A new study, covered widely across the media, analysed the causes of cancers to a depth never reported before. It is the result of a huge international effort, including Leukaemia & Lymphoma Research scientist Prof Mel Greaves, to examine the precise changes to the DNA of patients affected by a wide range of cancers.
The causes of cancer
We often think of a genetic fault, or ‘mutation’, as causing a cancer. But this study takes the question one step back and asks, “what caused the mutations in the first place?”. What caused the cause, in a way.
The new study is a feat of genetic sequencing that would have been impossible a few years ago. It took over a decade to decode the entire genetic material of a human (a 'genome'), whereas these researchers were able to draw on the assembled data of over 500 whole genomes, together with more than 6,500 samples restricted to functionally important gene sequences. It’s a real testament to the continued innovation in science and technology – the computing power now available is unearthing information that the human mind alone cannot ever reveal. It’s also a demonstration of what can be achieved by working together, collaboratively not competitively, as a collective force on some of the toughest problems in understanding cancer.
Writing in the journal Nature, the authors present 21 different ‘molecular signatures’ that underpin over 30 different cancers, including a number of blood cancers. These molecular signatures, a bit like genetic fingerprints, are distinctive patterns of genetic change, which are the imprint of different cancer-causing agents.
DNA is made up of long sequences of four chemical building blocks, abbreviated to C, T, A and G. Genes are stretches of DNA that produce functioning proteins, and the exact string of these four letters forms the blueprint for the resulting protein. This means that changes to DNA sequence, in some cases just a single ‘letter’, can alter the protein that is made and therefore its biological activity. Genetic errors, as a result of environmental carcinogens or lifestyle factors, are the fuel for cancerous cells to form.
We already know about many factors that alter the genetic material to drive certain cancers, such as tobacco smoke, UV light, and, in the case of some leukaemias and lymphomas, viral infection. But many causes remain a mystery.
This is what the new study attempted to address. For a comprehensive look, then Ian Sample in The Guardian and Henry Scowcroft for Cancer Research UK have both done a very good job. So instead of repeating their wise words, I here wanted to take a closer look at the implications for blood cancers.
What does it all mean for blood cancers?
First, it seems that blood cancers are less genetically messed up at the time the tissue samples were taken. This may be because blood cancers are inherently simpler at a genetic level than other cancers, or it may be that we’re better at picking up blood cancers before massive amount of DNA damage has accumulated. Either way, it strikes an optimistic note for being able to one day figure out blood cancer biology as a whole and design treatments to cripple blood cancers at their genetic root.
Another observation is that not all mutational fingerprints seen across the various cancers are associated with blood cancers. Instead, leukaemias, lymphomas and myelomas have just a few signatures associated with each disease. Nevertheless, some of these profiles are also associated with non-blood cancers. This makes sense, in that there are distinct environmental or lifestyle factors driving blood cancers, but some of these factors can also trigger other cancers.
As for what these error-inducing factors are, a chief driver in most blood cancers analysed – acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and B cell lymphoma – is age. In fact, for AML, the associated molecular profiles were exclusively associated with aging, rather than any external factors.
Another major cause, found in all blood cancers except AML and this time including myeloma, is the rogue activity of enzymes called APOBECs. In normal circumstances, these are thought to, amongst other things, deactivate invading viruses by attacking their DNA. Unfortunately, it seems that these can misfire and damage our own DNA. Immune cells called lymphocytes are largely responsible for defending us against viruses and it is rogue cells of this type that fuel many leukaemias and lymphomas, so the link with APOBECs is logical.
The final factor that popped out of the analysis as a probable cause of blood cancers, specifically B cell lymphoma and CLL, is a process within us all that primes our bodies to fight invaders. To deal with the multitude of foreign nasties that our bodies come into contact with, the immune system has developed a way of generating a diverse army of antibodies. It does this by actively rearranging the genes that produce antibodies. If this usual mechanism of gene ‘shuffling’ goes awry, too much genetic rearrangement can lead to faulty, potentially cancerous genes being created. It makes sense that this is associated with B cell lymphoma and CLL because both diseases occur when special immune cells, known as B cells, grow out of control – the chief job of a B cell is to produce antibodies.
And what does it mean for patients?
For each blood cancer, there are at least two mutational fingerprints present. This could potentially mean that for someone diagnosed with a blood cancer, doctors will have a clearer idea of what exactly caused their cancer, for example whether it was age-related damage or a misfiring immune response. Put together on a population scale, this will give us greater power to assess the relative contribution of each cause and to advise and develop preventative measures.
There was an additional molecular signature detected in B cell lymphoma and myeloma patients, as well as in other cancers like lung, thyroid and brain tumours, that had an unknown cause. The challenge now is to conduct more laboratory research to find out from what source this kind of genetic damage arises, which would be informative for novel cancer preventative strategies.
The overlap in molecular signatures between blood cancers and non-blood cancers could mean that in the future, when we understand a bit more about what these genes are (after even more laboratory research), treatment options are shared or tweaked. A treatment that is shown to be effective in, say, breast cancer could be used in leukaemia patients (or vice versa), if the genetic fault at the root of both diseases is the same.
What the study does not address is the diversity of genetic changes within each cancer type. For example, we know that AML and B cell lymphoma are not two diseases but many. More detailed investigation may reveal subtly different genetic fingerprints characteristic of different causes.
The study also did not look in detail at the genetic variation within an individual cancer, something known as genetic heterogeneity. This means that we cannot tell from this study which genetic mistakes initiate and drive the cancer and which ones are the result of DNA damage accumulated along the way. It is important when designing targeted therapies to home in on the genetic drivers at the root of the cancer, so that all rogue cells are killed and not just a few. We’re supporting some pioneering work in this area, such as Prof Mel Greaves and Prof Richard Houston’s eloquent studies on the genetic ‘evolution’ of ALL. The experience from acute promyelocytic leukaemia and chronic myeloid leukaemia indicate that such targeted therapies can transform patient outcomes.
So if you saw this story and wondered what it meant for blood cancers in particular, I hope I’ve given you a flavour. More research into the genetic basis of blood cancers will be vital in driving forward new therapeutic and preventative approaches for patient benefit.