Personalized Cancer Screening Will Lead to Many False Diagnosis of Blood Cancer
Here is an interesting paper that calls into question many commonly accepted notions about GWAS and ‘personalized medicine’. The authors studied somatic mutations in blood samples of cancer patients not known to have leukemia or lymphoma, and found many of them to carry mutations linked with blood cancer.
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Somatic mutations
It is well-known that our genome is not static, and the cells in the body of every individual accumulate mutations over her lifetime. Ken Weiss often points that out in his blog post in discussing the limitations of genome-based comparative studies for predicting common traits or disease risks. From his recent series -
What if Rev Jenyns had agreed? Part I. Would evolutionary theory be different?
What if Rev Jenyns had agreed? Part III. ‘Group’ selection in individuals, too.
But individuals are populations too
Let’s ask something very simple: What is your ‘genotype’? You began life as a single fertilized egg with two instances of human genomes, one inherited from each parent (here, well ignore the slight complication of mitochondrial DNA). Two sets of chromosomes. But that was you then, not as you are now. Now, youre a mix of countless billions of cells. Theyre countless in several ways. First, cells in most of your tissues divide and produce two daughter cells, in processes that continue from fertilization to death. Second, cells die. Third, mutations occur so that each cell division introduces numerous new DNA changes in the daughter cells. These somatic (body cell) mutations dont pass to the next generation (unless they occur in the germline) but they do affect the cells in which they are found.
But how do we determine your genotype? This is usually done from thousands or millions of cellssay, by sequencing DNA extracted from a blood sample or cheek swab. So what is usually sequenced is an aggregate of millions of instances of each genome segment, among which there is variation. The resulting analysis picks up, essentially, the most common nucleotides at each position. This is what is then called your genotype and the assumption is that it represents your nature, that is, all your cells that in aggregate make you what you are.
In fact, however, you are not just a member of a population of different competing individuals each with their inherited genotypes. In every meaningful sense of the word each person, too, is a i of genomes. A person’s cells live and/or compete with each other in a Darwinian sense, and his/her body and organs and physiology are the net result of this internal variation, in the same sense that there is an average stature or blood pressure among individuals in a population.
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Is somatic variation important?
An individual is a group, or population of differing cells. In terms of the contribution of genetic variation among those cells, our knowledge is incomplete to say the least. From a given variant’s point of view (and here we ignore the very challenging aspect of environmental effects), there may be some average risk–that is, phenotype among all sampled individuals with that variant in their sequenced genome. But somatically acquired variation will affect that variant’s effects, and generally we don’t yet know how to take that into account, so it represents a source of statistical noise, or variance, around our predictions. If the variant’s risk is 5% does that mean that 5% of carriers are at 100% risk and the rest zero? Or all are at 5% risk? How can we tell? Currently we have little way to tell and I think manifestly even less interest in this problem.
Cancer is a good, long-studied example of the potentially devastating nature of somatic variation, because there is what I’ve called ‘phenotype amplification’: a cell that has inherited (from the person’s parents or the cell’s somatic ancestors) a carcinogenic genotype will not in itself be harmful, but it will divide unconstrained so that it becomes noticeable at the level of the organism. Most somatic mutations don’t lead to uncontrolled cell proliferation, but they can be important in more subtle ways that are very hard to assess at present. But we do know something about them.
Evolution is a process of accumulation of variation over time. Sequences acquire new variants by mutations in a way that generates a hierarchical relationship, a tree of sequence variation that reflects the time order of when each variant first arrived. Older variants that are still around are typically more common than newer ones. This is how the individual genomes inherited by members of a population and is part of the reason that a group perspective can be an important but neglected aspect of our desire to relate genotypes to traits, as discussed yesterday. Older variants are more common and easier to find, but are unlikely to be too harmful, or they would not still be here. Rarer variants are very numerous in our huge, recently expanded human population. They can have strong effects but their rarity makes them hard to analyze by our current statistical methods.
However, the same sort of hierarchy occurs during life as somatic mutations arise in different cells at different times in individual people. Mutations arising early in embryonic development are going to be represented in more descendant cells, perhaps even all the cells in some descendant organ system, than recent variants. But because recent variants arise when there are many cells in each organ, the organ may contain a large number of very rare, but collectively important, variants.
The mix of variants, their relative frequencies, and their distribution of resulting effects are thus a population rather than individual phenomenon, both in populations and individuals. Reductionist approaches done well are not wrong, and tell us what can be told by treating individuals as single genotypes, and enumerating them to find associations. But the reductionist approach is only one way to consider the causal nature of life.
Our society likes to enumerate things and characterize their individual effects. Group selection is controversial in the sense of explaining altruism, and some versions of group selection as an evolutionary theory have well- demonstrated failings. But properly considered, groups are real entities that are important in evolution, and that helps account for the complexity we encounter when we force hyper-reductionistic, individual thinking to the exclusion of group perspectives. The same is true of the group nature of individuals’ genotypes.
The authors of Nature Medicine paper had been looking into somatic mutations in cancer patients for several years. Here is one of their earlier papers on the topic.
Somatic mutations affect key pathways in lung adenocarcinoma
Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancersincluding NF1, APC, RB1 and ATMand for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
