Farewell to a Giant Leaper

When I was a boy, a nearly annual occurrence was a trip to Kentucky to my maternal grandparents' house.  My biological grandmother died when I was quite young, but there would be many visits to see my grandfather.  I enjoyed them greatly, but of course he is now long gone.  So I have a few regrets, and mostly I wish I had thought to ask him a few questions.

Owning a Sequencer is NOT a Prerequisite for Sequencing!

Besides the little cancer genomics piece yesterday, another genomics paper getting quite a bit of popular press attention is the nice work from the NIH tracking down a deadly outbreak of drug-resistant Klebsiella pneumoniae, with 11 of 18 infected patients dying.  Rapid genome sequencing provided a much higher level of detail for tracing the outbreak than older methods, even distinguishing isolates taken from different sites on the same patient.

The Perils of the Too Small Gene Panel

The newswires are alive with summaries of an item in Science Express which, discounting the supplementary material, isn't much bigger than the news articles describing it.  It's a nice piece showing the relevance of cancer genomics, but there's also a backstory fleshed out in the news items which is interesting.

The gist of the paper is this: a trial of everolimus, an MTOR inhibitor, in bladder cancer did not go well; very few patients showed benefit.  But, one patient did spectacularly well.  So the researchers performed whole genome sequencing and found inactivating mutations in the well-studied tumor suppressors TSC1 and NF2.  Screening 13 more bladder tumors with a panel of cancer-specific genes found 3 more cases of inactivating mutations in TSC1, plus one patient with a missense mutation of unknown significance.  In the trial, patients with TSC1 mutations stayed on trial longer than patients without the mutations.  

My first reaction was "this all makes sense" -- TSC1 and NF2 are genes which immediately suggested themselves as TOR-related. 

What's interesting from the news items is a suggestion that the original patient had been sequenced for a limited number of genes around mTOR, and that this did not include TSC1 or NF2.  Of course, the problem when doing a limited screen is picking who to include, and from my 2 second analysis on the train I would have included TSC1 and NF2.  But, that could be much easier said than done.  They are attractive, since they are tumor suppressors known to be mutated in cancer, but so are other genes in the neighborhood (such  as TSC2 or PTEN).  There are activating mutations known in the neighborhood as well, such as PI3K or various AKT family members.  Presumably it was a PCR-based (quite likely Sanger) method, in which case it can be challenging to target every exon both because you may have an "exon budget" (number of exons to be amplified) and some exons are nightmarish to amplify.  

I think the case illustrates one reason whole genome or whole exome sequence are by far the best strategies in a case such as this.  The potential payoff in understanding is huge, as you have one strong outlier patient.  The number of patients are small (though, admittedly, this is probably one success pulled from many dry holes).  Plus, these days the cost of WGS/WES is probably not much more than targeted PCR, given the costs of developing good PCR assays.  

The other potential advantage of WGS/WES, over even broad cancer-specific gene panels, for a case such as this, is that the field can change.  New oncogenes and tumor suppressors are identified periodically, perhaps even in the time period between when a panel is designed and it is used.  In a research setting to understand the basis of a clinical trial anomaly, it's particularly valuable to explore all corners, because what might not make sense today might become clear tomorrow.

Jackalopes & Guest Posts

Recently, the topic of jackalopes showed up at work.  Anyone who has toured the American West has probably come across postcards of these curious beasts, with the bodies of jackrabbits but antelope-like horns.  Even out East, at some frequency reports of these creatures appear stochastically.

An unconvincing case to X-out algebra

I had a bit of a long commute yesterday, driving from south-central New Jersey up to Starbase Cambridge.  In general it's a dull ride, having been done too often.  Still, it was the perfect time to absorb the magnificence of a George Washington Bridge crossing, followed by a great sunrise-lit view  from the loop ramp onto the Henry Hudson Parkway, and similar snippets of the Palisades also glowing in the early sun.  But, much of the time I was flipping through radio stations.  Due to this, I caught the tail end of a NPR interview with Andrew Hacker, who wrote a recent NY Times opinion piece calling for algebra to be removed from the required high school curriculum in the U.S., which has garnered letters both for and against.