DNA sequencing leads to new discovery

This research used samples of tumour tissue from people with follicular lymphoma (FL) and had them analysed by a lab to reveal their genetic structure. By looking at the patterns of genetic mutation in the tumour samples from a large group of patients, we were able to discern three new lymphoma subclusters. This new information can help us in a number of ways:

1. It aids research into the mechanisms underlying this complex blood cancer
   • this is important because the more we understand about what is happening, the more we can try to understand why it happens and prevent it.
2. It will hopefully help us to personalise treatments for patients with this type of cancer in the future
   • if the treatment is as specific as possible there is more chance of success and also of limiting collateral damage to the body from the treatment.
3. Looking at the data revealed that although the three subclusters were different to each other there was no evidence of a difference in outcome for the patients
   • none of them was worse than the others.

Background

Lymphoma is a type of blood cancer that develops when white blood cells called lymphocytes grow out of control. Lymphocytes are part of your immune system. 

Follicular lymphoma (FL) is a common subtype of non-Hodgkin lymphoma. It develops slowly from the type of lymphocytes called B cells. It is called ‘follicular’ lymphoma because the abnormal B cells usually develop in clumps called ‘follicles’ inside lymph nodes. Currently, it cannot be cured and is typically managed through monitoring and periodic treatment to control the disease.

The database

The Haematological Malignancy Research Network (HMRN) provides information about leukaemias, lymphomas, myelomas, and related blood disorders. HMRN is a collaborative venture between researchers at the University of York and NHS clinicians working across 14 hospitals. It comprises all patients diagnosed with a blood cancer, or a related precursor condition, within a study region of approximately 4 million people.

What we did

We started with samples from 878 people who had been diagnosed with FL between September 2004 and August 2012. We excluded some samples for various reasons and ended up with 548 samples to sequence.

The samples were sent to the internationally renowned Sanger Institute to have their DNA sequenced. Looking at the patterns of mutations in the tumour DNA enabled us to group similar mutations together and to discern the three new subclusters of FL.

The 3 new subclusters

The image below shows the pattern of genetic mutations in the 3 different subclusters of FL that we identified in this research:

The abbreviations on the image are the names of the genes involved in each subcluster. The coloured bars on the right of the names show how frequent the mutations of that gene are in each cluster, relative to the cohort as a whole. Positive numbers indicate that mutations are more common than the average, and negative numbers indicate less common. In this way they show the mutational signature of each subcluster. For example:

• the FL subcluster FL_STAT6 (green) shows high levels of mutation in the genes called STAT6 and CREBBP.
• The subcluster FL_Com (blue) shows fewer mutations in most of the genes compared to the other two subgroups, but does have a positive profile for mutations in the KMT2D gene.
• The final subcluster FL_aSHM (red) is associated with a failure in the mechanism by which the body’s immune system adapts to new pathogens.

Interestingly all three subclusters have a similar outcome for the patient.

What this means

Professor Reuben Tooze, senior author of the research, says:

"We show that follicular lymphoma, one of the commonest immune system cancers, resolves into three types based on patterns of genetic mutation characterised by: