Tim O’Brien

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

BackgroundGenomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution.ResultsWe 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.ConclusionsIn 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.

Hexylaminolaevulinate ‘blue light’ fluorescence cystoscopy in the investigation of clinically unconfirmed positive urine cytology

To investigate the value of photodynamic diagnosis (PDD) using hexylaminolaevulinate (Hexvix®, PhotoCure, Oslo, Norway) in the investigation of patients with positive urine cytology who have no evidence of disease after standard initial investigations.

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal

Summary Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

SHOULD UROLOGISTS BE SPENDING MORE TIME ON THE GOLF COURSE

An unshakeable principle of the surgical treatment of cancer is to dissect through normal tissue and to remove the tumour with a negative margin. Conventional wire-loop transurethral resection of bladder tumour (TURBT) does not achieve this. The tumour is deliberately incised and removed piecemeal, scattering millions of tumour cells throughout the bladder. In any other tumour type this would be considered oncological madness; in the bladder it is the norm. Perhaps unsurprisingly, recurrence rates for superficial bladder cancer are astronomically high, at up to 64% at 5 years. In other tumour types this rate of recurrence would be unacceptable: local recurrence after partial nephrectomy for renal cancer is 5–10% at 5 years; after breast conservation therapy it is 5–22%. Moreover, in rectal cancer surgery, operative technique has been shown to be a very important factor of local recurrence rates: after total mesorectal excision there is recurrence in 4–9%, compared with 32–35% with conventional surgery [1]. The question inevitably arises as to whether the technique of wire-loop TURBT is outdated. In particular, might a technique that attempts to remove a bladder cancer en bloc by dissecting through normal tissue be more oncologically appropriate? Could urologists take their cue from golfers; the perfect bunker shot is made by swinging the sand wedge through the sand under the ball with no contact between the club and the ball. The ball emerges from the bunker on a cushion of sand, to float gently onto the green (Fig. 1). Should we be looking to execute a ‘sand wedge resection’ of bladder tumours?

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

Summary The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

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

Summary 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.

So Much Cost, Such Little Progress

a School of Cancer Sciences, University of Birmingham, Birmingham, UK; Royal Society of Medicine Section of Urology, London, UK; c The Prostate Centre, London, UK; d The Urology Foundation, London, UK; Guy’s and St. Thomas’ NHS Foundation Trust, London, UK; British Association of Urological Surgeons Section of Oncology, London, UK; Royal Berkshire NHS Foundation Trust, Reading, UK; Action on Bladder Cancer, London, UK

BEYOND GOVERNMENT TARGETS: BUILDING HIGH QUALITY UROLOGICAL DIAGNOSTIC SERVICES

In urology there is much improving to do; fragmentation in time and place characterizes most services. Indeed, the current system seems to suit no-one. Patients often wait weeks to be seen and straightforward problems can take several visits to hospital over several months to resolve. Specialists see more and more patients in ever-shorter periods of time, leading to poor quality consultations, dissatisfaction and potentially to clinical error. Hospital managers spend inordinate amounts of time managing the waiting list and dealing with the queries and complaints that arise from the delays, rather than managing the service. Politicians become increasingly exasperated and issue ever more stringent directives which ‘creaking’ systems are not designed to deliver. The subliminal message to ‘work harder, longer, faster and later’ seems unlikely to be the answer; how could it be when lack of commitment is not the problem.