Archive for the ‘Uncategorized’ Category

Lessons learned from tumor heterogeneity

Tuesday, April 10th, 2012

My recent blog post, Tumor heterogeneity, revealed…, discussed the New England Journal of Medicine article by Gerlinger and colleagues describing the genetic heterogeneity found both within a patient’s individual tumor nodules and between spatially separate nodules.  There has been a substantial amount of discussion of this work and angst about how it might signal the end of personalized medicine even before it really got started.  I don’t believe that will be the case at all.  To the contrary, this paper made interesting contributions in three conceptual areas that may help pull the field forward.  These areas are the 1) relevance of prognostic gene expression profiles, 2) the nature of “driver” genetic mutations, and 3) the pathogenesis of cancer itself.  All of these areas are, in my opinion, very important to make headway in before personalized cancer medicine can become a truly effective tool in medicine.

Heterogeneity in gene expression profiles across the tumor specimen

The result that most seized on to proclaim the demise of personalized medicine was the finding that gene expression signature from spatially separated parts of a tumor nodule yielded different assessments of prognosis.  The implication is that a single biopsy specimen is inadequate to generate an accurate prediction of clinical course or response to treatment.  Most likely that is at least partially true.  However, the issue is with sampling, rather than the molecular biology.  We have known for decades that tumors have variable histology within their mass, with some regions reflecting poorer prognosis than others via their histologic grade.  Rather than reflecting a conceptual disconnect that dooms a new paradigm, it looks more like a technical problem to solve, which should be no surprise along this new path.

Convergent evolution

Both the Gerlinger paper, as well as others (e.g. Walter et al, NEJM), using NGS have now demonstrated that within a single patient the same gene can be found to be mutated multiple independent times, suggesting that this mutation creates a change in gene function that participates in the development of the cancer.  This had not been shown in humans before.  This finding will be useful for clinical diagnostics  and it may be game changing in basic research.  In clinical diagnostics identification of a multiply-mutated gene would give additional confidence that the damage it represents is causal and may help select targeted therapy.  In basic research, identification of such genes would represent novel evidence of the causality of specific genetic changes in the disease process.  This type of evidence is a smoking gun, a sign post saying “Needs to be mutated to reach this disease state”.  This type of evidence, which only deep sequencing can yield, is a new and useful application of NGS that was not previously available.

Pathogenesis

The picture that the Gerlinger paper, Walters paper, and others paints is one of clonal evolution of cancer.  This type of work paints this picture with clarity that has not been achievable before.  What is striking to me is that these results make it harder to ignore the concept that these molecular alterations, as important as they clearly are in the progression of cancer, may not be the cause of cancer.  They beg the question, “what initiated this evolutionary process?”.  Certainly, oncogenes, tumor suppressors, and the like are a part of cancer pathogenesis, carrying the developing disease along.  But it seems to me that there is still a “first cause” of some sort that we have not put our collective fingers on.  Genomic instability is certainly key, but then what is the genesis of the genomic instability?  What are the inputs that kick this process off?  Efforts to answer these questions will move us closer to effective treatments for cancer and other diseases that may share these pathogenic processes.

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Tumor Heterogeneity, Revealed…

Thursday, March 8th, 2012

A very interesting and timely article on tumor heterogeneity was published in the New England Journal of Medicine today.  Gerlinger and colleagues from the UK used next-generation sequencing to look for heterogeneity across various regions of renal tumors and metastases in four patients.  They report that indeed there is a great deal of heterogeneity within individual tumor nodules–in fact, most of the many alterations to the tumor genome were not shared across all nodules.  Further, analysis of the pattern of mutations revealed branching evolution of the primary tumor and its metastases, rather than a linear pattern of progression of the cancers.

A couple of important conclusions suggested by this work:

  • Single biopsies of the primary tumor may give you a very misleading understanding of the cancer.
  • Cancer stem cells may not be what we thought they were, if they exist.
  • Confirms the adaptability of cancers by demonstrating convergent evolution of functional gene alterations.

None of what was reported is inconsistent with evidence from previous decades of cancer research.  It was work that really needed to be done and I’m happy it appears to have been completed in a careful, thoughtful way.

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DTC Genomic Testing—What’s it good for anyways?

Friday, December 30th, 2011

What is the fuss over DTC genomic/genetic testing all about anyways?  DNA is just a sequence of letters, isn’t it?  Lots of people are experiencing angst over the fact that these upstart companies would have the nerve to sequence part of people’s DNA for them.  I mean, it’s just a bunch of letters, isn’t it?

