Vogelstein v. Lander, Round 1

- Ethan Cerami

Last month, Bert Vogelstein (of Johns Hopkins) and Eric Lander (of the Broad Institute) published head-to-head reviews surveying the successes and future of cancer genomics.

Lander and co-author Levi Garraway, offered a vision of an expansive frontier, a field just in its “infancy”, and ripe with future promise. Cancer genomics has given us much, and we have much work left to do – thousands more samples, rare cancer types, metastatic samples, probing the “dark matter” of the cancer genome, and better profiling of resistance mutations. And, this is just the beginning.

In sharp contrast, Vogelstein et al. offered a more measured vision, arguing that most recurrent drivers in most major cancer types have now been discovered. The parts list is more or less complete, and the opportunity for discovering major new cancer genes is “plateauing”. We therefore need to move onto new opportunities, including more detailed cancer pathway analysis, earlier diagnostics, and better cancer prevention. This is not a field in its infancy, as heralded by Lander. It’s a field that that’s only eight years old, but already winding down. It’s time to move on. Time for the next, new thing.

I love the idea of the ‘endless frontier’, and deep down, I really do hope Lander is right. But, reading this week’s Cancer Genome Atlas (TCGA) paper on AML, I worry that Vogelstein could be spot on. The paper is good, well done, well written, but as I read it, the main question kept nagging me: what’s new here? Significantly mutated genes? All known. Fusions? A few novel ones, but no real standouts. New pathways? No new ones, but certainly some interesting details regarding mutually exclusive and cooperative genomic events. Read the abstract, and it’s even harder to identify the real novel discoveries here.

Of course, the AML genome is one of the most studied, and it has a comparatively quiet genome, compared to other cancer types. Timothy Ley and colleagues at Washington University have also spent the past decade sequencing, profiling, and dissecting it – and have made major discoveries along the way, specifically in identifying IDH1 and DNMT3A mutations. But, this most recent paper feels like the cherry on top of all that hard work. And, David Steensma summed it up quite well in a companion essay in the New England Journal of Medicine:

It is likely that all the common, recurrent genetic lesions in AML - the molecular equivalents of major causes of death, such as stroke and heart disease – are now described… Within 2 years, the door to major new genetic findings will also close for most other common neoplasms and even for some rare tumors.

As the remaining TCGA tumor types are published, we can hope for some exciting new discoveries. But, as the TCGA wraps up in the next few years, what’s next? Are we entering a bold new frontier, or have we already plateaued?

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