Molecular genetics of non-Hodgkin lymphoma

Published on November 30, 2015   33 min

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My name is Jude Fitzgibbon. I am a Professor in Personalized Cancer Medicine at the Barts Cancer Institute. It's part of Queen Mary University of London. My lecture today is on the Molecular Genetics of Non-Hodgkin Lymphoma. I am going to be using an indolent B-cell malignancy called follicular lymphoma as an example.
I think it's important to preset that cancer represents almost the perfect genetic disease where it's radicalized maybe 10-20 genes to actually shift the balance from a normalcy to a malignant phenotype. And so we need to think of these genes as individuals but also how they kind of work together to cooperate to actually drive this change in phenotype. And it's helpful to think of a formula in relationship to cancer and indeed B-cell malignancy in relationship to the genetics and the microenvironment working together to give rise to cancer.
The technology has improved fantastically. When I started my PhD in the late '80s, you know, I did my first polymerase chain reaction, my first PCRs using three water baths set at different temperatures, a stopwatch, and a tweezers to actually move the chews from one place to another. Now we've got the opportunity to actually sample all genes, all DNA in one single experiment and monitor their expression at the same time.
So I think what we should do is we should try and get a very clear picture of what the human genome is. So if we can imagine the human genome as a stadium of 25,000 spectators, that corresponds to 25,000 genes. We know where each spectator, where each gene lies. We know the location and the position, and then we know exactly what they look like because that's their DNA sequence. And how they sound because that's the sequence of their messenger RNA. We've now the tools to define the DNA and the mRNA profiles of every cancerous cell in single experiments where we can focus in on the whole genome, that's the three billion base pairs of sequence. If we're just interested in looking at the coding sequence, which is less than 2 percent of the genome, we can focus in on 50 mega bases. But what's ideal is when we know the key genes that we know to be important, we can focus in on those using other different technologies. Now what's also key is to preset that we're not just looking at genes here because these are not just genes, they're genes with clothes on. So you can see the spectators have specific clothes on. And it's that combination of the gene sequence itself, but also the control of gene expression and gene function via epigenetics. That's key in this shift from normalcy to the tumor phenotype.
I think because of the nature of the talk and the different types of sequencing I'm going to discuss, I'm just going to give you a flavor of these. When it's whole genome sequencing where we sequence every piece of DNA within a particular cell, and we can do whole genome sequencing at a depth of approximately about 30X. That means that each base is sequenced about 30 times to capture the complexity of that sequence. Whole exome sequencing focuses in on just the coding mutations, just the coding genes. And that sequence occurs at about 100X. So each base that represents a coding sequence is actually sequenced about 100 times. We can do targeted resequencing to look at a key few genes and we can sequence these at a much, much greater depth. And that gives us a fantastic idea of the personality of that particular mutation. And we're moving away, therefore, from the simple interpretation of mutations being present or absent, but actually to be able to refine whether a mutation is present in all the tumor cells or just present in a small proportion of cells. Whether a mutation is clonal versus subclonal.
So the structure of the presentation is going to be very simply an overview of indolent B-cell lymphoma, to give you an impression of what precision medicine actually is and how we need to be thinking of precision medicine going forward. And also looking at follicular lymphoma genetics. Talking about the risk of developing follicular lymphoma, the role of the microenvironment, the mutational landscape that we have defined thus far looking almost entirely at the coding region, the evolution of the disease, the opportunities now that we can avail of to follow a precision medicine approach, and tumor profiling tools. And I'd wish to apologize to the many follicular lymphoma researchers and indeed researchers in cancer in general worldwide where I don't have the opportunity to present everybody's work in detail or indeed to reference this appropriately.
So lymphoma was first described in 1862 and follicular lymphoma is 1925. And it was given the name Brill-Symmers disease reflecting the two authors that originally kind of described the disease itself. And as you can see from the pathology, it has a very defined follicular architecture. And within these follicles, they are jam-packed with malignant B-cells. What's also important to realize when you are looking at this pathology is that it's not just tumor cells but there's a lot of different type of cells that occur within the tumor itself and so that's dilutes out the proportion of tumor cells that's within the biopsy.

Molecular genetics of non-Hodgkin lymphoma

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