Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution.
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.
Shah
Sohrab P
SP
Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada.
Morin
Ryan D
RD
Khattra
Jaswinder
J
Prentice
Leah
L
Pugh
Trevor
T
Burleigh
Angela
A
Delaney
Allen
A
Gelmon
Karen
K
Guliany
Ryan
R
Senz
Janine
J
Steidl
Christian
C
Holt
Robert A
RA
Jones
Steven
S
Sun
Mark
M
Leung
Gillian
G
Moore
Richard
R
Severson
Tesa
T
Taylor
Greg A
GA
Teschendorff
Andrew E
AE
Tse
Kane
K
Turashvili
Gulisa
G
Varhol
Richard
R
Warren
René L
RL
Watson
Peter
P
Zhao
Yongjun
Y
Caldas
Carlos
C
Huntsman
David
D
Hirst
Martin
M
Marra
Marco A
MA
Aparicio
Samuel
S
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
D033942:Adaptor Proteins, Vesicular Transport; C498528:COG3 protein, human; D047628:Estrogen Receptor alpha; D009711:Nucleotides; C486350:SRP9 protein, human; D018271:Signal Recognition Particle