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

被引：293

作者：

Hong, Matthew K. H. ^{[1
,2
,3
]}

Macintyre, Geoff ^{[4
,5
,6
]}

Wedge, David C. ^{[7
]}

Van Loo, Peter ^{[7
,8
,9
]}

Patel, Keval ^{[5
,10
]}

Lunke, Sebastian ^{[11
]}

Alexandrov, Ludmil B. ^{[7
,12
]}

Sloggett, Clare ^{[13
]}

Cmero, Marek ^{[1
,2
,3
,4
,6
]}

Marass, Francesco ^{[5
]}

Tsui, Dana ^{[5
]}

Mangiola, Stefano ^{[4
]}

Lonie, Andrew ^{[13
]}

Naeem, Haroon ^{[4
,6
]}

Sapre, Nikhil ^{[1
,2
,3
]}

Phal, Pramit M. ^{[14
]}

Kurganovs, Natalie ^{[1
,2
,3
]}

Chin, Xiaowen ^{[1
,2
,3
]}

Kerger, Michael ^{[1
,2
,3
]}

Warren, Anne Y. ^{[15
]}

Neal, David ^{[5
,10
]}

Gnanapragasam, Vincent ^{[5
,10
]}

Rosenfeld, Nitzan ^{[5
]}

Pedersen, John S. ^{[16
,17
]}

Ryan, Andrew ^{[16
]}

Haviv, Izhak ^{[18
]}

Costello, Anthony J. ^{[1
,2
,3
]}

Corcoran, Niall M. ^{[1
,2
,3
]}

Hovens, Christopher M. ^{[1
,2
,3
]}

机构：

[1] Royal Melbourne Hosp, Dept Surg, Div Urol, Parkville, Vic 3050, Australia

[2] Univ Melbourne, Parkville, Vic 3050, Australia

[3] Epworth Med Fdn, Epworth Prostate Ctr, Richmond, Vic 3121, Australia

[4] Univ Melbourne, Ctr Neural Engn, Dept Comp & Informat Syst, Parkville, Vic 3010, Australia

[5] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England

[6] Univ Melbourne, NICTA, Victoria Res Lab, Diagnost Genom, Parkville, Vic 3010, Australia

[7] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, England

[8] Katholieke Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium

[9] Canc Res UK London Res Inst, London WC2A 3LY, England

[10] Univ Cambridge, Addenbrookes Hosp, Hosp NHS Fdn Trust, Acad Urol Grp, Cambridge CB2 0QQ, England

[11] Univ Melbourne, Ctr Translat Pathol, Parkville, Vic 3050, Australia

[12] Los Alamos Natl Lab, Div Theoret, Los Alamos, NM USA

[13] Univ Melbourne, Victorian Life Sci Computat Initiat, Parkville, Vic 3050, Australia

[14] Royal Melbourne Hosp, Dept Radiol, Parkville, Vic 3050, Australia

[15] Univ Cambridge Hosp, Addenbrookes Hosp, Dept Histopathol, Cambridge CB2 0QQ, England

[16] TissuPath Specialist Pathol, Mt Waverley, Vic 3149, Australia

[17] Monash Univ, Fac Med, Clayton, Vic 3168, Australia

[18] Bar Ilan Univ, Sch Med, IL-1311502 Safed, Israel

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会; 澳大利亚研究理事会;

关键词：

LI-FRAUMENI-SYNDROME; 21 BREAST CANCERS; MUTATIONAL PROCESSES; GENOMIC INSTABILITY; PANCREATIC-CANCER; TYROSINE KINASE; SEQUENCING DATA; HETEROGENEITY; EVOLUTION; IDENTIFICATION;

D O I：

10.1038/ncomms7605

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

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