Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al.[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.RF and JL received funding from EU FP7 (PREDICT project), EB is a Rosetrees Trust fellow, NM received funding from the Rosetrees Trust, MG is funded by the UK Medical Research Council, IV is funded by Spanish Ministerio de Economía y Competitividad subprograma Ramón y Cajal, and CS is a senior Cancer Research UK clinical research fellow and is funded by Cancer Research UK, the Rosetrees Trust, EU FP7 (projects PREDICT and RESPONSIFY, ID:259303), the Prostate Cancer Foundation, and the Breast Cancer Research Foundation. This study was supported by researchers at the National Institute for Health Research Biomedical Research Centres at University College London Hospitals and at the Royal Marsden Hospital.Peer Reviewe

Mouse Chromosome 11

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46996/1/335_2004_Article_BF00648429.pd

Repression of the basal c-fos promoter by wild-type p53.

Mutations in the p53 gene are the most common genetic alterations observed in many inherited and sporadic forms of human cancer. Recent studies indicate that wild-type p53 may be involved in the regulation of gene expression. In the present report we examined the effect of p53 on the human c-fos promoter. Using a transient co-transfection assay we show that wild-type human p53, but not a transforming mutant of p53, negatively regulates the activity of the c-fos promoter in a dose-dependent manner. Promoter deletion analysis maps a sequence conferring p53 repression to the basal promoter region between nucleotides -53 and +42 relative to the cap site. In contrast, p53 strongly stimulates transcription when a sequence previously reported to bind p53 (TGCCT repeat) was inserted in front of the HSV-TK promoter driving CAT. These findings raise the question as to whether p53 may mediate its inhibitory effect on c-fos gene expression by interfering, directly or indirectly, with components of the basal transcriptional machinery