Details

Autor(en) / Beteiligte

• Mitchell, Thomas J.
• Turajlic, Samra
• Rowan, Andrew
• Nicol, David
• Farmery, James H.R.
• O’Brien, Tim
• Martincorena, Inigo
• Tarpey, Patrick
• Angelopoulos, Nicos
• Yates, Lucy R.
• Butler, Adam P.
• Raine, Keiran
• Stewart, Grant D.
• Challacombe, Ben
• Fernando, Archana
• Lopez, Jose I.
• Hazell, Steve
• Chandra, Ashish
• Chowdhury, Simon
• Rudman, Sarah
• Soultati, Aspasia
• Stamp, Gordon
• Fotiadis, Nicos
• Pickering, Lisa
• Au, Lewis
• Spain, Lavinia
• Lynch, Joanna
• Stares, Mark
• Teague, Jon
• Maura, Francesco
• Wedge, David C.
• Horswell, Stuart
• Chambers, Tim
• Litchfield, Kevin
• Xu, Hang
• Stewart, Aengus
• Elaidi, Reza
• Oudard, Stéphane
• McGranahan, Nicholas
• Csabai, Istvan
• Gore, Martin
• Futreal, P. Andrew
• Larkin, James
• Lynch, Andy G.
• Szallasi, Zoltan
• Swanton, Charles
• Campbell, Peter J.

Titel

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

Ist Teil von

• Cell, 2018-04, Vol.173 (3), p.611-623.e17

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• 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 5′ 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. [Display omitted] •Novel hotspot of driver mutations in 5′-UTR repressor of TERT, expanding telomeres•Most common cause of 3p loss is a chromothripsis event, generating concurrent 5q gain•t(3;5) event occurs in childhood or adolescence, decades before tumor diagnosed•Initial clonal expansion after 3p loss starts from only a few hundred cells Combination of whole-genome sequencing analysis and a multi-region sampling approach provides insights into the nature and timing of key oncogenic events in clear cell renal cell carcinoma, depicts the evolutionary trajectories of tumors in patients and highlights the opportunity for early intervention.