Seriously, I have to admit, I, as a molecular biologist, have experienced a degree of self-righteous indignation that these so called entrepreneurs would debase the field of genomics and medical genetics by offering to sequence anybody’s DNA for a price.  It seems beneath all of the effort and concern that has been invested in developing the field.  All of that hard-earned knowledge being sold off the shelf like a cheap tabloid.  That was the feeling, anyway, and I imagine some amount of that type of sentiment contributes to the resistance to the development of the DTC genomics field.

However, the reality is that those letters are attached to a lot of other information that may have health implications.  There are several serious genetic diseases (ironically, most discovered prior to the genomic era) whose sufferers (or carriers) traditionally receive genetic counseling to learn how to cope with the situation.

Beyond these known disease situations, the hype of the genomic age has led to lofty expectations for genomics.  Those letters are our shorthand for the substance (DNA) that gives us our individuality and which when altered is may give rise to disease, tell us who our relatives are, and potentially make us weller-than-well (if only we can change it a little bit).  We’ve bought pretty heavily into the idea that we are our DNA and therefore, revealing it is, in a sense, giving ourselves away.  There is an ever-growing body of genomic information that pins many hopes and dreams and futures to those four letters.  So, it’s not surprise that feelings run high when it comes to genomic information.

So, DNA/genes/genomics is loaded with expectation, but what’s DNA sequence information really good for when one takes a hard look at it?  How is it being used now?  We can start with a partial list of uses that have been found for DNA sequence information:

  • Disease risk assessment
  • Disease diagnosis
  • Preconception screening
  • Forensics
  • Genealogy
  • Recreation

The fuss that these upstart companies have created has revolved around health information for the most part.  That would be the first three items on the above list.  These companies are seeking to sell their customers their own DNA sequence information, along with an assortment of linked information regarding the health implications of the DNA sequence in question.  It’s the health information being sold along with the sequence information that has caused the kerfuffle with the FDA and the medical profession.  And, for some understandable reasons…

Long before we even knew what DNA was, enterprising companies and individuals were taking advantage of our sensitivity around health issues, selling remedies and other noxious (or inert) substances to solve health problems.  This profitable, but unethical, behavior was addressed through creation of the FDA, whose job it is to keep the nation’s healthcare resources safe.  So, here we have what might be called the modern day version of the snake oil salesmen (at least in the estimation of some): the DTC Genomics companies.  Not surprising, then, that the FDA might feel compelled to step in, as it appears they are likely do.  Similarly, many in the medical community have allowed as to how they would prefer that their patients not have access to their DNA information.  Also not surprising, since for known genetic diseases the medical profession has heretofore controlled this information  However, as it currently stands, the genomic profiles being sold by DTC genomic companies are pretty innocuous, so it doesn’t stand to reason to restrict the type of genomic information the DTC companies are selling.

My view is that we stand at a crossroads of sorts.  Down one road we regulate human DNA sequencing as a medical procedure, bequeathing control of the resulting information to specialists licensed to dispense that information in carefully predetermined ways.  This is a suitable model when the dispensing requires extensive training to avoid injury to the receiving party, as in the case of prescription drugs or cardiac catheters.  For genetics in the current information-rich environment and age of patient empowerment, I believe that there are a limited number of situations in which harm would come to a person who knew their own DNA sequence.  And, even those cases (e.g. Tay Sachs disease) it is questionable if the actual harm is sufficient to bar access except under carefully controlled conditions.

The other road might be one in which one can obtain the sequence of their genome, if they are so motivated and can afford it.  It is likely that reasonable quality services will be available to provide this information soon (currently there are concerns about quality with many of the providers; note to DTC genomics companies: you would do well to pay attention to the quality of your sequencing if you want to survive).  The latter three items on the list above would be supported by relatively simple, low hurdle access to sequencing services.  In fact, my guess is that FDA regulations or no, in the near future a motivated person will be able to get their genome sequenced.  Somewhere.

My concern  is what we might lose if we over-regulate DTC genomic testing.   The latter three items on the list have emerged in recent years.  What else might be added to the list in the future?  What uses for DNA sequence data are not on that list?

What is DTC genomic testing good for anyways?  I don’t think we know the answer to that question yet.  Should we follow the Silicon Valley paradigm, let go of the information, and see what millions of “users” out there do with it?  Should we “crowd source” genomics?  Maybe there is someone out there with a marketing degree, a penchant for spreadsheets, and the interest in genetics who can offer a creative solution for the problem of missing heritability of SNPs.  Maybe a user group will surprise us by producing a creative solution to one or another vexing biology or health problem that has stumped the collective brain power of us professionals?  We may not know what DTC genomics is good for unless we give it a chance.

