November 13 2008 post. A blog reader (thanks!) told me about a study published earlier this month in “Nature.” I’ll start with a quote from the Eureka Alert I read yesterday (http://tinyurl.com/5nesch): For the first time, scientists have decoded the complete DNA of a cancer patient and traced her disease – acute myelogenous leukemia – to its genetic roots. A large research team at the Genome Sequencing Center and the Siteman Cancer Center at Washington University School of Medicine in St. Louis sequenced the genome of the patient – a woman in her 50s who ultimately died of her disease – and the genome of her leukemia cells, to identify genetic changes unique to her cancer.
The scientists believe that these genetic changes originated from a single clone (!) and occurred one after the other—a sort of domino effect. They discovered three types of mutated genes: genes that are tumor-suppressors under normal circumstances, genes that promote cancer growth, and genes that may unlock the mystery of chemoresistance. Ahhh, chemoresistance…this phenomenon is unfortunately common to many cancers, including myeloma (incidentally, while doing research for this post I made an unexpected discovery…must do some major research this weekend…hope it pans out!).
The Eureka Alert provides a good, easy-to-understand summary. But I like to check my sources whenever possible, so I looked up the full study: http://tinyurl.com/57yd6j. Using a simple skin sample taken from the AML patient, these Washington University scientists found ten genes with acquired mutations. Two had already been studied, as they possess typical AML mutations and are involved in disease progression, but eight presented “new” mutations. The researchers determined that all of these mutations […] were present in nearly all tumour cells at presentation and again at relapse 11 months later, suggesting that the patient had a single dominant clone containing all of the mutations. No kidding: a single clone!!! Do I smell an AML stem cell, here?
The study is very detailed, very technical. At one point I found myself wading through a sea of alleles and genome gapped alignments and putative small indels and coding exons and split reads algorithms. Mamma mia. Eh, sometimes it is best to give up and glide gracefully over to a study’s Discussion part, which is usually more intelligible. So, let’s have a look at the Discussion. The fact that most of the genes discovered by this team have not been targeted in the treatment of AML justifies the use of next-generation whole-genome sequencing approaches to reveal somatic mutations in cancer genomes. I couldn’t agree more.
Of the unidentified (above-mentioned) eight mutations, four had not been previously implicated in cancer pathogenesis, which I found verrrry interesting. Further on we read that The importance of the eight newly defined somatic mutations for AML pathogenesis is not yet known, and will require functional validation studies in tissue culture cells and mouse models to assess their relevance. So mutations do exist, but they may be harmless, in other words. Probably not, though.
And also: the same mutations were detected in tumour cells in the relapse sample at approximately the same frequencies as in the primary sample. All of these mutations were therefore present in the resistant tumour cells that contributed to the patient’s relapse, further suggesting that a single clone contains all ten mutations. Ah, the single clone theory again.
The study ends on a note of prudence: For AML and other types of cancer, whole-genome sequencing may therefore be the only effective means for discovering all of the mutations that are relevant for pathogenesis. Okay, that, to me at least!, means that a cure for all of these presently incurable cancers, including my own, is not in the near future. This is not easy for me to say, but now I know why my skin crawls whenever I hear myeloma specialists declaring that a “cure” is around the corner or visible on the horizon (it just so happens that I recently heard one say words to that effect)…oh, I wish it were true…
But I don’t want to end on a negative note. I really do hope that genome sequencing for all cancer patients will shift quickly into high gear. And there are reasons to be optimistic. The sequencing technology has improved a great deal. It used to be very expensive and complicated to perform these genetic tests, plus the necessary genomic DNA samples had to be very large, but that is no longer the case. Reduced costs and smaller samples should make this new-generation technology more widely available to us.
It’s a first step.