNA from the primary tumour of the same patient, which arose 9 years earlier. Five of the 32 mutations (in ABCB11, HAUS3, SLC24A4, SNX4 and PALB2) were prevalent in the DNA of the primary tumour removed at diagnosis 9 years earlier, six (in KIF1C, USP28, MYH8, MORC1, KIAA1468 and RNASEH2A) were present at lower frequencies (1-13%), 19 were not detected in the primary tumour, and two were undetermined. The combined analysis of genome and transcriptome data revealed two new RNA-editing events that recode the amino acid sequence of SRP9 and COG3. Taken together, our data show that single nucleotide mutational heterogeneity can be a property of low or intermediate grade primary breast cancers and that significant evolution can occur with disease progression.
authors.affiliation: Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada.
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.forename: Jaswinder
authors.initials: J
authors.lastname: Khattra
authors.forename: Leah
authors.initials: L
authors.lastname: Prentice
authors.forename: Trevor
authors.initials: T
authors.lastname: Pugh
authors.forename: Angela
authors.initials: A
authors.lastname: Burleigh
authors.forename: Allen
authors.initials: A
authors.lastname: Delaney
authors.forename: Karen
authors.initials: K
authors.lastname: Gelmon
authors.forename: Ryan
authors.initials: R
authors.lastname: Guliany
authors.forename: Janine
authors.initials: J
authors.lastname: Senz
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Robert A
authors.initials: RA
authors.lastname: Holt
authors.forename: Steven
authors.initials: S
authors.lastname: Jones
authors.forename: Mark
authors.initials: M
authors.lastname: Sun
authors.forename: Gillian
authors.initials: G
authors.lastname: Leung
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.forename: Tesa
authors.initials: T
authors.lastname: Severson
authors.forename: Greg A
authors.initials: GA
authors.lastname: Taylor
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.forename: Kane
authors.initials: K
authors.lastname: Tse
authors.forename: Gulisa
authors.initials: G
authors.lastname: Turashvili
authors.forename: Richard
authors.initials: R
authors.lastname: Varhol
authors.forename: René L
authors.initials: RL
authors.lastname: Warren
authors.forename: Peter
authors.initials: P
authors.lastname: Watson
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D047628:Estrogen Receptor alpha / Q000378:metabolism; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009711:Nucleotides / Q000235:genetics*; D017393:RNA Editing / Q000235:genetics; D018271:Signal Recognition Particle / Q000235:genetics; D013997:Time Factors
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C498528:COG3 protein, human; D047628:Estrogen Receptor alpha; D009711:Nucleotides; C486350:SRP9 protein, human; D018271:Signal Recognition Particle