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Are most published research findings false?

Friday, October 7th, 2011

Many people are aware of the work of John Ioannidis regarding the analysis of research findings and the conclusions drawn from those analyses.  In particular, these concepts were described by him in a paper published in PLOS Medicine in 2005 is apparently the most downloaded article from that journal.

I’ve had this article on my mental favorites list for some time now.  I am finally putting a few words in print about it mostly to put a stake in the ground on this issue because I believe it is an important one in this era of high volume research reporting.  In short, I agree with the article’s main conclusions, although I might phrase it as “most published biomedical research conclusions are not true”.  This is not to say I think there is some conspiracy or that statistics are useless.  To the contrary:  statistics is an enormously useful field of applied mathematics.  I also think a great deal of very good research is being done in labs and clinics around the world by very dedicated and smart researchers.

My concern over the veracity of biomedical research and how these results are reported stems from the nature of statistical models and test versus how they are interpreted and reported.  Within that discussion is another around the unspoken assumptions underlying both our biological and statistical models.

Perhaps the stickiest issue for me is the use, or misuse, of p values in many published studies.  Without getting too long-winded about it, far too often the p value is used all by itself and given the status of a “stamp of approval”.  Using a p value in isolation (i.e. p=0.001 therefore I won!) is ignoring a lot of important information.  What type of test did you “win”?  What distribution of p values for this test did you assume?  Are your assumptions correct?  Did you keep testing data until you found the p value you were hoping for?

Fortunately, I think the wider scientific community is waking up to the deficiencies in the most commonly used statistical analysis scenarios.  This recent article from Genomeweb does a nice job describing the basic appropriate role for statistical analyses in biomedical research.  An important distinction pointed out in their article is that statistical significance and biological (or clinical) significance are two different things.  When we rely on statistics to identify important relationships within a vast ocean of information, it is all the more important to understand what these mathematical tools are telling us.

As the wise scientist once said, “Never assume anything other than a 4% mortgage.”  I mentioned assumptions above in the sense of statistical models; assumptions also come into play in experimental design.  My sense of it is that these assumptions are usually underappreciated or perhaps even ignored.  The danger, of course, is that incorrect assumptions, statistical or experimental, can invalidate the results and conclusions of any research.  Often these assumptions difficult to verify, which we might be able to cope with, if we knew what these assumptions were.  Unfortunately, they are not part of the standard scientific reporting paradigm.  This recent article in PLoS Computational Biology sheds some light on the issue of reporting experimental assumptions.  Again, by bringing the issue to light there is hope that we can begin to change our science reporting procedures to incorporate some discussion of assumptions.

I find it reassuring that these discussions about accurate analysis and reporting of scientific research are surfacing.  Opening up communication about these critical issues will greatly enhance our ability to navigate through the ocean of biomedical studies available to us.

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A Couple of Glimpses at the Genomic Future

Thursday, January 27th, 2011

There were a couple of stories in the news in the last few days regarding genomic/genetic testing that hit on recent controversies surround said testing.

In earlier posts, such as this one, I commented on the now world-wide discussion about the balance between regulation of DTC genetic testing and innovation.  A new browser plugin for viewing genomic data for data from Direct to Consumer testing company, 23andMe, was released by 5AM Solutions.  This plugin does some add-on processing of web pages as they are loading, such that single nucleotide polymorphisms (SNPs) mentioned by their common abbreviations are highlighted.  In addition, if one mouses over the highlighted SNP a balloon appears showing your genotype at that SNP, as well as links to SNP analysis resources.  This development is reminiscent of other internet technologies, such as Facebook and Linked In, where third party companies develop an overlay to platform software or datasets.  Only this time, it is personal genomics.  This little program represents the next step in mapping your genotype onto the mass of information available out there about genes, health, and life.  One can imagine where creativity may take personal genomics if it is not over regulated.

The second story could raise the specter of universal genomic testing in some people’s minds.  It certainly did touch that nerve for me.  The Department of Defense advisory group, Jason, produced a report that was released last week advising the DoD to move toward “’take a leading role’ in using personal genomics data”.  Among the goals that the report suggests is “eventual collection of complete human genome sequence data from all military personnel”, based on the notion that $100 complete genomic sequence will be available in the near future.  The supposition is that this information will give an advantage to the military in its missions.  If that is the thinking of the DoD advisory scientists with respect to genomic sequence data, then it is hard to imagine that the trend will go any other way than towards consideration of complete sequence data on individuals under other circumstances, too.  Given recent discussions on genome hacking we might want to keep an ear to the ground with respect to routine genome sequencing and its uses.

