STP Specialisms | Cancer Genomics

When people ask me what I do, I always need to take a little time to think. Partly because STP is a mix of so many varied experiences that every week is different to the previous one, and partly because my own understanding of my specialism keeps evolving as I move through these experiences. When I first applied for this course, I thought I had a reasonable understanding of what cancer genomics was. But now I see how naive I was and that three years is not anywhere near enough time to fully comprehend this very diverse and quickly developing area of science. So summarising it all in a few paragraphs will be a challenge but… let’s give it a go!

So what really is cancer genomics?

I’m sure that you are familiar with at least some of the laboratories found in the pathology block of any larger hospital. Biochemistry, haematology, immunology, histopathology… But have you ever heard of HODS? If it’s of any help, HODS stands for Haematopathology and Oncology Diagnostic Service. But I’ve seen so many faces going completely blank at the sound of this name that my guess is you still have no idea what it is. Well, neither did I, until August last year when I found out that HODS was going to be my home for the next three years.

HODS in itself is such a diverse environment, plus slightly on a chaotic side, that it took me a good few months to get my head around how the department actually works and what is what. Even today when people ask me for some specifics, I have to think twice before I answer their question to make sure that I’m getting the details right. The simple explanation is that we receive specimens from patients with suspected or known cancer – these can be either liquid samples, such as blood or bone marrow aspirate, or sections of solid tumours such as colorectal or skin cancers – and we process these samples to detect the presence of specific genetic variants. Information about the presence or absence of such variants can then be used to establish the correct diagnosis for each patient and predict how well they are likely to respond to a given course of treatment. Simple, right?

The truth is that cancer is a very complex disease and the sheer multitude of different cancer types that are out there can be overwhelming. Even the cancers that develop from the same type of cell can vary greatly from one another due to different environmental factors and mutations that direct their growth. The current classification recognises over sixty subtypes of lymphoma alone and what about all other cancers out there? So the real role of scientists working in cancer genomics is to find ways not only to easily distinguish between all these different tumour types but also to identify molecular targets which allow us to treat these tumours in the most efficient way. And this has proven to be a very challenging task.

Recognising the tumour cell

When we diagnose cancer, we have to take into consideration many different factors. There is no single test that can tell us exactly what type of tumour a person has, but rather we use a combination of different tests and clinical observations to determine the most likely diagnosis. For example, blood cancers are classified based on patient’s clinical presentation, cell morphology, immunophenotype (a profile of molecular markers present on the surface of the cell) and genetic abnormalities detected by cytogenetic and molecular testing. In fact, HODS laboratories are set-up in a way which reflects this classification and allows to quickly obtain results that then direct the specimen for appropriate further tests if necessary. 

In a typical scenario, a blood or bone marrow sample from a patient with suspected blood cancer is received by HODS specimen reception and passed on to flow cytometry laboratory where its morphology and immunophenotype are assessed. This helps us determine whether tumour cells are present in this sample and, if yes, what cell type do they originate from.  For instance, finding immature cells in the blood suggests that the patient may be suffering from acute leukaemia and their immunophenotypic profile tells us whether the cells are immature B-cells, T-cells or myeloid cells. From this information we can then determine which other tests should be performed next – this would typically be cytogenetic or molecular tests or both. These further tests check for the presence of more specific genetic abnormalities that can help to further classify the subtype of leukaemia and put the patient in the low, intermediate or high risk group, based on the predicted clinical outcome. To coordinate all this testing, flow cytometry, cytogenetics and molecular labs have to work closely with each other and with the haematology and histopathology consultants who review all results and issue the final diagnosis. 

But… can we act on it?

The truth is that at the moment we can’t test for everything. Well, in principle we can, but really there isn’t much point to it. Each one of us carries many thousands of variants in our genome and, for the most part, we scientists are not quite sure yet what they all mean. Although many of the genetic changes have been associated with specific cancer types, we often don’t fully understand their role in the disease and in most cases we don’t yet have treatment that could target them. So the key goal, for now, is to test for the things that we know can make a difference to the person that the sample came from.

Coming back to the blood cancer example, there is a specific subtype of acute leukaemia which is life-threatening when untreated but which, if diagnosed quickly, can be treated very effectively. This subtype is known as acute promyelocytic leukaemia (APML) and it is caused by a structural change in the genome of myeloid cells, in which portions of chromosomes 15 and 17 become swapped over, forming a new gene referred to as PML-RARA. Detection of this genetic change is key in making diagnosis of APML and ensuring that correct treatment is administered to the patient as soon as possible. 

There are many more genetic variants in both blood and solid tissue tumours which can in similar way be used to guide patient management in the clinic. We refer to such variants as ‘actionable’ because they are the ones that we can target with the currently available treatment options. Large genetic abnormalities like PML-RARA can be tested for with the use of cytogenetic methods such as karyotyping and fluorescent in-situ hybridisation (FISH). Smaller variants can be detected by gene panels in which specific portions of the genes are sequenced and compared to normal DNA to identify changes that could play a role in response to treatment or may even allow to enrol the patient in one of the current clinical trials. The hope is that, as the new drugs are developed, the list of actionable variants will keep on growing and we will be able to target more and more cancers based on their genetic profile.

What does the training involve?

Cancer genomics STP is based around learning about these different variants and the role they play in the management of cancer patients. The training itself is very varied as we need to get a good overview of all the different aspects that contribute to the final outcome for the patient. A big part of it is learning about the laboratory procedures for setting up the assays and how the results are interpreted and reported back to clinicians. But every now and then we get out of the lab and see things like clinics or MDTs. We also get to rotate through different departments – during my first year I spent a month over at medical genetics, learning about the methods used to study inherited genetic variants, and another month in bioinformatics, finding out about the cool work that the NHS computer geeks do to help us make sense of the gigabytes of data coming out of the sequencing machines. More recently I spent a couple of days in histopathology labs where I could observe the full pathway for solid tumour specimens. If you’re like me and you don’t get grossed out by seeing somebody’s stomach lying on a chopping board, you’d probably enjoy these various experiences that STP offers. One thing that I have learnt over the year is that people are generally happy to show you things if you ask so it helps to be proactive and make the most of every opportunity you have!

Moving with the times

There’s a good chance that many of the things I’m saying here are going to go out of date pretty quickly. The field of cancer genomics is growing at an exponential rate and big changes are happening in the NHS as we speak. There are many questions that remain unanswered and only time will tell what can work long-term. Some of the hot topics you may want to look into if you’re interested in applying for this specialism are the use of whole-genome sequencing (WGS) for personalised cancer management and the application of liquid biopsies to detect cancer DNA without the need for invasive procedures, allowing to not only diagnose but also track evolution of cancer cells and predict relapse before it happens. These new developments are now starting to get introduced into clinical practice and, though they carry a lot of promise for the NHS cancer patients, there is still much controversy around their real clinical value and feasibility in a public healthcare setting. But this really is a topic for a whole other blog post.

I’d say, whichever way this goes, things are going to get interesting. For me, this is what makes my specialism all the more exciting and makes me want to persevere through challenges of the STP. There is so much still left to explore, so many possible paths for the future, and it is thrilling to be part of it all. I can’t wait to see what the future brings and I hope that I have managed to share a little bit of this excitement with you.