10779/crick.12746171.v1
Matthew KH Hong
Matthew KH
Hong
Geoff Macintyre
Geoff
Macintyre
David C Wedge
David C
Wedge
Peter Van Loo
Peter
Van Loo
Keval Patel
Keval
Patel
Sebastian Lunke
Sebastian
Lunke
Ludmil B Alexandrov
Ludmil B
Alexandrov
Clare Sloggett
Clare
Sloggett
Marek Cmero
Marek
Cmero
Francesco Marass
Francesco
Marass
Dana Tsui
Dana
Tsui
Stefano Mangiola
Stefano
Mangiola
Andrew Lonie
Andrew
Lonie
Haroon Naeem
Haroon
Naeem
Nikhil Sapre
Nikhil
Sapre
Pramit M Phal
Pramit M
Phal
Natalie Kurganovs
Natalie
Kurganovs
Xiaowen Chin
Xiaowen
Chin
Michael Kerger
Michael
Kerger
Anne Y Warren
Anne Y
Warren
David Neal
David
Neal
Vincent Gnanapragasam
Vincent
Gnanapragasam
Nitzan Rosenfeld
Nitzan
Rosenfeld
John S Pedersen
John S
Pedersen
Andrew Ryan
Andrew
Ryan
Izhak Haviv
Izhak
Haviv
Anthony J Costello
Anthony J
Costello
Niall M Corcoran
Niall M
Corcoran
Christopher M Hovens
Christopher M
Hovens
Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer
The Francis Crick Institute
2020
Adenocarcinoma
Aged
Bone Neoplasms
Brain Neoplasms
DNA Copy Number Variations
Disease Progression
Humans
Longitudinal Studies
Male
Middle Aged
Mutation
Neoplasm Metastasis
Polymorphism, Single Nucleotide
Prostatic Neoplasms
RNA, Messenger
Sequence Analysis, DNA
Tumor Suppressor Protein p53
Van Loo
2020-07-31 13:09:40
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Tracking_the_origins_and_drivers_of_subclonal_metastatic_expansion_in_prostate_cancer/12746171
Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.