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DTC Genomic Testing—Policy Perspective in Science Magazine

Friday, October 8th, 2010

Today’s Science magazine included a policy perspective on regulating Direct-to-Consumer genetic and genomic tests written by university ethics scholars.  In this article, the authors do a nice job of reviewing recent regulatory actions around DTC genomic testing, particularly in the United States, but also in some European countries.  As an illustration of the continuing global policy debate, the authors point out that both the United States and United Kingdom have opted so far to focus on educating the public and producing policy reports, while Germany has implemented a ban on DTC genetic and genomic tests.

After the set up, the authors tackle the question: “How should DTC genomic tests be regulated anyways?”  The authors recommend a “risk-stratified approach” to regulation of these tests.  A risk-stratified approach, you say?  Please elaborate!  This regulatory approach recognizes a) the multitude of potential uses for this type of information and b) that regulation is time consuming and expensive.  Therefore, regulatory effort is applied to those uses that are most likely to impact health and safety. Other applications, which do not have health and safety implications, such as perhaps hair color allele determination, would have a light regulatory burden, perhaps a registry or risk disclosure measures.  In this way a new industry can be given some “room to run” while at the same time key public health protections are put in place.  “All tests should be analytically valid (able to accurately and reliably measure what they say they are measuring), and any clinical claims made about the test must be accurate and substantiated”, regardless of the risk, say the authors.

Key questions remain.  How will we determine the risk level assigned to a certain type of test?  Perhaps just as interesting, given the internet-based nature of current DTC genomic offerings, how will off-shore testing be regulated?  This has the makings of a spirited international debate!

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UC vs. NPG

Monday, June 14th, 2010

Round two: you go, Librarians! http://www.genomeweb.com//node/942840?hq_e=el&hq_m=741462&hq_l=1&hq_v=a2a10fac80

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Genetic Testing, Walgreen’s, and the FDA

Monday, May 17th, 2010

To read some of the initial reports on the FDA’s announcement that it would like to discuss approval of Pathway Genomics’ OTC genetic tests, one might conclude the FDA acted rashly.   Since Pathway Genomics was planning to sell medical information to large numbers of consumers via Walgreens, the nation’s largest drug store, it seems to me that this is the kind of situation that is well within the FDA’s charter.  How does this balance the right of individuals to know information about themselves, including their genetic makeup, and the FDA’s mission to protect public health?

It seems clear to me that individuals have every right to know information about their genes.  Certainly genetic testing is not new, witness Tay Sachs disease testing and BRCA testing from Myriad Genetics.  My feeling is that this type of patient empowerment can be a driving force in many facets of healthcare, including cost control and preventative medicine.  So, why not sell OTC genetic testing at Walgreen’s?

Tests such as Pathway Genomics is offering are a fundamentally new paradigm in testing.  I bet the FDA sees potential problems cropping up, including inaccurate test results that may also be of questionable utility.  So, it may be that the Agency is within its rights to insist on quality standards and improved relevance of the results, if that is what they are after. I am sure the companies that currently offer or plan to offer DTC genetic testing are capable of producing quality results.

The utility of this type of information is also within the Agency’s purview under that aegis of effectiveness.  If the information dispensed is not at all useful, then money spent on these tests potentially represents money needlessly spent on healthcare resources.  Even worse, if the information dispensed induces the recipients to undertake a harmful treatment course, then it is a public health problem.

I’m not sure we understand most of the genetic information sufficiently to dispense it en masse.  Witness an article published just this week in Nature describing five new breast cancer risk loci.  How would you handle a person who received their results, did internet searches on their gene variants, and discovered they might have a newly discovered breast cancer risk allele?  We should ensure that appropriate resources are available to recipients to help them interpret their results.  I agree with Archelle Georgiou (http://bit.ly/aHvWEu, thanks to John Sharp), I would rather if this wasn’t a prescription thing.  I don’t think that is essential, but some type of resource to assist individuals with interpretation is probably a good idea.

I am hoping the FDA will rise to its best service of the public and help ensure that what is ultimately available is accurate, useful, and readily available.

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Welcome!

Friday, October 30th, 2009

Hi! This is VMWA’s blog. I’m working on my first post. Please check back again soon!

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