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Title: Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

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. As a result, 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.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [7] ;  [6] ;  [8] ;  [9] ;  [9] ;  [6] ;  [6] ;  [6] ;  [1] ;  [10] ;  [1] ;  [1] ;  [1] ;  [11] more »;  [12] ;  [12] ;  [9] ;  [13] ;  [14] ;  [15] ;  [1] ;  [1] ;  [1] « less
  1. Royal Melbourne Hospital and Univ. of Melbourne, Victoria (Australia); Epworth Hospital, Victoria (Australia)
  2. Univ. of Melbourne, Victoria (Australia); Univ. of Cambridge, Cambridge (United Kingdom)
  3. Wellcome Trust Sanger Institute, Hinxton (United Kingdom)
  4. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); KU Leuven, Leuven (Belgium), Cancer Research UK London Research Institute, London (United Kingdom)
  5. Univ. of Cambridge, Cambridge (United Kingdom); Cambridge Univ., Cambridge (United Kingdom)
  6. Univ. of Melbourne, Victoria (Australia)
  7. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  8. Royal Melbourne Hospital and Univ. of Melbourne, Victoria (Australia); Epworth Hospital, Victoria (Australia); Univ. of Melbourne, Victoria (Australia)
  9. Univ. of Cambridge, Cambridge (United Kingdom)
  10. Royal Melbourne Hospital, Victoria (Australia)
  11. Univ. Cambridge Hospitals, Cambridge (United Kingdom)
  12. Univ. of Cambridge, Cambridge (United Kingdom); Addenbrookes Hospital, Cambridge Univ., Hospitals NHS Foundation Trust, Cambridge (United Kingdom)
  13. TissuPath Specialist Pathology, Victoria (Australia); Monash Univ. Faculty of Medicine, Victoria (Australia)
  14. TissuPath Specialist Pathology, Victoria (Australia)
  15. Bar-Ilan Univ. Medical School, Safad (Israel)
Publication Date:
OSTI Identifier:
1236642
Report Number(s):
LA-UR--14-29031
Journal ID: ISSN 2041-1723; ncomms7605
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 6; Journal Issue: C; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES biological sciences; cancer; genetics