Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution
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- 作者：Rosalie Fisher (1) (2)
Stuart Horswell (1)
Andrew Rowan (1)
Maximilian P Salm (1)
Elza C de Bruin (3)
Sakshi Gulati (1)
Nicholas McGranahan (1) (4)
Mark Stares (1) (2)
Marco Gerlinger (5)
Ignacio Varela (6)
Andrew Crockford (1)
Francesco Favero (1) (7)
Virginie Quidville (8)
Fabrice Andr茅 (8)
Carolina Navas (1)
Eva Gr枚nroos (1)
David Nicol (2)
Steve Hazell (2)
David Hrouda (9)
Tim O鈥橞rien (10)
Nik Matthews (1)
Ben Phillimore (1)
Sharmin Begum (1)
Adam Rabinowitz (1)
Jennifer Biggs (1)
Paul A Bates (1)
Neil Q McDonald (1)
Gordon Stamp (1)
Bradley Spencer-Dene (1)
James J Hsieh (11)
Jianing Xu (11)
Lisa Pickering (2)
Martin Gore (2)
James Larkin (2)
Charles Swanton (1) (3)
1. Cancer Research UK London Research Institute ; London ; WC2A 3LY ; UK
2. Royal Marsden NHS Foundation Trust ; London ; SW3 6JJ ; UK
3. University College London Cancer Institute ; London ; WC1E 6DD ; UK
4. Centre for Mathematics & Physics in the Life Science & Experimental Biology (CoMPLEX) ; University College London ; London ; WC1E 6BT ; UK
5. Centre for Evolution and Cancer ; Institute of Cancer Research ; London ; SW7 3RP ; UK
6. Instituto de Biomedicina y Biotecnolog铆a de Cantabria (CSIC-UC-Sodercan) ; Departamento de Biolog铆a Molecular ; Universidad de Cantabria ; Santander ; 39011 ; Spain
7. Cancer System Biology ; Center for Biological Sequence Analysis ; Department of Systems Biology ; Technical University of Denmark ; Lyngby ; DK-2800 ; Denmark
8. Institut Gustave Roussy ; Villejuif ; 94805 ; France
9. Imperial College Healthcare NHS Trust ; London ; W6 8RF ; UK
10. Guy鈥檚 and St Thomas鈥?NHS Foundation Trust ; London ; SE1 9RT ; UK
11. Department of Human Oncology and Pathogenesis Program ; Memorial Sloan Kettering Cancer Center ; New York ; 10065 ; USA - 刊名：Genome Biology
- 出版年：2014
- 出版时间：August 2014
- 年：2014
- 卷：15
- 期：8
- 全文大小：2,384 KB
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- 出版者：BioMed Central
- ISSN：1465-6906
文摘
Background Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. Results We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma. Conclusions In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.