Diffuse Large B-Cell Lymphoma: Genetics and Subtyping

The doctor may request certain tests to help him or her understand the genetics and subtyping of the patient’s DLBCL. 


Subtyping DLBCL: Immunophenotyping 

Immunophenotyping is a process used to distinguish between different types of cells based on the presence of specific proteins, or markers, expressed on the surface of the cells. These proteins form a coat on the cell surface that is critical in defining the exact type of DLBCL a patient has. Two different types of diagnostic tests – immunohistochemistry and flow cytometry – can be used to determine a patient’s disease immunophenotype. Sometimes both processes are used to ensure an accurate assessment. 

Like gene expression profiling (GEP), immunophenotyping can be used to help determine which subtype of DLBCL a patient has. Two DLBCL markers, CD10 and BCL6, are associated with the GCB subtype, while the IRF4/MUM1 marker identifies the non-GCB subtypes. Another marker, Bcl2, can be found in both GCB and ABC subtypes, but the genetic origins of this biomarker differ between the two groups. Another important gene expressed in some types of lymphoma is c-myc. C-Myc is an oncogene that defines a particularly aggressive form of DLBCL. Sometimes, co-expression of c-myc and Bcl2, a gene that make cells resistant to dying, defines a kind of lymphoma known as double hit DLBCL. This lymphoma is more challenging to treat than the more common varieties. 

While GEP and immunophenotyping can both provide useful information about DLBCL subtype, these two types of testing work in different ways. As a result, the subtypes determined by GEP and those identified by immunophenotype do not always correlate exactly with each other. The GEP method is the most precise and accurate way of subtyping a disease, but immunophenotyping is also a clinically useful tool in helping to determine the cell of origin. Immunophenotyping techniques are also much less expensive and much more widely available than GEP, which is why immunophenotyping is often the first step in determining the subtype of a lymphoma. Researchers are constantly working to develop new types of genetic tests that are faster and less expensive than the current tests. These would allow doctors to use GEP in more practice settings to provide the most accurate diagnosis of a DLBCL subtype. 


Subtyping DLBCL: Gene expression profiling 

Gene expression profiling (GEP) is the process of determining which genes are turned on or turned off in a cell. The measure of essentially all genes in a cancer cell provides a profile of what genetic functions are occurring within that cell. 

Like all cancers, lymphoma is caused by genetic changes that lead to an imbalance between cell proliferation (how cells multiply and increase) and apoptosis (how cells die). B-cells are especially prone to the kinds of genetic mutations and changes that can give rise to cancer. In recent years, researchers have used GEP to identify several genetic subtypes of DLBCL. The subtypes are based on the cell of origin of the lymphoma, which refers to the type of B-cell that becomes cancerous and the point in cell development when these changes take place. 

Today, most DLBCL cases can be divided into three molecular subtypes: germinal center B-cell-like (GCB), activated B-cell-like (ABC), or the intermediate subtype, primary mediastinal B-cell lymphoma (PMBL). The GCB subtype is the most common, with about 50 percent of DLBCL cases falling into this subtype, including most cases in children and younger patients. The ABC subtype accounts for another approximately 30 percent of cases, including most cases in patients of advanced age. The PMBL subtype accounts for about 10 percent of all DLBCL cases and is most commonly found in younger female patients. A few remaining cases of DLBCL do not fall into any of these categories, and they are referred to as “unclassifiable.” 

Sometimes these subtypes are divided into two groups known simply as GCB or non-GCB, with the non-GCB group including all three of the less common subtypes – ABC, PMBL, and unclassified. 


Precision Medicine in DLBCL 

Precision medicine is a term that describes treatment that is individualized to each patient. Identifying which molecular subtype of DLBCL an individual patient has – GCB, ABC, PMBL, or unclassifiable – has now become an important consideration in the diagnostic process and in making treatment decisions. This is because recent research has shown that different subtypes may respond better to different combinations of chemotherapy. In clinical trials, patients with the GCB subtype tend to have a better response to the standard chemotherapy than those with the ABC subtype. Also, patients who do not have increased expression of the BCL2 protein tend to have better treatment outcomes than patients who do have this marker. 

Doctors and researchers are attempting to develop customized therapies based on a patient’s DLBCL subtype and which proteins are found on the cancerous cells. The idea is to pick only those medications that will most effectively target the exact type of cancer cells in that patient’s body based on their genetic profile. As clinical trials in this area continue, more information about the differences in how each subtype responds to each treatment will continue to be discovered, and this will help doctors more precisely tailor treatment to a patient’s specific type of lymphoma.

At the present time, many of these customized approaches to treatment have not yet become the standard of care, because researchers are still testing them against traditional treatments to make sure that they truly improve outcomes for patients. For this reason, the best way for a patient with DLBCL to gain access to the most cutting-edge developments in precision medicine is to enroll in a clinical trial that is testing one of these newer approaches to treatment.


Figure 1. Continuous Loop of Precision Medicine

Scheme representing the circle (continuous loop) of precision medicine. For newly diagnosed DLBCL patients, information about the disease subtype and the risk level will guide plans for therapy. If patients experience refractory (disease does not respond to treatment) or relapsed (disease returns after treatment) DLBCL, then tumor profiling and risk determination will be repeated, often resulting in changes to the original approach to treatment. As DLBCL is a disease that can change over time within an individual patient, this procedure can be used repeatedly to treat the lymphoma, thereby optimizing precision medicine at every stage of the patient’s disease.

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