ABSTRACT
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.
Subject(s)
Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , von Hippel-Lindau Disease/genetics , Adult , Aged , Carcinoma, Renal Cell/pathology , Chromosome Deletion , Chromosomes, Human, Pair 3/genetics , Exome , Gene Expression Regulation, Neoplastic , Genetic Heterogeneity , Germ-Line Mutation , Humans , MAP Kinase Signaling System , Male , Middle Aged , Models, Molecular , Phylogeny , Sequence Analysis, DNA , von Hippel-Lindau Disease/complications , von Hippel-Lindau Disease/pathologyABSTRACT
Despite advances in the diagnosis and treatment of cancer, the majority of advanced metastatic solid tumours remain incurable. Differential gene expression, somatic mutational status, tumour-specific genetic signatures and micro-environmental selection pressures within individual tumours have implications for the success of predictive assays to guide therapeutic intervention. In this review we discuss the evidence for genetic and phenotypic heterogeneity and its potential implications for clinical decision making. We highlight areas of research that could be improved in order to better stratify patient treatment. We also discuss the predictive potential of patient-derived models of tumour response, including xenograft and cell line-based systems within the context of intratumour heterogeneity.
