A genetic explanation for lymphoma patients that cannot be cured by standard treatment

Some patients with non-Hodgkin lymphoma respond poorly to standard treatment. Thanks to DNA sequencing, scientists now know why.

The most common form of non-Hodgkin lymphoma, known as diffuse large B-cell lymphoma (DLBCL), is considered a curable disease with the exception of a subset of patients for whom the standard treatment is not effective. But scientists at Canada’s Michael Smith Genome Sciences Centre (GSC) have uncovered a genetic explanation for why some patients have poor prognosis.  

Like all forms of cancer, DLBCL is the result of DNA mutations. And these patients have particularly damaging ones termed “double hit”. Unfortunately, some patients test negative for double hit mutations using a standard laboratory test called fluorescent in-situ hybridization (or FISH) yet still respond poorly to standard treatment. This means they may not receive the intensive treatment they require.

In a new study published this week in Blood, Dr. Ryan Morin, a senior scientist at the GSC and associate professor at Simon Fraser University, and his team employed DNA sequencing to shed light on these discrepancies. Their results revealed the presence of double hit mutations in samples that had tested negative by FISH, confirming the inaccuracy of the test.

“We are systematically under-identifying patients that have the genetic event that predicts poor outcomes,” says Dr. Laura Hilton, a post-doctoral fellow in Dr. Morin’s group and lead author on the study, “Our findings reveal why.”

The study demonstrated that testing by FISH may miss up to 19 per cent of patients with double hit mutations, illuminating a need for better screening methods.

The group found that these patients can more reliably be identified by looking for a particular cellular signature, or pattern of behavior. Rather than looking at the DNA itself, which can be likened to a blueprint of a cell, this method looks at how cancer cells are reading that blueprint. And importantly, their analyses identified additional DNA mutations that cause this same signature, representing even more patients with poor prognosis that cannot be detected using FISH.  

Fortunately, there is a laboratory test called a NanoString that can be used to identify the signature, allowing clinicians to more accurately determine which patients may need more aggressive treatments. Exactly what those treatments should be remains a current area of research. But clinical trials show that a more intensive drug regimen may be effective. By identifying more of these cases, further clinical trials will be made possible.  

The group is hoping that more accurate testing will soon become part of standard care for patients with DLBCL.   

“We hope our result will encourage clinicians to adopt the NanoString test to a greater degree than they do currently,” says Dr. Hilton.

Background
This research was supported by grants from the Terry Fox Research Institute and Canadian Institute for Health Research and MITACS Accelerate, a Scholar Award from the ASH Foundation and support from the BC Cancer Foundation. The study was published in the journal Blood.