Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal

被引：366

作者：

Mitchell, Thomas J. ^{[1
,2
]}

Turajlic, Samra ^{[3
,4
]}

Rowan, Andrew ^{[3
]}

Nicol, David ^{[4
]}

Farmery, James H. R. ^{[5
]}

O'Brien, Tim ^{[6
]}

Martincorena, Inigo ^{[1
]}

Tarpey, Patrick ^{[1
]}

Angelopoulos, Nicos ^{[1
]}

Yates, Lucy R. ^{[1
,4
]}

Butler, Adam P. ^{[1
]}

Raine, Keiran ^{[1
]}

Stewart, Grant D. ^{[2
]}

Challacombe, Ben ^{[6
]}

Fernando, Archana ^{[6
]}

Lopez, Jose I. ^{[7
]}

Hazell, Steve ^{[3
]}

Chandra, Ashish ^{[6
]}

Chowdhury, Simon ^{[6
]}

Rudman, Sarah ^{[6
]}

Soultati, Aspasia ^{[6
]}

Stamp, Gordon ^{[8
]}

Fotiadis, Nicos ^{[9
]}

Pickering, Lisa ^{[4
]}

Au, Lewis ^{[4
]}

Spain, Lavinia ^{[4
]}

Lynch, Joanna ^{[4
]}

Stares, Mark ^{[4
]}

Teague, Jon ^{[1
]}

Maura, Francesco ^{[1
]}

Wedge, David C. ^{[10
]}

Horswell, Stuart ^{[11
]}

Chambers, Tim ^{[3
]}

Litchfield, Kevin ^{[3
]}

Xu, Hang ^{[3
]}

Stewart, Aengus ^{[11
]}

Elaidi, Reza ^{[12
]}

Oudard, Stephane ^{[12
]}

McGranahan, Nicholas ^{[3
,13
]}

Csabai, Istvan ^{[14
]}

Gore, Martin ^{[4
]}

Futreal, P. Andrew ^{[15
]}

Larkin, James ^{[4
]}

Lynch, Andy G. ^{[5
,16
]}

Szallasi, Zoltan ^{[17
,18
]}

Swanton, Charles ^{[3
,13
,19
]}

Campbell, Peter J. ^{[1
,20
]}

机构：

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

[2] Univ Cambridge, Acad Urol Grp, Dept Surg, Addenbrookes Hosp NHS Fdn Trust, Hills Rd, Cambridge CB2 0QQ, England

[3] Francis Crick Inst, Translat Canc Therapeut Lab, 1 Midland Rd, London NW1 1AT, England

[4] Royal Marsden Natl Hlth Serv NHS Fdn Trust, Renal & Skin Units, London SW3 6JJ, England

[5] Univ Cambridge, CRUK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England

[6] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Great Maze Pond, London SE1 9RT, England

[7] Univ Basque Country, Biocruces Inst, Cruces Univ Hosp, Dept Pathol,UPV EHU, Baracaldo, Spain

[8] Francis Crick Inst, Expt Histopathol Lab, 1 Midland Rd, London NW1 1AT, England

[9] Royal Marsden Natl Hlth Serv NHS Fdn Trust, Intervent Radiol Dept, London SW3 6JJ, England

[10] Univ Oxford, Big Data Inst, Old Rd Campus, Oxford OX3 7FZ, England

[11] Francis Crick Inst, Bioinformat & Biostat STP, 1 Midland Rd, London NW1 1AT, England

[12] Hop Europeen Georges Pompidou 20, Rue Leblanc, F-75908 Paris, France

[13] UCL, Canc Inst, Canc Res UK Lung Canc Ctr Excellence, Paul OGorman Bldg,72 Huntley St, London WC1E 6BT, England

[14] Eotvos Lorand Univ, Dept Phys Complex Syst, Budapest, Hungary

[15] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[16] Univ St Andrews, Sch Med, St Andrews KY16 9TF, Fife, Scotland

[17] Tech Univ Denmark, Ctr Biol Sequence Anal, Lyngby, Denmark

[18] Harvard Med Sch, Childrens Hosp Informat Program, Harvard Div Hlth Sci & Technol, CHIP HST, Boston, MA USA

[19] Univ Coll London Hosp, Dept Med Oncol, 235 Euston Rd, London NW1 2BU, England

[20] Univ Cambridge, Dept Haematol, Cambridge CB2 2XY, England

来源：

CELL | 2018年 / 173卷 / 03期

基金：

英国惠康基金; 欧洲研究理事会; 英国医学研究理事会;

关键词：

TERT PROMOTER MUTATIONS; COPY-NUMBER; SOMATIC MUTATIONS; PATTERNS; IDENTIFICATION; CHROMOTHRIPSIS; TRANSCRIPTION; LANDSCAPE; HETEROGENEITY; ACTIVATION;

D O I：

10.1016/j.cell.2018.02.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 50 UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention.

引用

页码：611 / +

页数：30

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